Proceedings of the Seminar on Health Research Ethics in Africa

Proceedings of the Seminar on Health Research Ethics in Africa

Acta Tropica 78 (2001) S1 – S126 www.parasitology-online.com Proceedings of the Seminar on Health Research Ethics in Africa 1 Edited by J.B. Rugemali...

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Acta Tropica 78 (2001) S1 – S126 www.parasitology-online.com

Proceedings of the Seminar on Health Research Ethics in Africa 1 Edited by J.B. Rugemalila a, W.L. Kilama b,* b

a Hakika Medical Centre, PO Box 12521, Dar-es-Salaam, Tanzania African Malaria Vaccine Testing Network, Costech, PO Box 33207, Dar-es-Salaam, Tanzania

Abstract The first conference of the African Malaria Vaccine Testing Network (AMVTN) identified as a leading priority, the promotion of ethics in health research undertaken in Africa. The participants at the 1995 meeting expressed the need for mainly increasing awareness of ethics in health research and of reviewing current practices and existing guidelines. The conference also noted that there were very limited national health research capacity, and the continuing reliance on non-African participation in health research on African health issues, and the attendant short-comings thereof, including inherent ethics issues. From its founding about 5 years ago, AMVTN in all its capacity building endeavours, particularly in its workshops on study designs and methodology, good clinical practice (GCP), and data management, has identified promotion of ethics to be a top priority. This activity being such a major challenge required considerable preparations, which started in earnest during 1997. It was decided very early that a workshop would not suffice and a conference would lack sufficient focus. It was therefore decided to organize a Seminar on Health Research Ethics in Africa. After wide ranging consultations, the relevant topics and respective speakers were identified and invited. © 2001 Published by Elsevier Science B.V. Contents Acknowledgements . . . . . . . . . . . Seminar Organizing Committee . . . . 1. Summary of Proceedings. . . . . . 1.1. Introduction . . . . . . . . . 1.2. Acknowledgements . . . . . 1.3. Seminar Objectives . . . . . 1.4. Strategies. . . . . . . . . . . 1.5. Seminar Participants . . . . 1.6. Seminar Recommendations

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2. Welcome Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3. Statement on Behalf of the WHO Regional Director . . . . . . . . . . . . . . . . . . . . . . .

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4. Opening Speech by the Guest of Honor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. E-mail address: [email protected] (W.L. Kilama). 1 Compilation of the plenary speeches, presentations and discussions held at the Seminar on Health Research Ethics in Africa organized by the African Malaria Vaccine Testing Network (AMVTN). 0001-706X/01/$ - see front matter © 2001 Published by Elsevier Science B.V. PII: S0001-706X(00)00149-2

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Health Research Ethics in Africa / Acta Tropica 78 (2001) S1– S126 5. Introduction to the Seminar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Seminar Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Seminar Proceedings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Country Reports on Supervision of Health Research Ethics . . . . . . . . . . . . . . . . . 6.1. Supervision of Health Research Ethics in the United Republic of Tanzania . . . . 6.1.1. Background Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Institution Overseeing Health Research . . . . . . . . . . . . . . . . . . . . . 6.1.3. Medical Research Coordinating Committee . . . . . . . . . . . . . . . . . . 6.1.4. National Committee for Ethics in Health Research . . . . . . . . . . . . . . 6.1.5. Successes and Achievements . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.6. Barriers and Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.7. Circumventing Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Supervision of Health Research Ethics in Zambia . . . . . . . . . . . . . . . . . . . 6.2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Terms of Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.3. Composition of the Committee . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4. Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.5. Achievements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.6. Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.7. Future Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Supervision of Health Research Ethics in Malawi . . . . . . . . . . . . . . . . . . . 6.3.1. Size and Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Institutions Overseeing Health Research . . . . . . . . . . . . . . . . . . . . 6.3.3. Awareness for Research Ethics Among Researchers . . . . . . . . . . . . . 6.3.4. Structure and Operations of the Ethics Review Committees . . . . . . . . . 6.3.5. Membership of the College of Medicine Research Committee. . . . . . . . 6.3.6. Functions of COMRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.7. Submission and Review of the Proposals. . . . . . . . . . . . . . . . . . . . 6.3.8. COMRC and Other Relevant Committees . . . . . . . . . . . . . . . . . . . 6.3.9. Successes During 1997/98 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.10. Constraints and Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.11. Future Projections and Plans. . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Supervision of Health Reseach Ethics in The Sudan. . . . . . . . . . . . . . . . . . 6.5. Supervision of Health Research Ethics in Ivory Coast . . . . . . . . . . . . . . . . 6.5.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.2. Institutions Overseeing Health Research . . . . . . . . . . . . . . . . . . . . 6.5.3. Implementation and Observance of the Guidelines . . . . . . . . . . . . . . 6.5.4. Ethical Review Committee Structure and Operations . . . . . . . . . . . . . 6.5.5. Structure and Operations of the Enforcing Machinery . . . . . . . . . . . . 6.5.6. Successes and Achievements . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.7. Constraints and Barriers Encountered . . . . . . . . . . . . . . . . . . . . . 6.5.8. Future Projections and Plans. . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Supervision of Health Research Ethics in Kenya. . . . . . . . . . . . . . . . . . . . 6.6.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.2. Institutional Framework for Health Research . . . . . . . . . . . . . . . . . 6.6.3. Ethics Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.4. Implementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.5. Structure and Operations of Ethical Review Committees. . . . . . . . . . . 6.6.6. Successes in Ethical Regulation . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.7. Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.8. Future Projections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7. Supervision of Health Research Ethics in The Democratic Republic of the Congo 6.7.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.2. National Ethics Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.3. Other Initiatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. International Guidelines for Health Research Ethics . . . . . . . . . . . . . . . . . . . . . . 8. Burden of Disease in Africa in the Early 21st Century . . . . . . . . . . . . . . . . . . . .

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8.1. Assessment of Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Disability Adjusted Life Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Magnitude and Causes of Disease Burden in Africa . . . . . . . . . . . . . . . . . 8.4. Future Patterns of Disease Burden in Africa . . . . . . . . . . . . . . . . . . . . . 8.5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6. Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Traditional African Perception of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Normal and Abnormal Illnesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Mitigating Factors for Health Care Seeking Patterns . . . . . . . . . . . . . . . . Traditional African Perception of a Person: Implications on Health Research Ethics . . 10.1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Group Perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4. Perception of a Person . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.5. Implications on Health Research Ethics . . . . . . . . . . . . . . . . . . . . . . . . The Regulatory Review Process in the Licensure of Biologics . . . . . . . . . . . . . . . 11.1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3. Steps in the Licensure of Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.1. Documentation of the Manufacturing Process . . . . . . . . . . . . . . . . 11.3.2. Investigational Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.3. Environmental Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.4. Method Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.5. Current Good Manufacturing Practices for Biologics (cGMP) . . . . . . 11.3.6. Preclinical Evaluation of Biologics . . . . . . . . . . . . . . . . . . . . . . 11.3.7. Clinical Studies to Substantiate the Licensure of Biologics. . . . . . . . . 11.4. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Composition and or Responsibilities of Ethics Committees and Investigators . . . . . . 12.1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3. What do these guidelines say about the role of Ethics committees in biomedical research? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.4. What role do investigators also play in biomedical research . . . . . . . . . . . . 12.5. Goals and challenges of Ethics committees and investigators. . . . . . . . . . . . 12.6. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Informed Consent in Health Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2. Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2.1. Origins of the Concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2.2. Derivation of the Concept . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2.3. Functions and Justifications for Informed Consent . . . . . . . . . . . . . 13.2.4. Requirements for Informed Consent . . . . . . . . . . . . . . . . . . . . . 13.3. Practice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.1. How is Informed Consent Obtained in Practice? . . . . . . . . . . . . . . 13.3.2. Consent from the Specially Vulnerable . . . . . . . . . . . . . . . . . . . . 13.3.3. Informed Consent for Research and or Patient Care . . . . . . . . . . . . 13.3.4. Conflict of Obligations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.5. Can Informed Consent Really be Achieved? . . . . . . . . . . . . . . . . . 13.3.6. Alternative World Views and Informed Consent in Clinical Practice . . . 13.3.7. Empirical Data About the Use of Informed Consent in Practice . . . . . 13.3.8. Alternative World Views and Informed Consent in the Research Setting 13.4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intellectual Property Rights and Confidentiality . . . . . . . . . . . . . . . . . . . . . . . 14.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2. Research Agreements to Ensure Reasonable Availability . . . . . . . . . . . . . . 14.3. Trial of Chloramphenicol for Meningitis in Nigeria . . . . . . . . . . . . . . . . .

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Illustrative Examples of Past Research in Developing Countries . . . . . . . . . . . . . 14.4.1. The Hepatitis A Vaccine Trial in Thailand. . . . . . . . . . . . . . . . . . . . . 14.4.2. Short Course Treatment of Tuberculosis . . . . . . . . . . . . . . . . . . . . . . 14.4.3. Malaria Prophylaxis for Pregnant Women . . . . . . . . . . . . . . . . . . . . . 14.4.4. Zidovudine Treatment for Pregnant Women in sub-Sahara Africa . . . . . . . 14.4.5. A Breast Cancer Study in Vietnam . . . . . . . . . . . . . . . . . . . . . . . . . 14.5. Short Course AZT Treatment of Pregnant Women . . . . . . . . . . . . . . . . . . . . 14.6. Availability and Intellectual Property Rights . . . . . . . . . . . . . . . . . . . . . . . . 14.7. Confidentiality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current Vaccine Research in Africa Engaging Ethics Problems . . . . . . . . . . . . . . . . . 15.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2. Ethical Imperative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3. Cost, Allocation of Resources and Security of Investment . . . . . . . . . . . . . . . . 15.4. Benefits to a Population During a Vaccine Trial . . . . . . . . . . . . . . . . . . . . . . 15.5. Benefit to the Community if the Vaccine Works . . . . . . . . . . . . . . . . . . . . . . 15.6. Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.7. Altruism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.8. Mechanism of Ethical Evaluation of Vaccine Studies . . . . . . . . . . . . . . . . . . . 15.9. Fundamental, Basic, and Pre-clinical Vaccine Research in Africa . . . . . . . . . . . . 15.10. Special Considerations for Field Trials of Vaccines Against HIV . . . . . . . . . . . . 15.11. Confidentiality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.12. Clinical Services. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.13. Specific HIV Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.14. Inducement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.15. Undue Expectation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.16. Spread of Responsibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.17. Impact of HIV on Trials of (Non-HIV) Vaccines . . . . . . . . . . . . . . . . . . . . . 15.18. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.19. Duration of Follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.20. Surrogate Markers of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.21. Long-term Effects on Disease in a Population . . . . . . . . . . . . . . . . . . . . . . . 15.22. Other Preventive Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.23. Applicability of Results Elsewhere . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.24. Ownership of Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.25. Getting the Community’s Views . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Research Involving Human Subjects: Ownership, Control, and Access to Research Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.3. Need for Research Involving Human Subjects . . . . . . . . . . . . . . . . . . . . . . . 16.4. Ownership, Access, and Control of Records in Clinical Practice . . . . . . . . . . . . . 16.5. Patients Access to Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6. Ownership and Access to Research Results . . . . . . . . . . . . . . . . . . . . . . . . . 16.7. Participation in Health Research by Non-medical Personnel . . . . . . . . . . . . . . . 16.8. Storage of Research Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Equitable Sharing of Research Burden and Benefits . . . . . . . . . . . . . . . . . . . . . . . . 17.1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.3. Investments in Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.4. Subjects of the Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.4.1. Risks and Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.4.2. Access to and Affordability of New Products . . . . . . . . . . . . . . . . . . . 17.5. Sponsors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.6. Research Scientists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.7. Empowering African Scientists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Archived Specimens: Ethics Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Health Research Ethics in Africa / Acta Tropica 78 (2001) S1– S126 18.1. 18.2. 18.3.

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Archived Specimens . . . . . . . . . . . . . . . . . . . . . . . . . Types of Collections . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.1. Pathology Samples Retained by Hospitals after Surgery 18.3.2. Newborn Screening Samples . . . . . . . . . . . . . . . . 18.3.3. Forensic DNA Databanks . . . . . . . . . . . . . . . . . 18.3.4. The Armed Forces DNA Bank . . . . . . . . . . . . . . 18.3.5. DNA Collected for Clinical Care . . . . . . . . . . . . . 18.3.6. Commercial DNA Banks . . . . . . . . . . . . . . . . . . 18.3.7. Blood Banks . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.8. Research Collections . . . . . . . . . . . . . . . . . . . . 18.4. Identifiers on Samples . . . . . . . . . . . . . . . . . . . . . . . . 18.4.1. Actual Names . . . . . . . . . . . . . . . . . . . . . . . . 18.4.2. Identifying Numbers which Can be Linked to Names . 18.4.3. No Individual Identifiers (Anonymous)6 . . . . . . . . . . 18.5. Uses in Research . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.6. Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . 18.7. Access to Stored Specimens . . . . . . . . . . . . . . . . . . . . . 18.8. Issues of Concern . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.8.1. New research on samples taken for other purposes. . . 18.8.2. Identifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.8.3. Use of Samples by other Researchers . . . . . . . . . . . 18.8.4. Length of Storage . . . . . . . . . . . . . . . . . . . . . . 18.8.5. Contacting Donors about Important Results . . . . . . 18.8.6. Access for Blood Relatives or Spouse (Partner) . . . . . 18.8.7. Compensation . . . . . . . . . . . . . . . . . . . . . . . . 18.8.8. Informed Consent . . . . . . . . . . . . . . . . . . . . . . 19. Optimum Ethical Standards . . . . . . . . . . . . . . . . . . . . . . . . . 19.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2. Concept of ‘Optimum Standards’. . . . . . . . . . . . . . . . . . 19.3. Characteristics of Optimum Ethics Standards. . . . . . . . . . . 19.4. Identifying the Issues . . . . . . . . . . . . . . . . . . . . . . . . . 19.5. Nature and Scope of Ethics . . . . . . . . . . . . . . . . . . . . . 19.5.1. Respecting the Integrity of the Person . . . . . . . . . . 19.5.2. Responding to Human Needs . . . . . . . . . . . . . . . 19.5.3. Promoting the General Good . . . . . . . . . . . . . . . 19.5.4. Promoting Justice . . . . . . . . . . . . . . . . . . . . . . 19.6. Types of Ethical Issues. . . . . . . . . . . . . . . . . . . . . . . . 19.6.1. Protection Issues . . . . . . . . . . . . . . . . . . . . . . . 19.6.2. Communication issues. . . . . . . . . . . . . . . . . . . . 19.6.3. Relevance Issues . . . . . . . . . . . . . . . . . . . . . . . 19.6.4. Strengthening Accountability . . . . . . . . . . . . . . . . 20. Health Research Ethics for African Countries . . . . . . . . . . . . . . 20.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.1.1. Health Research . . . . . . . . . . . . . . . . . . . . . . . 20.1.2. Health Research Ethics . . . . . . . . . . . . . . . . . . . 20.1.3. Health Research Ethics in Africa . . . . . . . . . . . . . 20.1.4. Seminar Objectives and Strategies . . . . . . . . . . . . . 20.2. Africa Highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.2.1. Environment . . . . . . . . . . . . . . . . . . . . . . . . . 20.2.2. Population Profiles. . . . . . . . . . . . . . . . . . . . . . 20.2.3. African Cultures . . . . . . . . . . . . . . . . . . . . . . . 20.2.4. Burden of Disease . . . . . . . . . . . . . . . . . . . . . . 20.2.5. Health Research Needs . . . . . . . . . . . . . . . . . . . 20.3. Currently Available Guidelines . . . . . . . . . . . . . . . . . . . 20.3.1. Universal Ethics Guidelines . . . . . . . . . . . . . . . . 20.3.2. South African Ethics Guidelines . . . . . . . . . . . . . .

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Health Research Ethics in Africa / Acta Tropica 78 (2001) S1– S126 20.4. Seminar Recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21. Opening Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.1. Vote of Thanks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Country Reports on Supervision of Health Research Ethics . . . . . . . . . . . . . 22.1. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. International Guidelines for Health Research Ethics . . . . . . . . . . . . . . . . . . 23.1. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24. Burden of Disease in Africa in Early 21st Century . . . . . . . . . . . . . . . . . . 24.1. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25. Traditional African Perception of a Person . . . . . . . . . . . . . . . . . . . . . . . 25.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26. Traditional African Perception of Illness . . . . . . . . . . . . . . . . . . . . . . . . 26.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27. The Regulatory Review Process in the Licensure of Biologicals . . . . . . . . . . . 27.1. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28. Composition and Responsibilities of Ethics Committees and Investigators . . . . . 28.1. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29. Informed Consent in Health Research . . . . . . . . . . . . . . . . . . . . . . . . . . 29.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.1.1. Discussant 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.1.2. Discussant 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.1.3. Other Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30. Intellectual Property Rights and Confidentiality . . . . . . . . . . . . . . . . . . . . 30.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30.2. Other Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31. Current Vaccine Research in Africa: Engaging Ethics Problems . . . . . . . . . . . 31.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2. Other Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32. Research Involving Human Subjects: Ownership, Control and Access to Research Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32.1.1. Discussant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32.1.2. Other Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33. Equitable Sharing of Research Burdens and Benefits . . . . . . . . . . . . . . . . . 33.1. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34. Archived Specimens: Ethics Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . 34.1. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35. Optimum Ethics Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35.1. Question and Answer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35.2. Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36. Group One Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.2. International CIOMS Ethical Guidelines . . . . . . . . . . . . . . . . . . . . 37. Group Two Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.2. Burden of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.3. Traditional African Cultures . . . . . . . . . . . . . . . . . . . . . . . . . . . 38. Group Three Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.2. General Observations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.3. Ethics Committees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Health Research Ethics in Africa / Acta Tropica 78 (2001) S1– S126 39. Group Four Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.2. Opening Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.3. Intellectual Property Rights and Confidentiality . . . . . . . . . . . . . . . . . . 39.3.1. Confidentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.3.2. Intellectual Property Rights . . . . . . . . . . . . . . . . . . . . . . . . . 39.4. Ownership and Use of Research Outputs . . . . . . . . . . . . . . . . . . . . . . 39.4.1. Ownership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.4.2. Use of Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.4.3. What to Do When the Study is Over . . . . . . . . . . . . . . . . . . . . 39.5. Future Access to Archived Specimens . . . . . . . . . . . . . . . . . . . . . . . . 39.6. Equitable Sharing of Research Burdens and Benefits . . . . . . . . . . . . . . . 39.6.1. General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.6.2. Burdens and Benefits for Research Subjects, Communities and Society 39.6.3. Sharing of Burden and Benefits between Research Scientists . . . . . . 39.6.4. Sharing of Burden and Benefits between Sponsors and Scientists . . . . 39.7. Conclusions and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . 40. Final Plenary Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . List of Registered Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Secretariat and Interpreters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Participants Discussion Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Summary of Proceedings

1.1. Introduction The first conference of the African Malaria Vaccine Testing Network (AMVTN) identified as a leading priority, the promotion of ethics in health research undertaken in Africa. The participants at the 1995 meeting expressed the need for mainly increasing awareness of ethics in health research and of reviewing current practices and existing guidelines. The conference also noted that there were very limited national health research capacities, and the continuing reliance on nonAfrican participation in health research on African health issues, and the attendant shortcomings thereof, including inherent ethics issues. From its founding about 5 years ago, AMVTN in all its capacity building endeavours, particularly in its workshops on study designs and methodology, good clinical practice (GCP), and data management, has identified promotion of ethics to be a top priority. This activity being such a major challenge required considerable preparations, which started in earnest during 1997. It was decided very early that a workshop would not suffice and a conference would lack sufficient focus. It was therefore decided to organize a Seminar on

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. 121 . 121 . 121 . 121 . 121 . 121 . 121 . 121 . 122 . 122 . 122 . 122 . 122 . 122 . 123 . 123 . 123 . 124 . I . VII . VIII

Health Research Ethics in Africa. After wide ranging consultations, the relevant topics and respective speakers were identified and invited.

1.2. Acknowledgements The AMVTN gratefully acknowledges the financial support obtained from the Organization of African Unity, European Commission, Danish International Development Agency, Swedish International Development Agency, World Health Organization (WHO) African Regional Office, WHO Special Programme for Research and Training in Tropical Diseases, Wellcome Trust, US National Institutes of Health, United Nations Educational, Scientific and Cultural Organization, Marcel Merieux Foundation, and Africa Viva Foundation.

1.3. Seminar Objecti6es The objectives of the Seminar were to receive and discuss commissioned presentations aiming at identification of health research needs and priorities in sub-Sahara Africa; socio-cultural characteristics of the populations in the region; mechanisms being used for ethics review of pro-

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posals and monitoring of the health research undertaken in the region; and available health research ethics guidelines and licensure of medical products. The Seminar was also expected to make recommendations for appropriate ethics guidelines meeting the special needs of sub-Sahara Africa, and to identify related future plans and activities.

1.4. Strategies The Seminar programme accommodated plenary and parallel group discussion sessions. The opening plenary session was addressed by the AMVTN Chairman, Representative of the WHO Regional Director, and the guest of honour, J.A.M. Rugumyamheto, Permanent Secretary, President’s Office, Civil Service Department. The plenary sessions also received and discussed among other presentations: country specific experiences on supervision of health research ethics; international health research ethics guidelines; burden of diseases in Africa during the early 21st century; traditional African perception of a person and illness; the regulatory process in the licensure of biologics; composition and or responsibilities of ethics review committees and investigators. The other subjects were informed consent in health research; intellectual property rights; confidentiality; ethics problems in current vaccines research in Africa; ownership, control, and access to research medical records; equitable sharing of research burdens and benefits; ethics concerns over archived specimens; optimum ethics standards; and guidelines for health research ethics for African countries.

1.5. Seminar Participants The seminar participants being recognized for their expertise, were invited either to make commissioned presentations or as key discussants of the presentations. There were also invited participants from known functioning national and institutional ethics review committees from African countries. There were in all 54 participants made up of 34 Africans, 14 Europeans, three Americans, and three from international institutions.

1.6. Seminar Recommendations 1. Most of the issues raised at the Seminar on Health Research Ethics in Africa, were to a large extent covered by the International Ethical Guidelines for Biomedical Research Involving Human Subjects, developed by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). The latest edition of these guidelines published 1993, was noted to have taken into account most of the currently known ethics issues and needs of developing communities found in Africa, elsewhere in other developing regions, and to some extent in developed countries. It was further noted that these guidelines would be regularly reviewed to take into account new scientific and other developments. The guidelines were therefore acceptable for adoption as a minimum standard for African countries. 2. However, there was dissatisfaction with the CIOMS WHO Guidelines’ definition of ‘under-developed’ communities. The definition being basic to the principles of the ethics issues in the reference communities should go beyond economic values to encompass socio-cultural and other dimensions. Furthermore, the expression should be rephrased to the conventional ‘developing’ communities, which was less offensive and acceptable. Similarly, the International Conference on Harmonization/Good Clinical Practice (ICH/GCP) Guidelines do not address community concerns. It is recommended that the next review of the guidelines should address these concerns. 3. It was noted that most African countries individually and collectively, unlike European, American, and some Asian countries, had neither national nor regional certification for drugs and vaccines. African countries were, therefore, urged to establish and develop certification of drugs and vaccines at national, or better still, at the African regional level. The certification institution should also be empowered to undertake public inquiry into cases suspected of violations and penalize those found guilty. The certification institution should be strengthened and mandated to promote exchange of experiences between researchers, manufacturers, and institutions within and out-

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side Africa; and to undertake harmonization and supervision of the certification standards. 4. Having agreed that there was a need for a bioethics forum to look after and safeguard African interests in that field, African countries were urged to form as a matter of urgency a Pan African Bioethics Initiative. The forum should be empowered to promote, set standards, undertake harmonization, supervision, and co-ordination of related activities between researchers, institutions, within and between African countries, and at regional and international levels. It was recommended that the African Malaria Vaccine Testing Network, which already has an appropriate secretariat and database, should take up the necessary action towards the establishment of the Initiative. 5. It was regrettably noted that some African countries although undertook health research, had either inadequately developed institutional and or national ethics review committees, or none at all. These countries were urged to establish and develop these committees, preferably at both national and institutional levels. Although the ethics review committees should be independent at all levels, the national committees should undertake the responsibilities of supervision, co-ordination, setting standards, and harmonization. The committees should promote good and stop bad research, respectively, through policing of all proposed and ongoing research. The ethics review committees should be empowered to raise their own funds to meet their operational costs, but without jeopardizing their autonomy in so doing. The funds could be raised through charging administrative overheads on research and other development projects, in the same way as similar institutions do in developed countries. 6. It was agreed that ethics clearances given by partner non-African institutions including international organizations for research to be undertaken in African countries were by themselves insufficient. For such research, ethics clearance must be obtained also from the host partner African institutions. 7. Since research based on bad science is unethical, the countries have the prerogative of either having the ethics review committees combine the

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roles of ethics and scientific reviewing of research proposals or having separate committees for these roles. When the two roles are combined by one committee, the reviewing process may be expedited, especially if the reviewers are carefully selected to take into account underlying scientific and ethics issues. 8. The quorum of the ethics review committees should be based on representative memberships, and not merely on numbers of members. The membership composition should have a broad base of disciplines, should certainly include lay members, and be balanced for the two sexes. The committees should have options for coopting temporary members for their special expertise or interests in the subjects under review. However, such members should not have voting rights, and conflicts of interests must be avoided. 9. In order to ensure standardization and avoid errors of omission and commission, the reviewing process of proposals should use a checklist ensuring among other things: “ Capacity building of local researchers and institutions; “ Community awareness and participation in the proposed research; “ Sensitivity to local cultures and children’s welfare; “ Protection of populations vulnerable to abuse by health research; “ Targeted dissemination and promotion of utilization of the results, particularly by the beneficiary populations; “ Agreement on ownership, use, and access to the research outputs by those in and outside the research partnership and medical profession; “ Procedures for obtaining and documenting informed consent; and “ Compliance to the CIOMS WHO Guidelines and GCP. 10. Community consent must always be obtained because it is an effective safeguard against abuse of vulnerable populations within developing communities. Furthermore, it is symbolic of respect and recognition of the local socio-cultural arrangements. Community consent should be obtained directly from the community itself and or

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indirectly from its political leadership, and or relevant institutions such as non-governmental organizations (NGOs), schools, and public health service departments. However, individual consent must always be obtained and preside over community consent. 11. It was noted that good health research invariably involves collaboration between investigators themselves; investigators and donors; investigators, communities, and donors; various local and external institutions; and or all the above. In order to ensure transparency, avoid conflicts, and facilitate equitable sharing of research burdens and benefits, such research must have a collaborative memorandum of understanding. The memorandum should among other things specify: “ Ownership of data and specimens; “ Intended original use of the data and specimens; “ Requirement for host permission for any other use of the data and specimens; “ Conditions for getting access to data and archived specimens; “ End of study disposal of the above research outputs and spin-offs; and “ Arrangements for authorship consonant with the inputs from the investigators. 12. Research proposals as well as memorandums of understanding should show that research hosts, institutions, and sponsors have: “ Collaborated in setting the research agenda and priorities; “ Commitment to mutual trust, transparency, development of sustainable research capacity for local researchers, host institutions, health services, community welfare, and equitable sharing of benefits resulting from intellectual property rights; and “ Budgetary allocations for topping up remuneration of local researchers, as a motivation as well as a preventive measure against brain drain; “ Binding agreement providing access to test products with proven efficacy being made available to participating individuals and communities;

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Recognition of inputs made by host communities and according them the right of being the first to receive and discuss the research findings, specifically thanked for their participation, and small presents given to children if warranted by their participation.

2. Welcome Remarks Prof. W.L. Kilama, Chairman cum Coordinator, African Malaria Vaccine Testing Network I feel greatly honoured and indeed privileged, to welcome you all to my home country, Tanzania, and to the Seminar on Health Research Ethics in Africa. The idea of promoting ethics in health research in Africa, was conceived here in Arusha, almost 5 years ago, at the First Meeting of the African Malaria Vaccine Testing Network (AMVTN). Since then, the Network has been formed, and among the leading activities so far undertaken, has been the training of African research scientists in various aspects of malaria vaccine testing. In each of these training activities whether concerned with study designs or good clinical practice, ethics has featured prominently. Through these AMVTN workshops, and other activities undertaken elsewhere, and some of them not at all related to malaria research, it has become abundantly clear that ethics in health research, should be accorded the prominence it rightly deserves. Initially, we thought it was enough to merely create awareness of ethics among African malaria researchers. However, it has become abundantly clear even to those of us who are shear novices in this specialty, that ethics in all kinds of health research deserves much greater attention. We quickly realized that although there are in existence international ethics guidelines, these are not optimally suited for real life situations obtaining in sub-Saharan Africa. As discussions went on, and as the situation unfolded, it became abundantly clear that there was need to look at health research ethics from an African perspective.

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These ideas went through an evolution. In this regard, I wish to particularly thank Dr Pedro Alonso and his team at the Africa Viva Foundation of Barcelona, Spain, for encouraging and supporting the growth and development of the idea within the AMVTN Secretariat. The Foundation provided funds that enabled us to host several focused international meetings, which among other things, identified the ethics issues that now constitute the leading sub-themes of this Seminar. I also wish to single out Prof. Solomon Benatar, the co-chair of this Seminar, who was very instrumental in this crucially important exercise. Once the problems and sub-themes were identified, the AMVTN Secretariat in collaboration with other members of the AMVTN Coordinating Committee, prepared the documentation essential for raising the required funds. I am pleased to report that these efforts were awarded through the grants provided by the: “ Organization for African Unity (OAU); “ European Commission (EC); “ Danish International Development Agency (DANIDA); “ Swedish International Development Agency (SAREC); “ Regional Office of the World Health Organization (WHO Afro Region); “ WHO Special Programme for Research and Training in Tropical Diseases; “ Wellcome Trust; “ USA National Institutes of Health; “ United Nations Educational Scientific and Cultural Organization; “ Marcel Merieux Foundation, and “ Africa Viva Foundation. It is the combined contributions of all these agencies that have made it possible for us to host this seminar, and for all of us to be here. Please join me in giving them a hand of applause. By no means last, I wish to thank our guest of honour, Mr Joseph Rugumyamheto, Permanent Secretary in the Office of the President, for agreeing to travel all the way to Arusha to open this Seminar. As the head of the Civil Service, we know you are a very busy man.

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We also know that only a week and a half ago, you had the onerous duty of organizing fitting arrangements for the send off of the body of our Father of the Nation, Mwalimu Julius Kambarage Nyerere. We all appreciate very much your joining us this morning. As is clear to all of us, ethics in health research is crucially important, particularly to those charged with health promotion in Africa. It is now my singular pleasure to call upon the World Health Organization Representative to the United Republic of Tanzania, to kindly address us on behalf of the Regional Director, World Health Organization. Dr Wedson Mwambazi, please.

3. Statement on Behalf of the WHO Regional Director Dr Wedson Mwambazi, WHO Representati6e, Tanzania and Sychelles On behalf of the World Health Organization and on my own behalf, I wish to welcome all the distinguished participants to this important meeting. I would like to thank Prof. Wen Kilama and his team, for making this meeting a reality. Our leadership in WHO, both at headquarters and regional levels, saw the need for supporting this initiative financially and technically, because of the importance they attach to the subject before you. I agreed to come and render moral support to this august gathering, knowing all too well, that the subject you will be discussing is one that is supposed to concern all of us in our professional daily lives. However, it is actually and systematically applied on a day-to-day basis by a few. For that reason, ethics is a very special area of concern. Ethics is that body of thought, knowledge, practice of moral issues, and aspects in one’s professional life, and indeed in ones lay life. Many professional disciplines are guided by some form of ethics: law, sociology, theology, and indeed our own medical profession, to mention but a few. In the medical profession, biomedical ethics has transcended centuries of evolution that can be

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traced back to the time of Hippocrates. Up to this day, it is the pride of every medical doctor to honor and uphold the Hippocratic oath. The message conveyed by this oath is very simple, and can be summarized in three words: ‘do no harm’. Since the early time of enlightened and documented medical practice, biomedical ethics has passed through several phases and it is increasingly becoming more and more complex. By and large, this increasing complexity to the technological revolution that has been growing and expanding fast, especially over the past two and a half centuries. In the 18th century, an English physician, Thomas Percival, elaborated further work on the medical ethics code existing up to that time. By mid 19th century, the founders of the American Medical Association, thought that it was necessary to expand the code, and so they did. The international partnership has also been growing and covering in the area of medical research during the past half century. For instance, the revelations of the Nazi experiments on humans during the Second World War, led to the establishment of the Nuremberg Code. Later on, WHO and the Council of International Organizations of Medical Sciences (CIOMS) established the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Most recently, during the past 2 – 3 decades, medical and related ancillary technology, have accelerated human health development by leaps and bounds acting as motivation and inspiration to medical scientists and practitioners. The technology has also been a source of the challenges bringing in new ethics traps in important areas of medical endeavor, for instance reproductive health, surgery, genetic engineering, cloning, embryology, and euthanasia. While observing and appreciating these technological advances, it is believed that the African medical scientific establishment should resolve and rededicate itself to accomplishing the unfinished job of getting rid of malaria, HIV/AIDS, and tuberculosis. There still lies ahead of us a lot of work in these priority areas, for example in designing and implementing preventative programmes, the development of and drug clinical trials, not to forget of

course the development of vaccines and their clinical trials. African medical scientists have been playing a significant role already. However, we need to get them more involved and better funded. One area that has not received adequate attention in the African region is that of health research legislation aiming at enhancing the protection of healthy as well as sick human research subjects. It is hoped that this meeting will propose some suggestions on the way forward in this connection.

4. Opening Speech Mr J.A.M. Rugumyamheto Permanent Secretary, President’s Office, Ci6il Ser6ice Department Firstly, I would like to thank you, Mr Chairman, and the Seminar Organizing Committee, for inviting me to participate in this important Seminar, and to officiate its opening ceremony. Secondly, on behalf of the Government of the United Republic of Tanzania and her people, and on my own behalf, I extend a hearty welcome to you all to Arusha and Tanzania, and particularly to those coming from outside these areas. Besides being a conference city, Arusha is also a tourist dream resort surrounded by national game parks and mountains, including Mount Kilimanjaro, only a stones throw away. While you are here, and especially when the Seminar ends, you should find time to visit these places. Do not wait to hear about these attractions from those who have been there! Mr Chairman, I acknowledge that the theme of your Seminar is most appropriate and most relevant at this point in time, particularly in Africa. There are reforms currently taking place in political, economic, administrative, and social sectors. These are placing major shifts and new demands and challenges on those managing the changes as well as to those executing technical functions which go with these transformation changes. In regard to health research it is highly appreciated now than ever before, that there can be no

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meaningful fight against existing poverty if the population continue to suffer from diseases which were eliminated many years ago in some parts of the globe. It is acknowledged that populations plagued with malaria, intestinal worms, resurging tuberculosis, AIDS scourge etc., cannot effectively contribute to national wealth and their own wellbeing. It is therefore no wonder that Africa has the greatest need for health research. Yet the continent has the least capacity for undertaking that desperately needed health research. For this reason collaboration between researchers and research institutions within and outside Africa, is an option which cannot be over emphasized. I understand that this Seminar is being held in that spirit. Many of my remarks will therefore highlight research collaboration between developing and developed countries. I will, if you will excuse me, view research and the research process from the perspective of a developing country, a government executive, highlighting areas which I believe need emphasis, particularly in research cooperation and partnerships. I hope and trust that by following these ideas health partners can greatly improve the working atmosphere, and indeed in the process, promote ethical health research. Mr Chairman, it has been observed that most major biomedical research, is initiated by scientists from the North, who frequently suggest areas of research collaboration. It is not infrequent, that these prospective partners arrive in our poor countries with research proposals and protocols already fully developed; they merely ask the Southern partner to sign on the dotted line, often under the pretext of beating the deadline. Poor as we are, we rush to sign them so as to seize this opportunity which does not come often. Scientists from both the North and the South hardly ask whether such an approach is really ethical. It is important that we decide on the research agenda together. Identification of research problems, and indeed the entire theme for research has to be shared between the funding source and the partner. The conception, development, and indeed execution of a research project should involve the communities

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who are the intended beneficiaries of the results, and should not merely satisfy the lofty ideas of scientists alone. We need to involve the stakeholders in what is now termed as participatory research if our findings have to have relevance to the communities on whom research in being done. It is by involving them in all research processes that they are likely to appreciate research results and how these can be used to solve their own health problems. At the decision- and policy-making levels, I strongly believe that we must set research priorities that really address the needs and interests of the host nation, region, and district. We must as far as is possible be area specific, while thinking globally. If we fail to do so, we shall fail to get research results that are locally or nationally applicable; the entire exercise will be in vain, casting doubts on whether the envisaged research is in line with the cultural, social, political, economic, ecological, environmental, and technical realities of the area. For research partnerships to succeed and flourish, we must build up mutual trust between the participating parties. This requirement will, to use a current parlance, demand transparency in all our dealings. It is not infrequent that one encounters difficult partnerships resulting from lack of openness, confidence, and trust. I find it appropriate for me to provide advice at this stage: look at the past experiences and use those that are positive to improve our processes. Equally, look at past modes of partnerships and use the positive arrangements to build further collaboration. Before launching a collaborative research endeavour, it is essential that the partners are fully knowledgeable of the planned research undertaking. Ideally, we should avail to all partners all the essential information, and even enable them to be constantly up to-date. Indeed promotion of communication within the partnership and with other networks is a must. Mr Chairman, if research partnerships are to succeed, the participating parties must share responsibilities. Before launching the research undertaking the exact division of responsibilities must be clearly spelt out, preferably in a memorandum of understanding, spelling out the rights and obligations of each party. Even

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at this stage, it would be fair to envisage how the results will be shared. The memorandum of understanding may even go to the extent of enforcing transparency by demanding a periodic presentation of financial accounts, audit reports and any other mechanisms that promote transparency. Once the research partnership gets underway, it will need periodic monitoring and evaluation. These exercises need to examine all the phases of the research collaboration, including conception, execution, management, and its final results. The evaluators must of necessity make sure that the research carried out abides fully by the proposed protocols, and where there is any diversion, these must be queried and fully explained. Evaluators must naturally be free to carry out the assignment, granting no favours and under no duress! Mr Chairman, often research scientists are primarily interested in obtaining and publishing research results, so as to inform their peers. Many scientists consider their job done when their results are accepted for publication in a prestigious journal. Many, especially the budding ones will use the results to get a better job or a promotion. Some will start on a new project as soon as the old one winds up. This should constitute only part of the story. As we saw earlier, collaborative research involves researchers of various backgrounds; if it is participatory it will have involved a broader set of the communities. Results from a study carried out in this manner must, be widely distributed. They must also be presented in such a manner as to be easily understood by all levels of research stakeholders including policyand decision-makers, other researchers, operational staff, and the communities. The often nagging question nowadays, is who should receive the results first? Whatever the answer one gives, study communities have the right to receive the results early, and in an easily understood language. The dissemination of research results to end-users should go beyond the readership of scholarly journals. We must seize all possible opportunities to present these results to appropriate and broad audiences at seminars, workshops, conferences, lectures, public meetings, public markets, and reli-

gious gatherings. Various print and electronic media should be used to disseminate research results. These may include journals, newspapers, booklets, leaflets, brochures, role plays, television, video, and cinema features etc. We may even have to seek out help from famous nationally known personalities such as community, religious, and opinion leaders to disseminate our appropriate research results. These are also responsibilities of the research team. Indeed very often, many researchers after undertaking the study, never return to the study community, let alone providing the community with the study results. They often shrug off this responsibility of seeing to it that the study results are indeed applied, at least with the purpose of benefiting the population that participated in the research. Although the translation of research results into utilization is complex, it is still the duty of the study teams to design mechanisms ensuring that their results are put into use! Informing and involving government bodies, non-governmental organizations (NGOs), communities, commercial enterprises etc in information dissemination, contribute in no small way towards the utilization of research results. Research results constitute intellectual property and must therefore be equally shared among the research partners. It is not infrequent in this country, and indeed in most other developing countries, to hear of indigenous researchers complaining about publications of research results from collaborative projects only listing the northern partners. In some cases the northern partners may raise patents or copyrights, or even make financial gains without involving their southern partners. I think it is only fair to include all partners who have contributed meaningfully, in such follow up activities as in authorship, speaking at international, regional, and other fora, and being mentioned and or appearing in the print and electronic media. Mr Chairman, traditionally, if the participating communities are lucky at all, they only receive acknowledgments in journal articles, which is not enough. In many of our countries, we have regulatory bodies established to coordinate, promote and control research. Yet, often scientists neglect to consider the pertinent regulations laid down by

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the national bodies. On the other hand and interestingly, they are ready to pay particular attention to the regulations and requirements of the funding source! When all is said and done, research partnerships should contribute towards research capacity strengthening of individual researchers and their home institutions, so much that research cooperation leads to meaningful self-reliance and sustainability. It should enable developing countries to increasingly address their leading health problems without always waiting for a northern initiative. In the spirit of sharing burdens, it is also important to promote South-South collaboration in research, and even in its application to solve health problems. As the saying goes, diseases recognize no boundaries, and infections require no entry visas! It is paramount that agencies funding research, should also strengthen health research ethics as part and parcel of research capacity building. Failure to do so is tantamount to promoting unethical health collaboration. May I suggest that part of the funds set aside for institutional over-heads in partner institutions, be earmarked for reviewing of proposals and monitoring of research for ethics compliance. Finally, even after all the above is said and done, there is need to sustain whatever has been achieved, particularly that relating to capacity building. We would surely be happier if our southern partners continue to prosper in embracing intellectual networks, do not succumb to the notorious brain-drain, undertake consultancies with multilateral and bilateral donor agencies, and are delegated to undertake research on behalf of the northern based international organizations. Mr Chairman, Ladies and Gentlemen, it was not my intention to make a long speech. I hope that what I have said has highlighted pertinent areas, and of some help to our southern and northern colleagues, especially when negotiating health research collaboration. I know you have a tight programme with challenging discussions, and I would not like to tire you before the actual work begins. Let me

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end here by assuring you that the publication of your deliberations and recommendations is awaited with a lot of enthusiasm for implementation. I wish you God-speed in your deliberations. It is now my pleasure to declare open this Seminar on Health Research Ethics in Africa.

5. Introduction to the Seminar Joas B Rugemalila, MD, MPH, PhD Chief Seminar Rapporteur, Hakika Medical Centre, Dar es Salaam

5.1. Background Most of the countries in sub-Saharan Africa have low income economies, high levels of illiteracy, unawareness and abuse of human rights and populations which are not conversant with modern concepts on health, medicine and research. These populations, therefore, are not in the best positions for giving informed consent for clinical care and research. Nonetheless, these populations have the heaviest burden of disease in the world, mostly from communicable diseases. The demographic and epidemiologic transitions, are also bringing non-communicable diseases into increasing prominence. The region, therefore, has the greatest need for health research and for which the industrialized countries are less inclined to have interest. However, most of the health research undertaken in the region involves collaboration with industrialized countries. Such collaboration requires regulations to make the research provide mutual benefits to the host and external researchers and institutions. The rampant economic poverty in the region, may particularly predispose research populations and communities to exploitation, and or abuse of their human rights. Furthermore, the situation may be complicated by the regional sociocultural norms, which are alien to western culture.

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Fortunately, there are already pertinent universal guidelines such as those developed and published by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO), and whose latest version was made in 1993. There are also the Guidelines of the International Conference on Harmonization (ICH) of Good Clinical Practice (GCP), which became effective in 1997. The African Malaria Vaccine Testing Network (AMVTN) and African Viva Foundation, believe that these guidelines and any other available ones, should be reviewed to accommodate the needs of African countries.

5.2. Seminar Objecti6es The objectives of this Seminar were to received and discuss commissioned presentations; identify health research needs and priorities in sub-Saharan Africa; determine socio-cultural characteristics of African populations; assess available health research ethics guidelines, regulations, and licensure of biologicals for meeting the special needs of Africa; make recommendations for appropriate ethics guidelines for Africa; and identify future plans and activities.

5.3. Strategies The Seminar programme consisted of plenary and group discussion sessions. The opening plenary session received remarks from the AMVTN Chairman, Representative of the WHO Regional Director, an opening speech from the Guest of Honour, and an introduction to the seminar from the Chief Rapporteur. The plenary sessions also received country specific experiences on supervision of health research ethics, commissioned presentations, comments thereon from one or two discussants, and open discussions from the audience. The commissioned presentations were on: 1. International Guidelines for Health Research Ethics;

2. Burden of Diseases in Africa During the Early 21st Century; 3. Traditional African Perception of a Person; 4. Traditional African Perception of Illness; 5. The Regulatory Review Process in the Licensure of Biologics; 6. Composition and or Responsibilities of Ethics Review Committees and Investigators; 7. Informed Consent in Health Research; 8. Intellectual Property Rights and Confidentiality; 9. Engaging Ethics Problems in Current Vaccine Research in Africa; 10. Ownership, Control, and Access to Research Medical Records; 11. Equitable Sharing of Research Burdens and Benefits; 12. Ethics Concerns over Archived Specimens; 13. Optimum Ethics Standards; and 14. Research Ethics Guidelines for African Countries. There were six discussion groups, and participants were requested to register in at least one of these for active participation. Each group at its first meeting had to elect a chair and a rapporteur to be responsible for presentation of the group discussions focusing on recommendations to the plenary sessions. Group rapporteurs were requested to hand in the group discussion notes to the chief rapporteur, who in turn had to compile and present a summary of the seminar recommendations for consensus during the last plenary session.

5.4. Seminar Proceedings The speakers presenting commissioned papers as well as the discussants, were requested to hand in to the chief rapporteur their respective papers and notes. These were to be edited by mutual consultations between the speakers and the chief rapporteur, and within a specified time frame. In order to simplify the editorial work, the papers had to adopt the circulated instructions to authors. It is expected that the seminar proceedings will be published, and that the recommendations will be sanctioned and implemented by African countries.

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6. Country Reports on Supervision of Health Research Ethics

6.1. Super6ision of Health Research Ethics in the United Republic of Tanzania Mwele Ntuli Malecela, PhD National Institute for Medical Research Headquarters, PO Box 9653, Dar-es-salaam

6.1.1. Background Information The United Republic of Tanzania is situated in East Africa and is surrounded by Kenya Uganda Rwanda, Burundi, People’s Republic of the Congo, Malawi, Mozambique, and Zambia. The country has an area of about 945 000 km2, and a projected population of about 30 million people. 6.1.2. Institution O6erseeing Health Research The National Institute for Medical Research (NIMR) established by the Parliamentary Act No. 23 of 1979, was mandated to oversee health research on human subjects in the country. The Institute became operational in 1980, and is also mandated to carry out, coordinate, control and promote health research in the country. Although other institutions have their own institutional ethics review committees, proposals submitted to them whether cleared or not cleared by these committees must be communicated to NIMR. Some institutions having institutional ethics review committees include, Muhimbili University College of Health Sciences (MUCHS), Sokoine University of Agriculture (SUA), Ifakara Health Research and Development Centre, National AIDS Control Programme (NACP), and Tanzania Food and Nutrition Centre (TFNC). 6.1.3. Medical Research Coordinating Committee This is the body within NIMR that deals with both scientific and ethics review of proposals. The committee meets quarterly, is comprised of seven ‘key’ members with voting powers, and five invited non-voting members as observers. The membership is drawn from health research, academic, and research and development (R&D) institutions, and is by nomination. The composition of the Committee is as follows:

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1. Director General, National Institute for Medical Research, as Chairperson; 2. Director of Research and Training, National Institute For Medical Research, as Secretary; 3. Tanzania Commission for Science and Technology; 4. Muhimbili College of Health Sciences; 5. Medical Association of Tanzania; 6. Ministry of Health, Directorate of Preventive Services, and 7. Ministry of Health, Health Systems Research Unit. The observers are Directors of NIMR centres and an affiliated institution, Ifakara Health Research and Development Centre. The committee deals with both scientific and ethics review of proposals, and keeps a national database of past, ongoing, and proposed health research.

6.1.4. National Committee for Ethics in Health Research This committee was formed as a working committee of the National Health Research Forum and is aimed to act as an advisory and consultatory committee both to the forum and the Medical Research Coordinating Committee on issues of ethics in health research. The committee has a wider composition in order to increase representation of other stakeholders other than health research institutions. This committee comprises of members from, academic institutions, research and development institutions, members from religious organizations, government ministries other than the Ministry of Health such as the Ministry for Community Development, Women and Children), and NGOs such as the Human Rights Centre. The Committee was formed in February 1999, and has since met twice. Its current agenda is to review the various institutional guidelines with added inputs from the international guidelines so as to have a set of harmonized guidelines for national use. 6.1.5. Successes and Achie6ements The main achievement has been the establishment of a national machinery for ethics review of research proposals and clearance, health research coordination, and a database, all of which could be improved upon. Another achievement has been the

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establishment of a committee with a national dimension ensuring that the institutions involved in health research in the country, speak with one voice in reference to research ethics.

6.1.6. Barriers and Constraints The notable barriers and constraints include: “ Limited and outdated legislation which is therefore as ineffective as ‘the toothless bulldog’; and “ Lack of coordination between institutions carrying out health research, updated information on health research ethics, and training in health research ethics. 6.1.7. Circum6enting Barriers The barriers are being circumvented through: “ strengthening the national and institutional ethics review committees; “ providing training in health research ethics; and “ harmonization and adaptation of ethics guidelines to conditions obtaining in the country. 6.2. Super6ision of Health Research Ethics in Zambia Prof. C. Chintu, MD, FRCP

6.2.1. Introduction Zambia is a landlocked country with eight countries bordering it. It has a surface area of about 740 720 km2, and a population of approximately 12 million people with an annual growth rate of 3.2%. The country does not have a national health research ethics review committee. However, each institution undertaking biomedical research has its own research and ethics committee. By far the largest institution doing biomedical research is the School of Medicine of the University of Zambia. The other institution is the Tropical Diseases Research Centre in Ndola. Other institutions refer their proposals for scrutiny to the Research and Ethics Committee of the University of Zambia. There is now more awareness of ethics research guidelines among researchers than 12 years ago when there were no research and ethics committees. However, the contents of the Nuremberg Code, Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research Involving

Human Subjects, are not widely known. Some 3 years ago the Research and Ethics Committee was placed under the University of Zambia, instead of the School of Medicine and University Teaching Hospital which established it over 16 years. This Committee scrutinizes and monitors all research activities in the University and other institutions.

6.2.2. Terms of Reference The terms of reference for the University of Zambia Research and Ethics Committee are to: 1. Receive and scrutinize proposals of all research which will involve human subjects and or other vertebrate animals, from all members of the University of Zambia, including seconded or affiliated students, researchers, other employees, and staff of the University Teaching Hospital. Human subjects may be involved: “ as patients subjected to investigative or therapeutic interventions which are additional to those required in standard management; “ through the analysis of confidential clinical information; “ in community-based studies which invade privacy or include the collection of biological specimens, or “ through alterations of the environment. Animals may be involved: “ as veterinary patients subjected to investigative or therapeutic interventions which are additional to those required in standard management; and “ in experiments in controlled environments such as the laboratory, in studies in the wild, or through alternations to the environment. 2. Safeguard the rights of all human subjects involved in research according to international accepted guidelines (eg CIOMS WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects; to this end, a research proposal may be approved, approved only subject to modifications, or not approved. 3. Ensure that no vertebrate animals are subjected to unnecessary or excessive pain or discomfort as a result of research; to this end, a research proposal may be approved, approved only subject to modifications, or not approved. 4. Protect the interests of all researchers who are

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conducting research which has been approved and who are following the approved protocols. 5. Advice on ethics issues arising from the practices of human or veterinary medicine. 6. Report through the Board of Research to the University Senate.

6.2.3. Composition of the Committee The quorum of the Committee is 6 members, meets once a month, and its composition is as follows: “ Two Heads of Department of the School of Medicine; “ Two academic staff of the School of Medicine who are not Heads of Departments; “ Head of the Department of Pharmacology; “ Executive Director of the University Teaching Hospital; “ Nursing Services Manager of the University Teaching Hospital; “ Representation of the Ministry of health; “ Two veterinary surgeons; “ Two representatives of the School of Natural Sciences; “ One representative of the School of Humanities; “ One representative of the Institute of African Studies; “ One practising lawyer; “ One statistician; and “ Two lay members of the public. 6.2.4. Monitoring The Committee receives reports of research activities that have been approved. Most research activities have data safety committee. These committees play a vital role in ensuring that any adverse effects of the research are reported to the researchers and to the Research and Ethical Committee. 6.2.5. Achie6ements Almost all research conducted in the University of Zambia have approval from the Research and Ethical Committee. The Committee handles about 100 proposals per year from the University staff, postgraduate medical students, and other researchers from within and outside the country.

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6.2.6. Constraints 1. The Committee is not sufficiently mobile to monitor research activities around the country. 2. There are few research scientists in the country who are able to develop fundable proposals. 3. Research funds come from abroad sometimes with strings attached to the funds. 6.2.7. Future Acti6ities 1. Research ethics to be included in the medical curriculum; 2. Seminars on research ethics for upcoming scientists; and 3. Recognition of research ethics committees by the Government. 6.3. Super6ision of Health Research Ethics in Malawi Godfrey Ssembatya-Lule

6.3.1. Size and Population Malawi is a small land-locked country. It has is borders with Mozambique in the South and East, Zambia to the West, and Tanzania to the East and North. It has a surface area of about 94 274 km2. Lake Malawi covers about 20% of this area. The country is divided into three administrative regions namely North, Central, and South, and these are subdivided into 26 districts. The districts are further divided into traditional authorities. The village is the smallest administrative unit in the country. The country has a population of about 9.8 million people with an annual growth rate of 1.9% and a high total fertility rate of 6.7. This high fertility rate is attributed to several factors, including early marriage, early age at first pregnancy, closely spaced births, and a low contraceptive prevalence rate now estimated at 14%. Almost half of the population is under 15 years of age, and the dependency ratio has risen from 0.92 in 1966 to 1.05 in 1995. 6.3.2. Institutions O6erseeing Health Research For a very long time research involving human subjects has been going on in Malawi in various fields, especially in malaria, schistosomiasis, and now HIV/AIDS. In order to safe guard the research

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interests of the country, an act of parliament was passed to set up the Malawi National Research Council (NRC), soon after independence in 1964. The Council has a sub-committee called the Health Sciences Research Committee (NHSRC) which oversees research specifically involving human subjects. The main activities of the NHSRC are to approve research proposals, with special reference to scientific merits, relevancy to Malawi, and ethics issues involved. Although the Committee has limited resources, it does a commendable job. The Malawi College of Medicine was opened in 1991, and has since initiated a lot of research involving human subjects and requiring clearance from the NHSRC. Unfortunately this committee meets very infrequently. Its quarterly meetings usually have a lot of research proposals to review at any one meeting. In order to speed up the review and approval processes of research to be carried out within, the College of Medicine Research Committee (COMRC) was officially launched on March 6 1996. It is one of the main committees of the College, and it is answerable to the Heads of Departments Committee, also established in 1996. However, COMRC is administratively under the University Research and Publication Committee.

6.3.3. Awareness for Research Ethics Among Researchers Although no research has been carried out to establish awareness levels, the quality of the proposals submitted to COMRC indicate that low awareness levels for ethics guidelines for biomedical research involving human subjects. Implementation of international health research ethics guidelines is still in the very early stages, and it is being enforced by the relatively newly established COMRC. 6.3.4. Structure and Operations of the Ethics Re6iew Committees Since its establishment, COMRC reviews most if not all the proposals for research involving human subjects carried out in Malawi. This is based on the evidence that within its short period of existence, COMRC has established a good

track record, and it has now been mandated to review proposals for health research to be carried outside the College.

6.3.5. Membership of the College of Medicine Research Committee The Committee has 12 members including senior staff of the 1. College of Medicine; Clinical Departments, Community Health, Division of Basic Medical Sciences, Diagnostic Services, and College Library, 2. Queen Elizabeth Central Hospital (the teaching hospital); 3. Senior Medical Superintendent (or appointee), Ministry of Health Representative; 4. Population Headquarters (representing both the Ministry and the NHSRC); 5. Non-medical Scientist representing the Community; and 6. Representative of the Research Projects within the College. 6.3.6. Functions of COMRC The main functions of the Committee are to: 1. Encourage the development of strong basic, clinical, applied and community based research programmes in each of the subject areas taught in the College, without any preference for any field of study. 2. Promote research activities within the College, including: assisting researchers with:  proposal writing,  research methodologies,  identifying possible sources of funding, and  identifying possible avenues for dissemination of research findings. 1. Raise funds for research and annual research dissemination workshops. 2. Hold monthly meetings to review research proposals submitted by College staff as well as discuss other relevant matters. 3. Update staff members regularly on current research activities within the College. 4. Disseminate information about college re-

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5. 6.

7.

8.

search at national and international conferences. Monitor research carried out under approved research proposals. Encourage both individual and team research whether these are unidisciplinary or multidisciplinary. Promote development of strong research links between researchers within the College, other colleges within the University, and outside Malawi. Ensure adherence to ethics including protection of human rights in accordance with the Declaration of Helsinki.

6.3.7. Submission and Re6iew of the Proposals 1. The Principal investigator prepares (12) copies of the proposal for all members of the COMRC. 2. The copies must reach the Secretary of COMRC at the latest fourteen days before the meeting. 3. The proposal must be accompanied by:  Letter(s) from the respective head(s) of department(s) indicating that the research has the blessing of the department(s), and  brief CVs of the investigators (except those which have been submitted within the same academic year). 4. Receipt of the proposal is acknowledged in writing. 5. Review the results and comments are sent to the principal investigator within 1 week. 6.3.8. COMRC and Other Rele6ant Committees COMRC has a representative on University Research and Publication Committee and vice versa. The COMRC Chairman and Secretary are members of the National Health and Sciences Research Committee. COMRC submits reports to the University Research and Publication Committee and the National Health Sciences Research Committees on approved, on going, and concluded research within the College. 6.3.9. Successes During 1997 /98 During the period COMRC: 1. Held regularly its monthly meetings; 2. Reviewed many proposals, approving 59 of

3. 4.

5. 6.

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which 41 and 18 were submitted by staff and students, respectively; Held three annual research dissemination workshops; Participated in the meetings and activities of the NHSR and University Research and Publications Committees; Provided research advice to academic staff and students; and Raised research funds for the College.

6.3.10. Constraints and Barriers The constraints and barriers which are being encountered include lack of support by some senior staff, severe financial constraints, lack of office space, inability to monitor approved research projects, and having to send samples and specimens for analysis overseas. The above barriers are being circumvented by enhancing openness, transparency, and accountability, and introducing fees for reviewing research proposals. 6.3.11. Future Projections and Plans 1. Officially take the responsibility of reviewing all research involving human subjects within Malawi; 2. Employ a full-time research officer to follow up approved projects; 3. Develop strategies compelling researchers to fulfil ethics obligations and punishing defaulting ones; 4. Empower heads of departments to be more responsible as well as have more authority over research in their departments; 5. Acquisition and publication of a Malawi Medical Journal; 6. Funding of research projects by junior staff. 6.4. Super6ision of Health Reseach Ethics in The Sudan Prof. A.M. El Hassan Institute of Endemic Diseases, Uni6ersity of Khartoum There is no national ethics review committee in the Sudan. However, institutions engaged in research have their own ethics committees. These

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institutions are the Faculties of Medicine in the Universities of Khartoum, Gezeira, and Juba, the National Centre for Research, and the Institute of Endemic Diseases, University of Khartoum. In the medical faculties, proposals are submitted to research committees only if funding is required. The committee would then evaluate the proposal scientifically as well as ethically. Projects for sponsorship by agencies such as WHO and the EU require ethics clearance. WHO also insists on a government ethics clearance in addition to the institutional clearance. The government ethics clearance is given by the Federal Ministry of Health.

6.5. Super6ision of Health Research Ethics in I6ory Coast Dr Lazare Marcelin Poame Directeur du Department de Philosophie, et de Recherches en Bioethique, Uni6ersite de Bouake, Cote d’I6oire

6.5.1. Introduction Ivory Coast has a surface area of about 322 000 km2, and a population of 14 million people. 6.5.2. Institutions O6erseeing Health Research The Ministries of Health and Higher Education have the responsibility of overseeing health research undertaken in the country. The level of awareness among researchers for ethics and guidelines is low for the Nuremberg Code, Declaration of Helsinki, International Ethical Guidelines for Biomedical Research Involving Human Subjects, and others. 6.5.3. Implementation and Obser6ance of the Guidelines This is either not enough or does not exist at the level of the Ministry of Health. Indeed there are no national guidelines. The researchers under the Ministry of Higher Education, have been trying without success for some time to produce national guidelines. The documentation which has been produced, has yet to be officially sanctioned, and also needs to be reinforced as far as biomedical research is concerned.

6.5.4. Ethical Re6iew Committee Structure and Operations Besides a special ethics review committee whose activities are limited to AIDS, the establishing documentation for the Faculty of Medicine of the University of Bouake, has a provision for setting up an ethical review committee in the Faculty of Medicine of the University of Bouake. However, this committee is not yet functional. There is also the National Bioethical Review Committee (Comite national de Bioethique) which tackles all the ethical aspects of research on human subjects. 6.5.5. Structure and Operations of the Enforcing Machinery These Ethical Review Committees are multidisciplinary. They enforce their activities through the press and the teaching of bioethics initiated 5 years ago at the University of Bouake. 6.5.6. Successes and Achie6ements The Ethical Review Committee focused on AIDS has recorded encouraging results. The National Committee of Bioethics with the support of the national UNESCO office, has successfully organized conferences and debates. 6.5.7. Constraints and Barriers Encountered There is lack of coordination between the specialized ethical review committees. It is really difficult to call together all the members of the National Ethical Review Committee. There is also lack of a comfortable office to work in, and of tools like computers. The distinction between professional ethics, ethical, and bioethics is not clear. It is hoped to circumvent the barriers by reinforcing the teaching of bioethics, obtain a comfortable office, and tools. 6.5.8. Future Projections and Plans 1. Conception and development of national ethics guidelines 2. Generalization of the education programme on bioethics which has been started at the University of Bouake. 3. Elaboration of a Network for African bioethicists

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4. Education of physicians and biologists in the subject.

6.6. Super6ision of Health Research Ethics in Kenya Drs S.K. Langat and N. Oduwo

6.6.1. Introduction Kenya is situated in East Africa between longitudes 34° and 42°E, and latitudes 4° and 6°N. It has a total area of 582 642 km2 of which water covers 11 230 km2. The country borders five countries namely Somalia, Ethiopia, Sudan, Uganda, and Tanzania. It has coastline with the Indian Ocean. The projected population is 30 million with a negative growth rate at 2058 people per year. It has a liberalized economy largely dependent on agriculture although pressure on land has accelerated urbanization. The country being a republic has a parliamentary system of Governance with the president being the executive authority. There are Government Ministries in charge of all major areas of the economy and social life whose function is to provide policy leadership and regulatory services. Kenya has a fairy elaborate research system comprising of regulatory and executing institutions. The research system comprises of the following: “ The National Council for Science and Technology (NCST); “ The Ministry of Education, Science and Technology; “ Public Research Institutes; “ Commodity Based Research Institutes; “ International Research Institutes; “ Institutions of higher learning; and “ Semi private non-governmental organizations (NGOs). About 90% of research expenditure is supported by the Government. The private sector research support is only 10%. In the last decade, research spending has been an average of 00.4% of GDP. Health research takes about 18% of all the allocations to research and development (R&D).

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6.6.2. Institutional Framework for Health Research Health research is carried on in various institutions both public and private. “ Public Research Institutes include: “ Kenya Medial Research Institute (KEMRI); “ Kenya Tryponomiasis Research Institute (KETRI); “ Institute of Primate Research (IPR); “ University of Nairobi; “ Jomo Kenyatta University; “ Jomo Kenyatta University of Agriculture and Technology; “ Egerton University; and “ Moi University; Private universities also have some health research programmes. Some health research is also undertaken in the country by international research institutes such as the International Centre for Insect Physiology and Ecology (ICIPE), and non-governmental organizations (NGOs) such as the African Medical and Research Foundation (AMREF). The NCST and the Ministry of Education, Science and Technology through the Department of Research Development, are the institutions overseeing research in the country. The legal framework for Science and Technology is provided by the Science and Technology Act of 1979. The Act established the NCST and all the Public research Institutes. Whereas NCST provides advice to the government on all matters relating to science and technology, the Ministry executes government policy on science and technology, including mobilization of resources for research, promotion, authorization, and coordination. Any research planned to be undertaken in the country, requires clearance and authorization. If the research will involve human subjects, ethics clearance must be obtained from an Ethics Review Committee duly approved by the Ministry of Health. 6.6.3. Ethics Clearance Kenya is a signatory to the Helsinki Declaration adopted by the World Medical Assembly in 1964. Ethics clearance is done by the institutional committees approved by the Ministry of Health.

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The Kenya Medical Research Institute, Kenyatta National Hospital, and Eldoret Referral Hospital, have approved institutional ethics clearance committees. The latter two are teaching hospitals serving the University of Nairobi Medical School and the Moi University Faculty of Medicine, respectively. Most researchers outside these institutions who wish to do clinical research will be collaborating with these institutions or will forward their research protocols for clearance by one of the committees. Awareness about issues of ethical clearance in Kenya is widespread, and most of the proposals submitted for ethics clearance show that the researchers adhere to the requirements. All ethical clearance committees use the Helsinki Code with the latest 1959 Amendment in their approval procedures, and ethical committees use updated instruments reflecting the latest changes.

6.6.4. Implementation The processes for research review, authorization, and monitoring use internationally accepted guidelines. Government clearance for research in Kenya is executed in two ways either by standing clearance or individual clearance for each proposal. Standing clearance is offered to public institutions and international research institutions accredited to undertake health research in Kenya, and to private research institutions that have satisfied the requirements for the grant of a standing clearance. Institutions with standing clearance include research institutes, universities, and organizations. Individual clearance is offered to individuals who may be citizens or non-citizens, and satisfying the criteria defined by the NCST. For medical research, the grant of ethical clearance must precede the authorization. Other projects in institutions with standing clearance are approved only with the concurrence of the ethics review committee. In the case of KEMRI, the process of proposal approval begins with the writing of the proposal by the authors, which is then passed on to the relevant scientific steering committee, and subsequently to the ethical review committee. The proposal becomes official once it is accepted by the Scientific Programmes Committee acting for the

Board of Management. The process in the universities is similar. Proposals from staff and students are first reviewed and approved by faculty organs for scientific soundness, and then are forwarded to the ethical review committee, and subsequently to the Senate Project Approval Committee. Universities without medical schools wishing to undertake health research are required to collaborate with appropriate medical schools or research institutes, where ethical review will be possible. Similar arrangements have to be used by NGOs and non-medical research institutions wishing to undertake health research involving human subjects.

6.6.5. Structure and Operations of Ethical Re6iew Committees Ethical review committees are organs of the institutions where they operate. The Ministry of Health approves their formation and provides the guidelines on how they may be constituted. The committees prepare their approval procedures from guidelines and other documents adopted by the Ministry of Health. The guidelines are in conformity with international agreements. The Committees sit at regular intervals of time in unison with other committees with which they work in order to examine proposals. Each committee has prepared and will constantly revise an informed consent form. The KEMRI Informed Consent Form consists of 15 sections including those dealing with the following issues: “ proposal number; “ details of patient; “ purpose of study; “ procedures to be followed in the study; “ risks benefits, alternative treatments; “ confidentiality of the records; “ if problems develop; “ financial considerations; “ obtaining additional information “ basis of participation, signature; “ pregnancy waivers for females, and “ voluntary statement of intent to avoid pregnancy. The ethics review committees are composed of members drawn from professional clinicians and lawyers, laymen, staff of the institution, and out-

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siders. This composition is expected to give the committees credibility and independence. Most of the members are outsiders.

6.6.6. Successes in Ethical Regulation The arrangements for adherence to health research ethics, human rights, and legal justice, have been satisfactory in Kenya. These have been based the Nuremberg Code developed after the Second World War. This code was a more elaborate qualification of the first code developed by William Beaumont and Claude Benard in the 19th Century, whose main principle was taken from the Hippocratic Oath. The principle prohibits performing on a human subject a harmful experiment to any degree whatsoever regardless of the benefits such manipulation may bring to science and society. This echoes the demands for human and society rights currently receiving great attention all over the world. 6.6.7. Constraints There are slow responses in the regulatory instruments and proposal review procedures to accommodate changes in the scientific, technical, and social spheres. There is, therefore, need for constant review of the procedures, values, and issues in order to cope with the changes taking place. Secondly, the clearance procedures are sometimes circumvented by those wishing to escape the responsibilities of observing health research ethics. Enlightenment of the public also plays a role in ethical adherence. Education increases enlightenment of the subject, and awareness to ethics, human rights, and justice. It is, therefore, advantageous to have an enlightened public which can contribute constructively to debates on how ethics can be handled in the country. 6.6.8. Future Projections Improvement of the standard of health research ethics in the country will depend on the trends of health research itself, developments in law on human rights, scientific, and information technology. The Nuremberg Code which has dominated the practice of health research ethics, is centered

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on protecting only the physician and patient. The scope and outlook of ethics have to be expanded to accommodate other researchers and research subjects. Genetic research is now increasingly featuring in the forefront of health research, and introducing new dimensions to the whole outlook of ethics. 1. Sharing of information with others who may benefit, and either wishing or not wishing to know because of the fear to be hurt. 2. These may be relatives of a patient who gave consent and the subsequent genetic research information showing that these may also be susceptible. 3. The use of samples at a later date for other related studies, and therefore, requiring fresh consent to be sought. 4. Commercial use of information or other research products, should loyalty and intellectual property laws appropriately recognize the source of such information and products. Besides these issues, human beings are increasingly becoming aware of their rights and more willing to get involved in legal battles that may slow down research work. Ethics committees may find themselves meeting more often to settle issues that have arisen from their work. It is important for regulatory institutions to project ahead and make necessary adjustments of existing ethics clearance structures before they are caught up with problems that would be both costly and time consuming. Lastly, healthy debates are necessary in order to define issues in areas where technological developments are moving faster than regulatory and policy institutions. Such a situation calls for popularization of technology within, to ensure informed debate, and build confidence on the ability of the research system to provide reliable answers. Secondly, there has to be greater cooperation among nations in the exchange of information and experiences and also in the development of uniform conventions governing emerging ethical issues since human rights are universal and scientific innovations quite often find universal application.

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6.7. Super6ision of Health Research Ethics in The Democratic Republic of the Congo

7. International Guidelines for Health Research Ethics

Dr Kakicha Marie Kapepela

Dr Francis P Crawley

Uni6ersity of Kinsasha, National Medical Council

Chairman, Ethics Working Party, European Forum for Good Clinical Practice & Uni6ersity of Brussels

6.7.1. Introduction The Democratic Republic of the Congo (DRC) is bordered by Congo Brazzaville, Tanzania, Rwanda, Burundi, Uganda, Angola, the Central African Republic, Sudan, and Zambia. It has a surface area of 2 635 000 km2, and a population of approximately 50 million people.

This paper was not submitted for publication along with the other commissioned presentations to the Seminar.

8. Burden of Disease in Africa in the Early 21st Century Dr F.K. Nkrumah

6.7.2. National Ethics Committee This Committee was established in the waked of the AIDS phenomenon. It is made up of sociologists, lawyers, doctors, moralists, religious leaders, university representatives, and members of the civil society. The Committee was also expected to have ramifications in the hospital system. Unfortunately this Committee has not become operational because of political instability and the lack of funds.

6.7.3. Other Initiati6es There is the Bioethics Committee which holds meetings to review specific problems such as abortions. Nonetheless, there is no implementation of its resolutions. The National AIDs Ethics Network is in the process of being established at the level of the provinces, and with international financial support. In view of the existing shortcomings, the National Medical Council has set up an ad hoc committee to review research proposals for ethics clearance. This ad hoc committee is working on the basis of the medical ethics code and the recommendations of the National Medical Association, of which the Council is a member. Due to its limited resources, the Council is not able to monitor the various researches being carried out in the country. It is considered to be an extremely urgent matter to make the National Ethics Committee operational.

Research Professor, Noguchi Memorial Institute for Medical Research, Uni6ersity of Ghana

8.1. Assessment of Disease Burden Over the last decade or so an overriding preoccupation in the health development arena, and one which has provoked intense debate among academic circles, policy makers and development agencies, has centered on health care reforms. There is now hardly any African country that in recent times has not, in varying degrees, embarked on some sort of reassessment and prioritization of its health problems under the umbrella of health sector reform. One of the dominant themes that can be universally identified in almost all health sector reform concepts, relates to identifying and responding to the major health problems of nations and populations. Assessment of disease burden and disease prioritization, including monitoring of time trends for diseases, constitute important elements of the health reform. Also in recent years, global, regional, and national burden of disease estimates, have come to be regarded as a prerequisite for health policy development, planning, and allocation of resources. An important element of these reform approaches, particularly promoted by the World Bank, and WHO, has been the emphasis on using analysis of burden of disease and cost effective-

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ness to identify packages of essential health services that governments must ensure are affordable and universally available. Also, assessment of burden of disease is one of the crucial elements for setting priorities in the field of health research, and for development of evidence based health policies. Traditionally, assessments of disease burden and statistics on the health status of populations, have utilized epidemiological methods of morbidity and mortality. Such data, collected usually through routine reporting systems are often partial, fragmented, and inadequate for the needs of decision and policy makers, even when the quality of the data is good. Such data alone may fail to capture the impact and therefore the true health needs of a population, regarding non-fatal but serious conditions like mental illness such as depression, alcohol dependence, and schizophrenia. Such illnesses have been usually seriously underestimated in the assessment of total disease burden by traditional approaches that take account of deaths without considering disability.

8.2. Disability Adjusted Life Years Recently in an attempt to overcome the problem of more accurately quantifying disease burden, a new measurement concept known as the disability adjusted life year (DALY) has been introduced and is being promoted globally, especially by international health and development agencies. The measurement actually expresses health life in year(s) either lost or gained. This method (Murray and Lopez) quantifies not merely the number of deaths but also the impact of premature death and disability on a population and combines these into a single unit of measurement of the overall ‘burden of disease on the population’. Each DALY indicates the loss of a year’s healthy life i.e., time lived with a disability or time lost through premature death. The higher the number of DALYs, the greater the disease burden. The DALY captures the impact of long term disability, premature deaths, and provides information that is absent from traditional mortality statistics. Another advantage of disease burden assessed in DALYs is that it can be used to

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measure the outcomes of interventions for specific health problems in term of DALYs averted by applying a particular intervention. Thus the relative costs of different interventions can be assessed in uniform and comparable manner. Current efforts continue to refine the DALY indicators (1).

8.3. Magnitude and Causes of Disease Burden in Africa In the past quarter of a century, Africa’s struggle to overcome diseases has produced a mixed record of success. Mortality rate for children under 5 has been cut in half and life expectancy has increased by more than a decade between 1950– 1990. Despite these modest achievements, life expectancy in sub-Saharan African is currently only 51 years compared to 62 years for all low income countries and 77 years for high income countries. At the close of the 20th century the disease burden in Africa still remains formidable. Communicable diseases, malnutrition, the childhood cluster of diseases, maternal and perinatal problems, still constitute major disease burden on large populations in the region. Africa certainly enters the 21st century with an unfinished agenda for health expected to be projected beyond year 2000. The profile of disease burden would probably not change substantially, for the next decade or so into the new century, although general health status will continue to improve, but new health challenges and health threats will emerge.

8.4. Future Patterns of Disease Burden in Africa Life expectancy is expected to continue to improve, as under-5 and maternal morbidity and mortality continue to decline through cost-effective intervention packages such as EPI, Integrated Management of Childhood Diseases, Safe Motherhood Programmes, and increased access to knowledge and health care. Although in general terms the share of communicable diseases is expected to decline as mortality rates and birth rates fall, specific communicable diseases will pose new health threats and challenges. HIV infection is likely to continue to spread in sub-Saharan

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Africa, with significant increases in AIDS deaths. The demographic impact of HIV/AIDS especially in the hardest hit countries will be dramatic over the next decade. For example, the average life expectancy at birth in nine Africa countries with an adult HIV prevalence of 10% or more, is projected to reach 48 years by 2000, whereas it would have reached 57 years in the absence of AIDS. By 2010–2015 the average life expectancy in these countries would be only 47 years. In the absence of AIDS, it would have been expected to reach 63 years. Drug resistant infections such as tuberculosis, malaria, other vector-borne endemic diseases such as onchocerciasis, and schistosomiasis, are likely to continue being major health problems well into the early next century. Human behaviour and or environmental degradation, population migration, poverty, new commercial and economic activities, and population pressures, will certainly continue contributing to the spread and effects of existing communicable diseases. Important new health challenges will also emerge over the next two decades in Africa, and will relate to significant increases in non-communicable diseases arising from continuing demographic and epidemiological transitions. Demographic transition will arise from and reflect changes over time in fertility and mortality, and epidemiological transition will reflect changes in health conditions resulting from increases of risk factors for non-communicable diseases such as smoking, alcohol, dietary changes, stress, pollution, and violence. Already adults under the age of 70 years in sub-Saharan Africa today face a higher probability of death from a non-communicable disease than those of the same age in the established market economies. The impact of such transition changes on future disease burden pattern, is difficult to assess or predict but generally noncommunicable diseases such as mental illness, cardiovascular diseases, hypertension, cancer, injuries, are expected to significantly increase as a result of these transition changes over the next 2 decades. These changes are expected from the rapid aging of the developing world’s populations. As a

population’s birth rate falls, the number of adults relative to children increases, and the population’s commonest health problems become those of adults rather than children. This so called ‘epidemiological transition’ is already much further advanced than many health specialists appreciate. In all regions the rapidity of change and the very large absolute numbers involved, will pose serious challenges to healthcare systems, and force difficult decisions about the allocation of scarce resources. Yet until now, many governments have lacked even the most basic data they need to assess priorities for public health or even the social response to these changes. As the population in Africa grows older, noninfectious diseases are expected to become important causes of ill health. Given the economic difficulties in the African continent, the rapidity with which populations are aging, lack of social infrastructures, and decline of traditional care provided by family members, only a few countries will be able to provide the required specialized health care, for example for cancer and cardiovascular conditions. The next 2 decades will see dramatic changes in the health needs of the world’s developing populations. In the developing regions where four-fifths of the planet’s people live, non-communicable disease such as depression and heart diseases are fast replacing the traditional enemies such as infectious diseases and malnutrition, as the leading causes of disability and premature death. By the year 2020, non-communicable diseases are expected to account for seven tenth of the deaths in the developing countries, compared to the current ratio of less than half. Injuries, both unintentional and intentional, are also growing in importance, and by 2020 could rival infectious diseases worldwide as a source of ill health. Of the unfinished agenda for health, poverty remains the main item, which by all intents and purposes, Africa will likely carry into the next century. Of the 1.3 billion people in the world estimated to live in extreme poverty of surviving on less than US$ 1 per day for all their needs, Africa has an unfortunately significant and unfair proportion. These are the people with no access to

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health services, education, and have limited prospects for a better life. For them poverty constitutes the major burden of disease first and foremost. As we enter the next millennium, let us hope that the economic, social, and civil strangleholds creating and sustaining widespread poverty, and resulting into unacceptable disease burden on the continent, will be alleviated and or averted, respectively. Let me conclude by reiterating that the burden of disease in Africa in the early 21st century, will be influenced by a number of predictable and non-predictable factors including: “ Income growth and poverty alleviation; “ Impact and rates of demographic and epidemiological transitions; “ Access to health care and technologies; “ Public health control of endemic and non-communicable diseases; and “ Burden of disease resulting from such risk factors as tobacco, alcohol, unsafe sex, violence, pollution, and stress.

8.5. Conclusions 1. Mortality from the childhood cluster of diseases and maternal mortality would decrease significantly. 2. Non-vaccine preventable and communicable diseases such as malaria, HIV/AIDS, and tuberculosis, would still pose a great challenge to African populations. 3. Non-communicable diseases such as hypertension, strokes, heart diseases, and injuries will increasingly contribute to premature deaths and disability.

8.6. Reference 1. Murray CL and Lopez AD: The Global Burden of Disease: A Comprehensi6e Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020, Harvard University Press.

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9. Traditional African Perception of Illness Prof. GL Cha6unduka Uni6ersity of Zimbabwe, Harare, Zimbabwe

9.1. Introduction The presence of mild ill health, is regarded by many people as a normal part of life. It is believed that people cannot always be in very good health because of poor living conditions and the presence of spirits and witches in society. But if the symptoms persist and are severe, the individual is likely to enter the second stage in which he adopts the sick role. At this stage some individuals seek professional help at once but others delay seeking medical care for as long as possible, and employ known traditional drugs or patent medicines suggested by friends, neighbours or relatives. There are many factors which may motivate patients to delay in seeking medical care. Such factors as fear of hospitalization, disturbing family life, social relations, leaving the familiar surroundings of home, unpleasant past experience, financial cost of medical care, and social stigma. Many sick individuals before seeking professional help, make contact with others with whom they have close ties. Such contacts may be made with members of their family, friends, neighbours, work-mates, and employers. These people influence the sick individual in the choice of therapy, and usually continue to take care of the sick person throughout his illness. Many people take some of their illnesses to modern medical practitioners in hospitals, clinics, and private doctors’ surgeries and others to traditional healers. In some cases the same illness is referred at different stages and sometimes simultaneously to several types of medical practitioners. There is a relationship between people’s ideas concerning the cause of illness and the treatment sought.

9.2. Normal and Abnormal Illnesses Many people believe that illnesses may have either a normal or an abnormal cause.

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Illnesses such as coughs, slight fevers, stomachaches and headaches are generally regarded as normal since they occur from time to time in the lives of individuals, are usually of a fleeting nature, and may disappear completely even without treatment. Normal illnesses are usually treated with modern or traditional medicines. Choice of treatment in this kind of situation largely depends upon the cost of each type of treatment, its accessibility, and the patient’s knowledge of the probable effects of each kind of treatment. Many people agree that normal illnesses are caused by such things as germs, bacteria, bad food, accidents, poisons, and so on. When an illness such as headache or a stomachache persists over a long period of time, it ceases to be a normal illness because it is considered unusual for a headache or a stomachache to fail to respond to treatment. The illness is then regarded as abnormal. Many people believe that such illnesses, are sent by social agents such as ancestor spirits, angered spirit, alien spirits and witches. Many of the patients with an illness defined as abnormal, will consult traditional healers alone because they know that most modern doctors are unable to attack the ultimate cause of such an illness. An angered spirit is of someone who died with a grudge. It is believed that an angered spirit may return to punish the wrongdoer or his kinsmen. The guilty person or his kin may become sick. An alien spirit is of a person from some other clan or tribal group who died uncared for, or perhaps was not properly buried according to custom. It is believed that the spirit of such a person may wonder restlessly until it settles on someone. The patient’s kin or relatives play an important role throughout the illness, partly because in certain cases relatives are held responsible for an individual’s illness, and can therefore be considered as extended patients. A much clearer example is where a member of the family commits an anti-social act. The angry ancestors may choose not to punish the wrongdoer with illness, but may do so to a brother, children, or any other kin. Many people who refer their illnesses to modern practitioners, may later take the same illness to traditional healers.

This often happens when the illness which was initially regarded as normal, is redefined as abnormal by the patient and members of his or her social group. This tendency to regard an illness initially as normal and later as abnormal occurs when: (a) modern medicines fail to achieve the expected results; (b) there is a worsening or failure of illness to respond to treatment; and (c) development of additional symptoms which are believed to be either peculiar or unusual to Africans.

9.3. Mitigating Factors for Health Care Seeking Patterns Many patients who choose traditional medical aid initially or switch to it eventually also seek modern medicine again. This change of therapy is more likely to occur in the following circumstances: “ traditional medicines fail to cure the illness; “ the patient and or his social group suspect illness causes which are not confirmed by traditional practitioners, are unable to accept the traditional practitioner’s diagnosis, uncertain about the diagnosis or prognosis of the illness and are willing to try both approaches to healing; and “ when symptoms which were initially regarded as strange or supernatural disappear. In certain cases the same illness is referred at different stages or simultaneously to both modern and traditional practitioners. This happens where people involved have made a distinction between medicine and traditional practice. Many modern medicines are often better than traditional medicines: they relieve symptoms better and faster than many traditional medicines. It is for this reason that now many people when ill resort to modern medicine. On the question of medical practices, however, western ideas have little in common with those found in Africa. Practices, such as change of climate, exercise, and cutting down on smoking are not generally found in African culture. On the other hand, such things as offerings to placate spirits or ancestors,

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rubbing oneself with a chicken or goat in order to transfer the sickness to that creature, are not generally recommended by modern doctors as curative techniques. Thus, the power of modern medicines in relieving symptoms may be sought from the modern doctor, while the practices suggested by the traditional healer for relieving the basic cause of the illness, plus the hope he gives the patient, may also lead the patients to him. These facts should alert us to the possibility that the process by which the definition of the illness is arrived at, the people making the definition, and the situation in which the definition is made may all be important in understanding illness behaviour. The inclusion of spirits in a discussion of causes of illness often puzzles many modern medical scientists. Spirits are unobservable objects. And because of this they belong to a realm about which the western scientist has no accumulated empirical knowledge. Western or modern medical science has, therefore, tried to disown this level of knowing. Modern medicine is rooted in scientific method; illness is viewed as a natural phenomenon which can be explained in terms of physical processes, and therefore curable by rational methods. Traditional medicine has added another dimension, that is, non-scientific or subjective knowledge. Traditional healers use both scientific and non-scientific knowledge. They are right because medical knowledge is, in fact, produced in a variety of objective and subjective ways, and medicine deals with human beings who exhibit both objective and subjective dimensions. Non-scientific or subjective knowledge has a place in the practice of medicine. Psychology can help us understand one way by which spirits can cause illness. People who believe in spirits can become sick as a result of this belief. They believe, for example, that ancestors can punish them if they commit certain anti-social acts. The ancestors, when offended, can punish an individual with illness and, in extreme cases with death. Thus, when people who believe in spirits commit certain anti-social acts which they believe will offend their ancestors, they may well become sick. After all, what people believe to be true is true in its consequences. Emotional shock induced

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by prolonged and tense emotion due to the belief that one has been attacked or is about to be attached by spirits is often sufficient to cause illness or death. Because these spirits are considered to be of such immense importance in the general conceptions of health and illness, religious rituals, invocations, and thus magical methods constitute integral parts of African traditional medicine and are often applied to the advantage of patients. Witchcraft is another major cause of illness. Many people agree that witches exist in society. On the other hand, modern science has taken the view that witches do not exist except in the minds of certain people. This difference of opinion has been caused by two main factors. There is, firstly, the absence of a shared, clear and correct definition of African witchcraft. People who take part in the witchcraft debate do not usually argue about the same thing. The second cause of conflict has been the reliance on the part of many people on the English or European literature relating to witchcraft. It is from this literature, and not from personal experience or research, that their ideas of witchcraft were acquired. There are important differences between European and African witchcraft ideas. Witchcraft in Africa includes the use of harmful medicines, charms, magic, and any other means or devices in causing any illness, misfortune or death in any person or animal or in causing any injury to any person, animal, or property. The connection between the use of certain types of harmful medicines and illness, can easily be demonstrated. Other ways such as the use of certain charms and contagious magic are more complex. It is important, however, to bear in mind that many people who accuse others of witchcraft are not seeking a legal ruling on the matter. The accusation may be a response to situations of anxiety and stress or a means for the expression of social strains and tensions. The accusation may also be a means of social control or of social rupture, or a means of adaptation to rapid and disruptive social change. These are not legal issues; they are cultural, social and psychological issues that nonetheless call for urgent attention. In other words, it is not always

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helpful to try and prove whether an individual accused of witchcraft is in fact a witch; it is often more useful to examine the events that led to the accusation of witchcraft, and attempt to solve the social problems involved. Many people believe that abnormal illnesses may to a certain extent be avoided or prevented by wearing charms, making the necessary offerings to the ancestors, behaving in such a way that does not make enemies, and avoiding places where witches may attack one. But all these measures may fail. Curative measures must then involve the use of medicine to correct the bodily condition, and also rituals to remove the basic cause.

10. Traditional African Perception of a Person: Implications on Health Research Ethics Godfrey B Tangwa, PhD Associate Professor of Philosophy, Uni6ersity of Younde 1, Cameroon Wir dze¨ wir! (A human being is a human being, simply by being a human being)

10.1. Abstract The dominant western conception and perception of a human person and an African view, are discussed and compared with regard to ethics implications for health care and research. The western conception of a person, as a self-consciously rational free chooser, has the implication that some human beings such as infants and severely mentally handicapped adults, are not persons, possess less moral worth, and therefore deserve less moral consideration than paradigmatic human persons. The African conception, on the other hand, applies to the human being in all its developmental stages, its possible contingent conditions, and therefore has no such implications. The western definition of a person seems to me to specify necessary and sufficient criteria for moral responsibility, liability, and culpability, rather than moral worth or desert. Moreover, the con-

ception seems to be basically a value judgment necessitated by economic imperatives, the need for scientific progress, and technological refinement that ought to be subjected to moral evaluation.

10.2. Introduction In ‘Lamnso’ which is my nataive language, there is the saying: wan dze¨ wan a dze¨ lim Nyuy, meaning a baby/child is a baby/child and a handiwork of God. It signifies the unconditional acceptance of a neonate, irrespective of how it comes about, no matter how it is, no matter its particularizing and individuating physical and mental attributes. Wan dze¨ wan develops directly into wir dze¨ wir at the level of the adult human being. Wir dze¨ wir can best be interpreted and rendered into English by saying that ‘a human being is a human being is a human being, purely and simply by being a human being’. The implication is that, the Nso’ who are the indigenous speakers of Lamnso’, surely make distinctions between babies, infants, children, young persons, adults, and elders, etc. The Nso’ society is a very hierarchical one with great respect accorded to titled individuals, age and experience, and can further regroup those who fall within any of the above categories according to any putative criteria of discrimination. Such categorizations and bracketings do not carry any moral significance or implication. The Nso’ morality is human centred in the sense that only human beings are deemed to be moral agents, with moral obligations and responsibilities, but not in the sense that moral consideration and concern are limited to human beings. Human beings have putative moral obligations, duties and responsibilities towards God, non-human animals, plants and inanimate nature and things, but these are not considered as being in any sense reciprocal (1). To some people the definition of ‘morality’ and ‘ethics’, may be directly the opposite to that of Joseph Fletcher, the Father of Situation Ethics, which most western scholars would endorse. Fletcher defines morality as ‘what people do in fact believe to be right and good’ and ethics as ‘critical reflection about morality and the rational

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analysis of it’ (2). Critical rational reflection about what is right and good. It is what I conceive as morality whose chief regulatory mechanisms are rationality and moral intuition. Ethics to me is a sub-set or derivative of morality, designating any set of specific general principles by reference to which any particular act, action, process or procedure can be morally evaluated. Morality is to ethics what thinking is to logic or religion to theology. The two terms are, of course, as Fletcher does recognize, justifiably used interchangeably in practice without much harm. Morality should not be confused with mores, and ethics with ethos. Critical discourse is necessary and possible at all levels. From the point of view of logic, wan dze¨ wan wir dze¨ wir may sound like mere contentless tautologies, but they connote, within their linguistic and cultural universe, the reverential respect with which anything human is considered, approached and treated, without regard for further particularizing credentials. Wan dze¨ wan/wir dze¨ wir are also plastically loose and flexible with regard to what they encompass exactly. The term ‘wir’ stands indiscriminately for both human being and human person as typically distinguished in western discourse while ‘wan’ performs the same function indiscriminately for child (irrespective of age), infant, baby, etc. But this imprecision and plastic flexibility may bear exactly what is required. The meaning of wan/wir is evident without being spelt out in precise detail. It is like a big Bamenda gown which is never made to be tight and can fit many different people of greatly differing shapes, sizes and other particular specifications, as well as a single individual through his/her changes in bodily shape, size and weight. Any attempt to nail either of these terms, is as it were, unto a hard analytic frame by, for instance, attempting to specify necessary and sufficient criteria, conditions or capacities for being human or for being a child, would make it evaporate into thin air. Western philosophy has a perennial obsession with the concept of a person and criteria for person-hood, aimed at isolating and clearly defining those entities deemed worthy of moral consideration as against those without or with less moral worth. This attempt at segrega-

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tion and discrimination has greatly compounded and confused moral discussion and deliberation on bioethical issues such as those relating to birth, health, and death. There have been great debates, for instance, as to the moral status of fetal material, fetuses, human infants, children, mentally defective people, brain-dead patients, animals, plants etc, all with assumptions and implications about how they can or should be used and or treated. It has been stated in a very influential book inter alia, that not all humans are equal (3). Health care confronts individuals of apparently widely divergent capacities: competent adults, mentally retarded adults, children, infants, and fetuses. These differences are the bases of morally relevant inequalities. Competent adults have a moral position not held by fetuses or infants. In addition, there are social inequalities among competent adults as a consequence of disparities in social power and wealth. The wealthy may buy goods and services not available to the less fortunate. These inequalities reach into the central fabric of health care decisions. Persons, and not humans, are special. Morally competent humans have a central moral standing not possessed by human fetuses or even young children. It is important to understand the nature of these inequalities in some detail, for physicians and medical scientists intervene in numerous ways in the lives of adult humans, children, infants, fetuses, and laboratory mice. There is a need to understand in some detail why secular obligations of respect or of beneficence vary according to the moral status of the entities involved. Only persons write or read books on philosophy. It is persons who are the constituents of the secular moral community. Only persons are concerned about moral arguments and can be convinced by them. Only persons can make agreements and convey authority to common projects through their concurrence. To choose, to make an agreement, is to be conscious of what one is doing. It requires the self-reflexivity of self-consciousness. Otherwise, there is a happening, and not a doing. Persons are defined as ‘entities who are selfconscious, rational, free to choose, and in possession of a sense of moral concern’. It is concluded

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that human ‘fetuses, infants, the profoundly mentally retarded, and the hopelessly comatose’, are non-persons having no ‘standing in the secular moral community’ and fall ‘outside of the inner sanctum of secular morality’. It is also suggested that a score of 20 on the Binet Scale of IQ be taken as the minimum or base line for determining personal status (2). What this elaborate trend of reasoning really establishes is that only human persons are moral agents, carrying the whole weight of moral obligations, responsibilities and duties on their shoulders, not that human persons possess greater moral worth and deserve greater moral consideration than other beings. It would appear evident, for instance, that a human infant or a mentally or physically handicapped human being deserves, if anything, even greater moral consideration than a paradigmatic human person as described above. The morality of a putative action or procedure is to be determined from the standpoint of the agent rather than that of the patient. In other words, a moral agent, such as a human person, can do moral good or evil, irrespective of whether the patient of his/her action (or lack thereof) is a human person/being, a non-human animal, a plant or even an inanimate thing. What the attributes of self-consciousness, rationality, freedom of choice and, we should add, intelligence, and power and wealth, in all their manifold manifestations, do, is to load the heavy burden of moral liability, culpability and responsibility on the shoulders of their possessor. Human persons are not morally special, they are morally liable, or, to put it another way, human persons are special only in the sense that they alone bear the weight of moral responsibility and are morally liable and culpable. In recent times, there has been an attempt by some western thinkers, especially ecologists, vegetarians, animal rights activists and biocentrists to move away from the anthropocentric/person focus of western moral thinking and discourse (4 – 7). It seems very difficult for thinkers of the western world to abandon the justificationist approach. In ethics, it is only a part of a broader epistemological paradigm which has been termed

‘classic justificationism’. According to this approach, any claim to deserve being considered as knowledge, must be fully justified or proven to be certain. A Cartesian epistemological obsession of western modernism is that post-modernism has done little to diminish or entertain this thought. A fallibilistic approach, which takes proper cognizance of human epistemological and other limitations, and which is to be found in the work which has been clearly proposed by some western thinkers such as John Dewey, Charles Peirce, and the late Karl Popper, all has been completely ignored in western discourse. Western ethical theory has greatly concentrated on the object (patient) of morality to the neglect of the subject (agent), probably because one of the greatest forces of western culture has been the principle that ‘might is right’, as is exhibited in exploitation, imperialism, colonialism, domination, and monopoly commerce. These things have given the western world and its culture a clear head start and lead in the long-distance race of human survival, well-being and prosperity. By concentrating on the patient rather than the agent of morality, westerners have been able to shift critical moral attention from themselves and their actions onto their victims. In that way, they have been able to carry out colonization, enslavement, and exploitation with a quiet conscience, and by stipulating ‘objective’ criteria and conditions for, say, being human that the victims of their actions did not clearly fulfill. It is an astounding fact, for instance, that western colonialists could describe some of the sorts of sophisticated cultures and civilizations they came across in Africa and other parts of the so-called third world as savage and barbaric. They may, of course, have honestly perceived them as such; but such perception was likely affected by the motivating agenda of the colonization, domination and exploitation enterprise.

10.3. Group Perception It is a very philosophical question inquiring about how any identifiable group of people perceive something. A group, even of thinking beings, is not a thinking thing and does not have a

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mind of its own to perceive or think with. The idea of a collective mind is only a metaphor and, in western philosophical literature, the critical examination of perception has often led to either epistemological skepticism or solipsism. Nevertheless, any identifiable group of people, sharing a common culture and world-view, necessarily shares certain ideas, convictions, attitudes and practices which can be attributed to it as a group, without any implication of exceptionlessness at the level of the individual. From this perspective, it is important to remember that, in every society or human community, there are two types of philosophy (oral or written)-latent and forensic. The forensic philosophies of a society or community are those openly admitted, recognized, presented or even propagated as such, and are thus usually more palpable. They could easily be mistaken for the whole of that society’s or community’s philosophy. Latent philosophies, on the other hand, are those which may be unconsciously accepted, not openly recognized or presented as such, but which, nevertheless, are manifested in attitudes, habits, practices and actions. They provide the general framework for the society’s or community’s world-view, belief systems, customs and recurrent practices. Controversy and disagreement are the marks of forensic philosophies while consensus is the chief attribute of latent philosophies. If we over-emphasize the critico-analytic attribute of philosophy, it may appear as if latent philosophies are not philosophies at all. But latent philosophies are no less philosophic than their forensic counterparts, just as oral philosophies are no less philosophies than written philosophies. We could even say that the latent philosophies of any society or community are more important than its forensic philosophies because they are the philosophies the people live by, rather than merely talk about. They are the reasons or grounds people act or react the way they do, do the things they do, refrain from doing the things they refrain from doing, and have the attitudes they have. The process by which communal consensus is reached on any controversial issue in any society, clearly shows that latent philosophies must once have been forensic, and that they generally transform from these.

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Moreover, it is the legitimate ambition and aim of every really earnest forensic philosophy to become, as far as possible, a latent philosophy. This is quite important because, in the domain of morality, correct practice, even without any theory, is, by far, better than correct theory without practice. Failure to fully appreciate this simple analysis of the nature and character of philosophy misled western trained African philosophers into a sterile debate that lasted almost a quarter of a century, about whether or not there was African philosophy comparable to the western one. Perception is connected more with latent than with forensic philosophies although erroneous or non-veridical perceptions are typically corrected by means of the latter. In fact, one of the proper missions of forensic philosophies in any society should be a constant re-examination and calling into question of its latent philosophies. At the forensic level, nearly all western societies and culture, in general, preach freedom and equality, autonomy and brotherly love for a neighbour as oneself. However, in practice at the latent level, possessive individualism, greed and survival of the fittest, seem to be more predominant and more successful. If we stay at a superficial level, we might rashly jump to the conclusion that Christianity is today quite peripheral and unimportant in western societies, rank with secularism and materialism as they are. In fact Christianity has greatly shaped western ways of thinking, talking, acting, and the general development of western societies. By and large, westerners live their lives within the framework of latent Christianity, even if they overtly seem to have rejected this religion. Similarly, many Africans, at the forensic level, today profess and adhere to Christianity (one among many of Africa’s colonial legacies), but live their lives, at a deeper level, according to the consolidated latent philosophies and implicit ideas of paganism and their traditional world-views. At the forensic level, African traditional religions, alias or paganism, would seem to be no match for Christianity with its sacred scriptures, prophets and preachers, clergy and liturgy, basilicas and cathedrals, catechisms, and missals. But, at the latent level, it is quite plausible to suggest that, in essence, paganism is equal, if not

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morally superior, to Christianity on account of its spirit of humility, absence of particularisticing self-righteousness and disinterestedness in proselytisation and accumulation of material acquisitions.

10.4. Perception of a Person In talking about the traditional African perception of a person, one could abstract for a specific prescriptive purpose. The abstractions is this presentation are based on the known cultural background of the Nso’ of Bamenda in Cameroon, and other African peoples and groups. In practically all essentials, African peoples, cultures, metaphysics, systems of ideas, outlooks, attitudes, customs and practices are very similar, if not entirely exactly the same. This close family resemblance, which is analogous to the family resemblance of western peoples and cultures, in spite of their particularizing and differentiating differences, is enough for my analytic purposes here because my generalizations, critical emphases and prescriptive statements do not need to be universally exceptionlessly true to be valid. In the book, Philosophy and an African Culture, Kwasi Wiredu critically and very amply discusses the underlying similarities and common elements of African cultures. The author notes that Africans among other things, have a communal outlook, similar approaches of consensus in resolving disagreements, importance attached to rhythm in art and to ceremonial, ritual and reconciliation, polygamy and love of large families, spontaneity, and hospitality (8). This author also highlights some of the common fundamental ailments and weaknesses of African cultures, such as the tendency to anachronism, authoritarianism, and avoidance of exact precision in measurements and supernaturalism. All these similarities and others, justify the employment of the adjective ‘African’. In general, it could be said that the African concept of a person is not and, in fact, cannot be any different from the western concept of a person. For both African and western concepts, the person is a self-conscious, rational, free and self-

determining being, unless there is some linguistic problem of translation or interpretation. If the African perception of a person is different from the Western perception, this is not because it does not recognize the various developmental stages of a human being, qualitative differences based on the degree of attainment of positive human attributes, and capacities. Rather, it is because the African perception does not draw from these facts the same consequences as are drawn in western ethical theory and practice. In particular, the African perception of a mentally retarded individual or an infant, as not being ‘equal’ with a fully self-conscious, mature, rational, and free individual, does not entail the consequence that such a being does not fall within the ‘inner sanctum of secular morality’, and can or should thus be treated with less moral consideration. Whereas the western preoccupation with person-hood, seem to be dictated by the need to draw such a consequence, it ought to be said that the African concept and perception of the human person are totally different. The African concept and perception of a human being applies to the human being in all its developmental stages and to all its possible contingent conditions. The western concept of a person is a value judgement rather than a descriptive abstraction. This value judgement, moreover, would seem to be dictated by economic considerations and the need for scientific progress and technological refinement. Science, technology and commerce constitute the unholy trinity of engines behind the constant rethinking of moral categories in the western world. It is instructive to note, for instance, that, until organ transplantation became a reality, western thinkers and moralists were not preoccupied with ‘defining death’, a task for which a ‘presidential commission’ was even set up in the USA in 1964. The current western classifications of peoples, cultures, nations and countries into: first, second, and third; advanced, advancing, and backward; developed, developing, and under-developed; resource rich and poor; are equally mainly a value judgement. They serve similar purposes, rather than a descriptive abstraction to which real content can be assigned.

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The African concept and perception of a person are related to its metaphysical ideas and worldview, which I have described as eco-bio-communitarian (9, 10), implying the recognition of plastic walls as well as interdependence between human beings, super-human spirits, non-human animals, plants and inanimate objects and forces. Within this world-view, transmigration, reincarnation, transformation and transmutation, within and across species, is believed to be possible. This has consequences as to how human beings regard what we may call the other items of the furniture of the universe, especially other living species. The result is an approach towards nature and all living things that is cautious, reverentially respectful, almost ritualistically ceremonial. All this engenders a deep-seated attitude of live and let live, be and let be, which finds practical expression in such practices as the system of consensus for resolving inter-personal and inter-community disagreements and differences. Julius Nyerere, the father of Ujamaa, has popularized the image of African elders sitting under a tree and discussing until they agree.

10.5. Implications on Health Research Ethics Traditional African societies were marked by an egalitarian impulse and leveling tendency that have been greatly eroded today by the colonial impact and contact with western culture. In traditional Nso’, for instance, wealth, by itself, did not confer any social status and, to gain social status, a wealthy person normally had to swap virtually all his wealth for redistribution in exchange for titles and honours. Within the context of awe and respect for ‘the other items of the furniture of the universe’, as exhibited through sundry taboos, human well-being was certainly prioritized. One aspect of this prioritization of human well-being was the very high value accorded human health. Health was seen as the value of all values, the value that made other values possible and achievable. As long as one was healthy, little else mattered and all other achievements were within the bounds of the possible. The Nso’ fear ill-health and suffering more than death. A si ngeh bong

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kpuh (death is preferable to irremediable suffering) so goes the adage. In traditional Africa, therefore, the arts of diagnosing illness, treatment, healing, and the practice of medicine generally, were considered as a life-long vocation rather than a profession or mere occupation. The practitioners of such arts were considered as specially gifted. Sometimes their skills and special innate endowments were detectable at birth, and sometimes they were acquired through long and dedicated free apprenticeship and tutelage under a master. These practitioners normally did not charge any fees for their very specialized services, under fear of losing or diminishing their special powers and endowments, although beneficiaries of their services, generally, as a matter of custom, always voluntarily came back to ‘thank’ them with appropriate gifts. Health care within traditional Africa was thus within the reach of all and sundry, irrespective of their social status or economic situation, because the only condition for access to health care and treatment was that one was ill. Recently, on my advice my mother to come from my native village of Ndzenshwai-Shisong to undergo medical consultation and treatment in our capital city of Yaounde. After we had been in and out of consultation rooms, laboratories, and pharmacies, and taking notice of the off-handed levity with which patients were treated, the amounts of money that changed hands at all stages of the process, my mother remarked that ‘medicine and commerce are very bad companions’. That remark neatly captures what we really need to keep in mind when deliberating on the ethics of health care and research in Africa. It would be extremely naive and illusive to suggest or think that we could walk backwards, as it were, and recapture the entire receding African traditional past, reverse the direction of its flight, so that it can accompany us into the 21st century. What is both realistic and absolutely imperative is to try to salvage the most important values and ideas of the African past, to modernize them where necessary, and to take them along with us wherever we may be going, and to globalize them wherever possible. The most compelling of such values are the ethical ideas which in principle and

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by their very nature, are universalizable, transcend space, time, and all contingent circumstances. In Africa today, we therefore need to tackle two fundamental projects of modernizing and globalizing the best of our traditional values, and truly indigenizing ideas, values, and practices, borrowed from other cultures and value systems, especially western ones with which Africa has a rather special relationship. In general, there is no doubt that western modern medicine, technologies and techniques, based as they are on science and the scientific method, are superior to African traditional medicine, which was rather weak in its techniques of diagnoses, pharmacology, and systematization of knowledge. But western medicine and medical technologies, like western culture and technology in general, have the fatal weakness of being driven and controlled by apparently morally blind economic forces and interests. Economic determinism rules the western world and culture to the extent that even ethics issues are couched and discussed in economic terms and language. The most imperative of moral categorical imperatives seems to leave the western world unimpressed and unruffled, unless it is somehow stated in terms of or connected with economic and marketing considerations and cost benefit analysis. The book Ethics of Genetic Control: Ending Reproducti6e Roulette (2), is a paradigm of American big thinking and talking. It is very impressive by both its very engaging arguments, and its preponderant and repeated use of economic concepts and vocabulary. The expressions include ‘quality control’, ‘increasing the quality of the babies we make’, ‘human reconstruction of humans’, ‘biological manufacture of human beings to exact specifications’, ‘variety of combinations and permutations in reproductive methods’, ‘controlled human baby making’ ‘Homo autofabricus’, ‘baby machines’, ‘seedcasters’, ‘make choices and contrive controls’, ‘uncorrectable fetuses’, ‘the womb is a very dangerous place-a hazardous environment’ ‘banking of human sperm’, ‘discarding the surplus’, etc. The trend and thrust of such thinking has already brought about the commercialization and

sale of human ‘spare’ parts, sperm, ova and the prospect of highly prestigious and expensive designer babies. The economic dimension of life is, no doubt, very important. But the moral dimension is even more important, in the sense that moral reasons are the highest and most compelling that can be given for doing or refraining from any putative action. Purely economic considerations, by themselves, can never morally justify a course of action, whereas any economic procedure can be faulted and disrecommended on moral grounds. It would be ideal to combine the efficiency and efficacy of western science and technology, the western obsession with economics, commerce and maximization of profit, with the moral sensibilities and sensitivities of traditional Africa. Whereas western culture can empower African culture, African culture can humanize western culture. The first step would be to try separating the kernel of western science and technology from its western packaging including the entire value system, assumptions, expectations, propaganda and promotion surrounding it. We must learn to put western science and technology to different and more humane uses.

Acknowledgements I would like to thank the Hastings Center, Garrison, New York, and particularly its Director of International Programs, Daniel Callahan, for his support, and Dr Virginia Ashby Sharpe, for her useful comments on an earlier version of this paper, which was read at the Center on 28 September 1999.

References (1) Tangwa, G.B., 1999. Is Bioethics Love of Life? An African View-Point’, Lab News, Summer Issue 9. (2) Fletcher, J., 1988. The Ethics of Genetic Control: Ending Reproductive Roulette, Buffalo, New York, Prometheus Books.

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(3) Engelhardt, T.H., 1996. The Foundations of Bioethics, New York/Oxford, Oxford University Press. (4) Regan, T., 1983. The Case for Animal Rights, Berkeley: University of California Press. (5) Taylor, P.F., (1986). Respect for Nature: A theory of En6ironmental Ethics, Princeton, New Jersey, Princeton University Press. (6) Warren, M.A., 1997. Moral Status; Obligations to Persons and Other Living Beings, Oxford: Clarendon Press. (7) Wetlesen, J., 1999. The Moral Status of Beings who are not Persons: A Casuistic Argument’. En6ironmental Ethics, 8(3). (8) Wiredu, K., 1980. Philosophy and an African Culture, Cambridge, Cambridge University Press. (9) Tangwa, G.B., 1996. Bioethics: An African Perspective, Bioethics 10(3). (10) Tangwa, G.B., 1999. Questions and Worries from an African Background. In: Thompson A.K., Chadwick, R.F. (Eds.). Genetic Information: Aquisition, Access and Control, New York, Boston, Dordrecht, London, Moscow, Kluwer Academic/Plenum Publishers.

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and licenses all vaccines, biologic therapeutics, and blood products that are marketed in this country. Successful development of products for use in humans is a process that requires the highest level of expertise from both the sponsor and the regulatory reviewer, especially in the case of biologics where unique methodologies are often required. After studies in the laboratory and in animal models demonstrate the safety of a potential biologic, clinical trials are done to show its safety and efficacy in humans. Rigorous assays to validate correct manufacture and maintenance of current Good Manufacturing Practice are critical as the product nears the licensure stage. Final clinical trials are used to support indications that can be included in the label for the product upon licensure. Any modifications in the manufacturing process before or after licensure must be evaluated and validated before implementation. These shared responsibilities between government and the pharmaceutical industry help ensure the advancement of public health and maintain confidence in the safety and effectiveness of marketed products.

11.2. Introduction 11. The Regulatory Review Process in the Licensure of Biologics Hira L. Nakhasi, PhD and Richard T. Kenney, MD Laboratory of Parasitic Biology and Biochemistry, Di6ision of Bacterial, Parasitic, and Allergenic Products, Office of Vaccines Research and Re6iew, Center for Biologics E6aluation and Research, US Food and Drug Administration

11.1. Abstract In the US, the Food and Drug Administration is charged with fully evaluating the manufacturing, pre-clinical, safety, and efficacy data of all products for human use as they move through the period of clinical evaluation, while maintaining the rights of patients in high esteem. The Center for Biologics Evaluation and Research regulates

The US Code of Federal Regulations (CFR) defines a ‘biologic’ as any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man [21 CFR 600.3]. This includes all types of vaccines, blood and blood products, allergenic products and diagnostics, and therapeutic proteins. The Center for Biologics Evaluation and Research (CBER) is charged with the regulation of traditional biological and wellcharacterized biotechnology products based on sound science, federal law, and public health impact. At CBER this is achieved by implementing a researcher/reviewer staffing model, which means involving scientists in the regulatory process who are trained as both researchers and reviewers. Regulations pertaining to biologics are contained in the Code of Federal Regulations (CFR); CFR Volume 21 series 200s, 300s, and 600s deal with most of the issues pertaining to biologics. Legal authority for these derives from the Public Health

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Service Act, first passed by the US Congress in 1944 (1), and the Food, Drug, and Cosmetic Act of 1906 (2), which was updated most recently with the Food and Drug Administration Modernization Act of 1997 (3). We will focus on vaccine manufacture in this discussion; detailed requirements for all types of biologics can be found in the referenced documentation. There is a step-by-step process that is essential for licensure of a biologic product, beginning with the first request to introduce the product into humans. Certain parts of the process are mandated by regulations contained in the CFR that are updated with publications in the Federal Register. In addition, CBER develops guidance documents for industry that address manufacturing and clinical trial issues. While the points contained in these are not mandatory, they represent methods and approaches that are acceptable and can be used as an aide to the development of specific products (see http://www.fda.gov/cber/ publications.htm). As development proceeds, the focus shifts from demonstration of safety to consistency of manufacturing and clinical effectiveness. The licensure process starts with the submission of an Investigational New Drug application (IND), which has three major sections [21 CFR 312.23]. These include the chemistry, manufacturing, and control (CMC) information, the pre-clinical data supporting the use of the product, and the clinical data that includes all protocols and an investigator brochure. Studies in humans are designed primarily to study the safety (Phase I), immunogenicity and dose response (Phase II), or efficacy (Phase III) of a product. With few exceptions [21 CFR 312.2 (b)], all clinical investigations of unlicensed biologics are required to be conducted under an IND. The quality of a biologic is assured during the manufacturing process by adherence to current Good Manufacturing Practices (cGMPs), which govern the production, characterization, process validation, and testing of all products. Safety and efficacy are established through pharmacological and toxicological studies in animals followed by clinical studies in humans before licensure. CBER monitors compliance with federal regulations by

reviewing the manufacturing process and data regarding the safety and efficacy of the product and by conducting research in related areas, organizing workshops, hosting advisory committees, and with post-marketing surveillance. A new biologic drug development plan can vary from 3 to 10 or more years, including the research and development of the product and clinical trials (Phases I–III), and culminates in the submission of a Biologics License Application (BLA). The BLA takes about a year to review and finalize, and includes an inspection of the manufacturing facilities. In exceptional circumstances, such as when products are being developed for severe and life threatening illnesses for which there are no established treatments, an accelerated approval process exists. The multitude of steps in the development process requires the expertise of many different people at CBER to review and suggest modifications along the way. The concept of cGMP is essential to maintaining the purity, potency, safety, and effectiveness of a product during its manufacture. Each of these terms can be defined in greater detail [21 CFR 600.3]. Purity is relative freedom from extraneous matter in the final product, whether or not it is harmful to the recipient or deleterious to the product. While many of the more recent biologics contain a single active component that can be ‘well-characterized’, this also applies to crude compounds and extracts and is accomplished by consistency of manufacture. Potency is the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result. Before a product can be marketed to the general population, criteria must be established and tests developed to ensure a predictable result when the product is administered. Safety is the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered taking into consideration the character of the product in relation to the condition of the recipient at the time. Efficacy is the capacity of the product to produce the antici-

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pated result when used in the intended manner. This is usually established in relatively large clinical trials comparing treatment to control groups to demonstrate a statistically significant effect.

11.3. Steps in the Licensure of Biologics 11.3.1. Documentation of the Manufacturing Process The concept of cGMP applies to an evolving set of standards that govern the manufacturing process. The specific application of these standards to the product being studied is contained in the CMC section of the IND, which is modified and expanded as the development process proceeds. CBER has written several guidance documents for the CMC section relevant to vaccines (4 – 6) that discuss the need to provide information regarding characterization of the product (physical and biological), a flow chart of the manufacturing process, description of raw materials, a floor diagram of the manufacturing facility, and contamination precautions. Manufacturing information to be documented in the CMC includes the identification and acceptance of source materials, details about the bulk production, down-stream processing, and final product. To monitor the manufacturing process, a manufacturer needs to develop methods that ensure quality control (QC) and quality assurance (QA) of the product. These methods need to be validated against a standard that can be either pre-existing or developed by the manufacturer. Manufacturers are strongly encouraged to consult the appropriate guidance documents to avoid common pitfalls in the manufacture of safe and effective biologics. (A) Drug Substance and Drug Product There are two main components of the biological product. (a) Drug substance, which is an unformulated active bulk immunogen, and (b) drug product, which contains the drug substance(s) formulated with ingredients such as adjuvants, preservatives, stabilizers and/or excipients. A description of the drug substance and the drug product should include its biological name and derivation (if applicable), physical and chemical properties, and a description of inactive

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ingredients. The drug substance should be characterized for its physicochemical properties and/or its biological activity, and appropriate tests should be selected to confirm these characteristics. A list of potential tests is given in the CMC guidance documents (4–6). For example, some of the commonly used tests are amino acid and nucleic acid analysis, SDS-PAGE analysis, and tests to determine modifications or contamination. Biological activity may be used to determine the potency of biologics when possible, as demonstrated by relevant in 6itro and in 6i6o tests. Detailed and validated manufacturing procedures that ensure, purity, identity, potency, and stability of the product should be provided. (B) Cell Substrate Production of many vaccines involves in vitro culture of the agent itself or culture with living cells as a substrate. Characterization of both is an important component of the manufacturing process, because of the concerns for the potential presence of adventitious contaminants in cellderived biological products. If the cell is of microbial nature, its origin, species, fermentation profile, serotype, virulence, genetic characterization, type of plasmids, and genetic stability should be described.If the cell substrate is of animal origin, the species, age, health, animal husbandry practices of the animals from which the cells were obtained should be mentioned. Description of the preparation of primary or continuous cell lines and demonstration of the absence of adventitious agents should be included. If a stable cell line is expressing a foreign protein, a detailed description of the plasmid, including a restriction enzyme map and complete sequence of the coding and flanking regions should be provided. Detailed guidelines for cell substrate issues are written in several guidance documents (6–8). (C) Cell Banking System Once the cell substrate for the product has been established, a cell banking system needs to be developed to provide a common and consistent source of material. There are two major types of cell banks: the master cell bank (MCB), and the working cell bank (WCB). The MCB is usually made first directly from an initial clone or from a preliminary cell bank derived from an initial clone. The WCB is derived from a MCB and is

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used to make the final product. Characterization of end of production cells (EPC) with the working cell bank is needed to define the maximum number of cell passages without affecting product attributes. Both MCB and WCB have to be characterized to ensure consistency as well as the safety of the product. Various methods to characterize the cell banks, depending upon the cell type, are illustrated in the ICH document on cell substrates (8) and in the CBER guidance documents for the CMC (4–6). (D) Cell Growth and Harvesting The description of cell growth should contain sufficient detail to support the consistency of manufacture of the drug substance. A brief description of all the parameters used to monitor growth should be provided. A list of in-process controls and testing for purity, viability, antigen yields, and phenotypic identity should be included in both the flow chart and the batch records. Methods to control contamination during this process should be described. A description of the methods used for separation of crude drug substance from the propagation system should also be provided. A detailed discussion can be found in the various guidance documents (4). (E) Purification and Down-stream Processing This section should contain a description of the methods and materials by which intermediate forms and the final bulk of the drug substance are separated and concentrated from the cells, media, solvents, or solutions used in the production process. A description of analytical methods developed or adapted by the manufacturer to show identity, purity, concentration, and levels of product related or unrelated impurities should be also included (4). (F) Stability Data of the Final Product The summary of results that support expiration period, under the recommended conditions in the final container and closure system should be provided. A stability study protocol that includes all the tests performed should be provided, and the plan in the case of ongoing stability studies (9).

11.3.2. In6estigational Formulation If an investigational drug formulation was different from that of the final product that is to be marketed, data supporting comparability, bioequivalence, and/or pharmacokinetic equivalence of the two formulations should be provided (10). If the manufacturing process and/or site were different, data from appropriate testing to assess the comparability of the investigational and commercial products should be provided. 11.3.3. En6ironmental Assessment If appropriate, an environmental assessment as outlined in 21 CFR part 25 should be submitted. It should address all the components involved in manufacturing and disposal of the product, and the impact this could have with respect to environmental concerns. 11.3.4. Method Validation Method validation means the documented successful evaluation of an analytical method that provides a high level of assurance that the method will consistently yield reliable and accurate results, within previously established specifications. All release or acceptance testing performed on the bulk or the final product should be provided as described (11). 11.3.5. Current Good Manufacturing Practices for Biologics (cGMP) Section 501(a)(2)(B) of the Food Drug & Cosmetic Act (2) states that a drug shall be deemed adulterated if the methods used in or the facilities or controls used for its manufacture, processing, packing, or holding do not conform to cGMP. These guidelines require a description of the organization, personnel qualifications, and their responsibilities during the manufacturing process to ensure the safety, identity, quality, and purity of the product. In addition, cGMP applies to the design and construction of the manufacturing facility, the equipment used, and to process control for components, drug product, and closures. Air quality of the facility and the water system used in the manufacturing is also important. The types of air quality will depend on the requirement of the level of sterility the product demands. Similarly,

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water quality will depend on the process in the manufacturing scheme. 21 CFR parts 210 – 211, and 600–680 describe in detail the steps needed to follow cGMP conditions (12).

11.3.6. Preclinical E6aluation of Biologics Studies in animals can be used to help define pharmacologic and toxic effects both prior to the initiation of human trials and throughout clinical development (13). Consideration should be given to the selection of the appropriate species, their age and physiological state, the dosage regimen, and the route of administration, as well as the capacity to assess the biological activity, stability, toxicity, and immune effects of the drug. Safety from local and systemic toxic effects, as well as potential immunogenicity, should be demonstrated in relevant animal models before a product is introduced into humans. This frequently includes the need for testing in a non-rodent mammal, such as rabbits or non-human primates, with the goal of assessing the product’s effect at a full human dose. Further pre-clinical studies may be required depending on the nature of the product. Challenge models of vaccine efficacy can be particularly useful to demonstrate the potential for activity in vivo before moving to human trials. 11.3.7. Clinical Studies to Substantiate the Licensure of Biologics The type of clinical trial required for each developmental phase dictates its design, conduct, and analysis, which depends on the outcome of prior studies with respect to toxicity, immunogenicity, and efficacy. There are three phases of clinical investigation. In Phase I, an initial introduction of the product into a small number ( 20 – 80) of humans (either patients or normal volunteers as appropriate to the product) is necessary to assess safety, pharmcokinetics, and immunogenicity of the drug. In Phase II, the immunogenicity of the drug is formally evaluated for one or more indications, and this is typically studied in dozens to several hundred patients. The most appropriate dosage and regimen is established at this time. Phase III trials are used to confirm the effectiveness and safety of a product

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in several hundred to several thousand subjects. These are considered pivotal for licensure and should be large enough to allow an evaluation of the overall risk-benefit relationship. Following licensure, Phase IV studies are often done to assess the potential for infrequent adverse events in a larger population. In designing clinical trials it is important to choose appropriate control groups. There are several types of controls, and their selection depends on the intent of the comparison. Examples include dose escalation studies, notreatment controls, dose response controls, external controls, and placebo controlled trials that are usually double blinded. There are several factors that can affect the outcome of the clinical trial. These include selection of appropriate dose and dose regimen of the control and treatment groups, selection of subjects that may respond favorably and experience fewer adverse reactions, and selection and timing of endpoints. CFR 21 part 312.21 and several guidance documents describe the requirements for clinical trials in detail (14–16). The evaluation of combinations of vaccines is beyond the scope of this discussion, but a guidance document has been developed to help with planning (17). (A). Guidance for Clinical Evidence of Effectiveness for Biologics To obtain marketing approval, the FDA requires that a manufacturer demonstrate the effectiveness of their products through the conduct of adequate and well-controlled studies [21 CFR 601.25]. The goal of trial planning, protocol development, conduct of trials, and data handling is to gather enough data to ultimately demonstrate the efficacy of an investigational drug. All trials should be conducted in accordance with Good Clinical Practices (GCPs) (14) to affirm that international standards of safe and ethical care are being followed. Effectiveness for alternative indications may be demonstrable with’bridging’ studies that compare established with investigational use. Data should be provided to document the bioequivalence of a new formulation or dosage strength. Multiple clinical trials may be required to demonstrate effectiveness, however a single trial will suffice in many cases.

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(B). Acceptability of Foreign Clinical Studies not Conducted Under IND Studies done outside the U.S. and not under IND can be acceptable provide they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principals acceptable to the world community [21 CFR 312.120]. This type of study will necessarily be affected by the impact of ethnic factors that may alter drug safety, immunogenicity, and efficacy at a particular dose. Ethnic factors are defined as intrinsic (genetic and physiologic) and extrinsic (cultural and environmental) characteristics of a population. If a foreign clinical study is not done under IND, there may not be a need to repeat the whole trial, but the clinical data and monitoring will need to be assessed for compliance with regulatory requirements. These include adequate characterization and documentation of dose response, safety, and efficacy in the population of foreign region. Bridging studies are needed for licensure in the US to provide clinical data on safety, dosage, and efficacy in this population. (I). Additional Data If the bridging study fails to verify efficacy in the new region, additional clinical trial data would be necessary. (II). Ethical Issues in Conducting Clinical Trials. Research conducted under IND is subject to all regulations protecting the rights and welfare of human subjects [45 CFR 46]. These regulations are based on the principals established by the Declaration of Helsinki [21 CFR 312.120(c)(4)]. The study sponsor should pay particular attention to clinical trial design and the process of informed consent (14 – 16). It is the obligation of the investigators to write the consent form in such a way that subjects understand the information and that openness and confidentiality are ensured. Finally, there should be an institutional review board (IRB) or ethical review committee in place to review all aspects of and approve the clinical trial protocol and consent forms.

11.4. Conclusion While the development of biologics is complicated and can take many years to complete, sponsors and regulatory authorities can work closely together to ensure the safety of those involved in the trials and that appropriate studies are done to establish consistency of manufacture and efficacy. The early phases of the process seek to establish safety and the best dose in relatively small groups of people. Development of valid assays to assess consistent production of the drug is critical. The final step before market licensure focuses on safety in larger numbers and efficacy for a given indication. Once licensed, changes in the manufacturing process require a full assessment of comparability before implementation. The collective efforts of all concerned help to ensure protection of the public health in the production and use of biological agents. Acknowledgments We would like to thank Drs Deal, Baylor, and Egan, for their comments.

References (1) Public Health Service Act (1944). Title 42 United States Code Chapter 6A. (2) Federal Food and Drugs Act (1906). Public Law Number 59-384, 34 Statute 768. (3) Food and Drug Administration Modernization Act (1997). Page 111, Statute 2296, Public Law 105–115. (4) Guidance for Industry Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product (1999). http://www.fda.gov/cber/ gdlns/cmcvacc.pdf (5) Guidance for Industry Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substance, (1998). http : / / www.fda.gov / cber / gdlns / cmcsyn.pdf

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(6) Points to Consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications, Dec 1996, http://www.fda.gov/cber/ ptc/plasmid.txt (7) Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, Feb 1997, http:// www.fda.gov/cber/points.htm (8) International Conference on Harmonization (Q5D): Quality of Biotechnological/Biological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products. FR 63, 182. Sept. 1998, http://www.ifpma.org/ pdfifpma/q5d.pdf (9) Draft Guidance for Industry: Stability Testing of Drug Substances and Drug Products. June 1998, http://www.fda.gov/cber/ gdlns/stabdft.pdf (10) FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products, April, 1996. (11) Guidance for Submitting Samples and Analytical Data for Methods Validation, 1987. In addition, a draft entitled ‘Guidance for Industry Manufacture, Processing or Holding of Active Pharmaceutical Ingredients’ is available at /www.fda.gov/cber/gdlns/ bulkguid.pdf (12) Code of Federal Regulations, Food and Drugs, 21 Parts, 200, 300, 600, revised April 1, 1999, and Public Welfare, 45 Part 46, Oct. 1, 1999. Published by the Office of the Federal Register National Archives and Records Administration, US Government Printing Office, Washington, DC. http:// www.access.gpo.gov/nara/cfr/ (13) Pre-clinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, July, 1997, http://www.ifpma.org/pdfifpma/s6.pdf (14) International Conference on Harmonization (E6): Guideline for Good Clinical Practice, May, 1996, http://www.ifpma.org/pdfifpma/ e6.pdf (15) International Conference on Harmonization (E8): General Considerations for Clinical

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Trials, July, 1997, http://www.ifpma.org/ pdfifpma/e8.pdf (16) International Conference on Harmonization (E9): Statistical Principles for Clinical Trials, Sept. 1998, http://www.ifpma.org/pdfifpma/e9.pdf (17) Guidance for Industry for the Evaluation of Combination Vaccines for Preventable Diseases: Production, Testing and Clinical Studies, April 1997, http://www.fda.gov/ cber/gdlns/combvacc.pdf

12. Composition and Responsibilities of Ethics Committees and Investigators

Opokua Ofori-Anyinam, Ph.D. SmithKline Beecham Biologicals, Rixensart, Belgium

12.1. Abstract Modern day clinical research requires ethics, science as well as good management skills to fulfill the requirements of Good Clinical Practice (GCP). This paper outlines the roles and responsibilities of investigators and ethics committees in clinical research with reference to internationally accepted guidelines for ethical research. The challenges that investigators and ethics committees in Africa may face in balancing their professional responsibilities, obligations to patients/research volunteers as well as the requirements of regulatory authorities are commented.

12.2. Introduction Today’s biomedical researchers are required to achieve a certain level of professionalism in their work called Good Clinical Practice (GCP). By definition, GCP is an international quality standard for designing, conducting, researching and reporting trials that involve the participation of human subjects. The Declaration of Helsinki (1) is the most fundamental guideline for clinical research where

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the responsibilities of doctors and those involved in clinical research are outlined. It focuses on the principles of ethical research. Three other guidelines commonly used as reference documents for GCP are the CIOMS (Council for International Organisations of Medical Sciences) (2), WHO (World Health Organisation) (3) and ICH (International Conference on Harmonisation) (4) guidelines. CIOMS ethical guidelines for biomedical research involving humans, focus mainly on the ethical principles involved in performing research in developing countries. WHO guidelines on GCP outline briefly the basic requirements for ethical research. The ICH guideline for GCP provides detailed practical glossaries, acts as a reference working document for translating ethics into GCP and provides unified technical standards to facilitate the mutual acceptance of clinical data by the regulatory authorities in the European Union, Japan and the United States. Fulfilling ICH requirements assures compliance of the other two guidelines.

12.3. What do these guidelines say about the role of Ethics committees in biomedical research? Their basic role is ‘to ensure the protection of rights, safety and welfare of subjects while ensuring the scientific validity of the data produced during a clinical trial’. In that capacity they have to ensure that “ Studies are designed to adequately address relevant ethical concerns and meet applicable regulatory requirements (e.g. prove what the objectives of the protocol are). “ The benefits of the study outweigh the risk to subjects. “ The selection of subjects is equitable and unbiased. “ The content and language of the informed consent documents are meaningful, reflect the study and the information about payments and compensation (where applicable) are made available to subjects. “ The process of gaining informed consent is appropriate. “ The privacy of the subjects and confidentiality of data is respected.

“

The investigator(s) of the study is (are) capable (by education and research background), committed to the research and has/have the right infrastructure for conducting the research as outlined in the protocol. “ They review all investigators brochures (where applicable), protocols, amendments and are informed of all protocol modifications even if they may not have a direct impact on the safety of the subject. “ During the study and the process of obtaining informed consent, there are safeguards to prevent or reduce unnecessary coercion of vulnerable subjects (e.g. mentally/physically infirm, children, educationally disadvantaged). “ Monitoring of safety data of a candidate product or procedure is performed at intervals appropriate to the degree of risk to human subjects but at least once per year. All serious adverse events and unexpected adverse drug reactions have to be reported to the committee. ICH recommends that independent ethics committees (IEC) are constituted according to local laws and customs, should be composed of at least 5 members (including one chairman) with at least one member independent of the trial centre and one member with a non-scientific primary area of interest. The size of the ethics committee should be such as not to make the group unwieldy. Membership of both sexes is highly recommended. Additional members can be invited as ad hoc members as per the needs of individual protocols. The number of individuals with voting rights should always be identified.

12.4. What role do in6estigators also play in bio-medical research?

The investigator has been defined as ‘an individual who actually conducts a clinical investigation, i.e. under whose immediate direction the test article is administered or dispensed or used involving, a subject, or in the event of an investigation conducted by a team of individuals is the responsible leader of that team (Code of Federal

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Regulations, U.S.)’ (5). Thus an investigator should be suitably qualified by education, training and experience to carry out the clinical trial, should comply with the protocol GCP and applicable regulatory requirements. Most importantly he/she has to exert clinical judgement and to ensure that subjects (healthy volunteers/patients) are appropriately protected during the course of a clinical trial. The investigator’s responsibilities are as follows: “ To be capable of recruiting the required number of subjects for the study and complete the trial within the agreed study period. “ To thoroughly review and understand information about the new drug/procedure (e.g. as supplied by investigator brochures, publications) and be willing to comply with and adhere to protocol specified procedures (e.g. inclusion and exclusion criteria, recruitment and enrolment of evaluable subjects, ensure randomisation of subjects and blinding when applicable). “ To obtain and document informed consent of volunteers. “ To communicate with ethics committees/Data and Safety Monitoring Boards (DSMB) and liase with the sponsors (e.g. ensure that protocols, informed consent are GCP compliant and subject to appropriate reviews and approvals, prepare and send out progress and safety reports). “ To establish a process for reporting serious adverse events and unexpected drug reactions to the sponsor and ethics committee. “ To complete and maintain source documentation and data – i.e. compile medical data into robust medical records and ensure that CRFs (Case Report Forms) are correctly and completely filled out and signed. “ Drug/device accountability – i.e. maintain accurate and complete records of shipment, storage, dispensing, administration and drug destruction where applicable. “ Document management – compile, organise and archive study records (e.g. study file) such that they are easily available to an outsider (e.g. an auditor) with little assistance.

“ “

“

“

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Should not have competing clinical trials. To manage and train research staff, provide rigorous supervision and be readily available and open to discussions with staff. To permit monitoring and auditing by sponsors (where applicable) and inspection by regulatory agencies. Maintain professional credentials, participate in meetings, publish and educate, ensure that their research is available to the medical, scientific and non-scientific world.

12.5. Goals and challenges of Ethics committees and in6estigators Fulfilling all the requirements outlined above is a real challenge for any ethics committee (EC) or investigator, since the work involves a lot of organisation (e.g. for collecting and maintaining sound, quality data and standard operating procedures) and dedication. However, since ICH is the standard in the 3 regions (US, Europe and Japan), where most of the pharmaceutical companies and major drug regulatory agencies are based, all companies have to be attentive to ethical and technical guidelines provided therein and will expect that their collaborators meet all basic requirements. The dilemmas that most ethics committees in Africa will face will be linked to their ability to work independently (influence of the government or institutions in the workings of the ECs such as decisions, appointments and terms of office) with adequate structures (financial and established written operating procedures) to achieve their objectives. Ensuring that consent is informed will be one of the biggest challenges. In a continent where not all languages that are spoken can be written, and where consent is usually collective, the ECs will have a responsibility in ensuring that people understand what they are undertaking (sign/ thumbprint) as research subjects. Coming to a decision of what is a good recompense for participating in a study will also be a constant challenge. Since the scientific community with research experience is limited, there may be the tendency to have the same group of individuals acting in a scientific and/or ethical capacity to

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review each other’s documents. This can be said to lead to biases and favouritism. However if ECs endeavour to train and educate other individuals within the scientific community at large this idea of a clique may be avoided. General guidelines for review of research proposals exist in most countries however finding an optimal or a most efficient review process has to be a consideration. Guidelines such as the ICH, FDA regulations have standardised recommended procedures but additional and locally adaptable guidelines are needed (e.g. for research into traditional medicines and genetics). The form in which ECs will exist may be a challenge. ECs may be established locally, regionally or nationally. They may be associated with universities, hospitals, or health administrations and institutions. However, in multi-centre trials involving different countries, a Pan African EC may even be a possibility. Associate boards may review documents and offer recommendations to the ECs. Examples are a separate scientific board to review scientific data and a Data and Safety Monitoring Board to review all data pertaining to safety of a candidate drug or procedure and offer recommendations (e.g. on stopping studies). The investigators will have to make a balance between their role as a scientist and a physician. They have to ensure that research volunteers understand what the research is about and what role they will play. They will be faced with collecting and maintaining sound, quality data and standard operating procedures within the constraints of their working environment (e.g. possible lack of funding, space, equipment and trained staff). Training staff and other potential investigators in addition to their workload will be a challenge. Educating the public and especially the governments on the idea of good clinical practice procedures that demand streamlined procedures with adherence to timelines have to be considered. Maintaining good relations with the ethics committee and the sponsors and coming up with processes of dissemination of knowledge to the public and scientific communities will be imperative if they are to be considered as good investigators. In Africa, because of the low level of education and the standard of living, the bulk of potential research subjects will be classified as vulnerable. As

such, the sponsors, the protocols and workings of the ethics committees and investigators and staff will be subject to scrutiny by media, patient advocacy groups and regulatory authorities. Attention will have to focus on establishing and working according to written operating procedures which can be made available to all interested parties. Balancing science and medicine while ensuring cultural sensitivity will always play a role. In addition, ethics committees and investigators will always have to be attentive for ‘disreputable companies or individuals’ that would like to perform research in an unethical manner. In view of the fact that regulatory bodies worldwide and the media are becoming increasingly watchful of research in developing countries, it is imperative that African ethics committees and investigators are considered credible. If the functioning and the results obtained from trials are always viewed with scepticism, sponsors (e.g. international companies/agencies) will be reluctant to perform clinical research in Africa because of unwanted negative publicity. This will have a negative impact on establishing African scientists as bona fide members of the international research community and as a result, their ability to find funds for research that will generate clinical data in African populations and/or drive research into diseases that are important for Africa.

12.6. References

1. World Medical Association, Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical Research In6ol6ing Human Subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964. Amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975; 35th World Medical Assembly, Venice, Italy, October 1983; 41st World Medical Assembly, Hong Kong, September 1989; and the 48th General Assembly, Somerset West, Republic of South Africa, October 1996. 2. Council for International Organizations of Medical Sciences (CIOMS), in collaboration with the World Health Organization (WHO).

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International Ethical Guidelines for Biomedical Research In6ol6ing Human Subjects. Geneva 1993. 3. World Health Organization (WHO). Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products. World Health Organization Technical Report Series No 850 (1995); 97–137. 4. International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). Note for Guidance on Good Clinical Practice (CPMP/ ICH/135/95) 1 May 1996. 5. Code of Federal Regulations, Title 21, Part 312, section 60 (US Government printing office, Washington DC. 1 April 1995. Suggested reading Odusunya O.O. Good Clinical Practice: how much do Nigerian doctors know. International Journal of Pharmaceutical Medicine (1999); 13: 265 – 267.

13. Informed Consent in Health Research Prof. Solomon R. Benatar, FRCP Department of Medicine and Bioethics Centre, Faculty of Health Sciences, Uni6ersity of Cape Town, Obser6atory 7925, Western Cape, South Africa

13.1. Introduction Informed consent has been a central and undisputed requirement in medical research on humans since the Nuremberg code was promulgated in 1947. Its widespread introduction into clinical practice followed in the mid-1950s (1). However, it has also been controversial, both due to the complexity of the concept and because the term informed consent is understood differently by different people. Lawyers are inclined to understand informed consent as a minimalist concept located within the context of tort law or malpractice, and to be concerned more about procedural than moral aspects of its implementation. In the legal sense, informed consent thus tends to be minimalist and

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policy oriented. Procedures and rules are formulated to regulate the behaviour of consent seekers, with the presumption that the patient has substantive understanding and authority. Philosophers understand informed consent in the context of a rich ethical framework, based on respect for human dignity on the grounds that humans are rational. They see informed consent expressed in practice through an interactive process, between doctor and patient, fostering implementation of the principle of autonomy. This moral sense of informed consent is more comprehensive. It emphasizes equality in the doctor patient relationship, and promotes a shared and interactive decision-making process, which shows respect for patient self-determination. Health care professionals tend not only to both dislike but also to be suspicious of informed consent. They often lack appropriate communication skills, tend to have unwillingness to openly discuss ethics issues with patients or research subjects, and are generally only vaguely aware of moral theory. Their concern, therefore, tends to be focused on the immediate legal implications and practical aspects of obtaining informed consent. Patients occupy a wide spectrum, from those who expect and demand fully informed consent to those who have such fear of illness and death that they abandon themselves to complete trust in their doctors.

13.2. Theory 13.2.1. Origins of the Concept The modern concept of informed consent has its foundations in the enlightenment thought and principles of liberalism and individualism clearly enunciated by Locke 1632–1734. However, respect for the dignity of the individual has a much longer and deeper history. The Nuremberg Code of 1947, Declaration of Helsinki of 1964 and its subsequent amendments, the increasing concern for abuse of human rights in medical research, and the human rights movement, all have been powerful forces enhancing the imperative for informed consent in research and practice (1).

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13.2.2. Deri6ation of the Concept A fairly uniform concept of informed consent can be derived from differing starting points. These include (i) ethics theories focusing on right actions; (ii) theories concerned with their consequences and utility value; (iii) the mid-level moral principles of autonomy, non-maleficence and beneficence that could be derived from either of these sets of theories; (iv) the legal right to privacy; or (v) merely the idea of respect for human dignity (2). 13.2.3. Functions and Justifications for Informed Consent Respect for and adherence to the ideals of informed, consent serve several functions: 1. promotion of individual autonomy; 2. encouragement of rational decision-making processes; 3. protection of patients, subjects and doctors; 4. the encouragement of professional selfscrutiny; and 5. involvement of the public in debate and education about medical practice, medical research, and human rights. 13.2.4. Requirements for Informed Consent The requirements for informed consent are: 1. disclosure of information by professionals; 2. patient competence and cognitive ability; 3. voluntariness (freedom from coercion); and 4. legitimate policies and procedures including appropriate documentation. Disclosure of factually correct information in language comprehensible to the patient is crucial. In the research setting full explanations are required. The purposes of the research should be explained; the risks, discomforts and potential benefits (for subjects and others) described and quantified; and information provided regarding compensation for any injury sustained during the research. There should be no deception, and the freedom to exit from the trial without prejudice should be stressed (2). In clinical practice debate about the standard of disclosure has ranged from the professional standard (the amount of information must conform with professionally approved practice); through

the reasonable person standard (what the average citizen would wish to know); to the subjective standard (determined by the patient’s wishes and needs). Cogniti6e ability refers to the patient’s: 1. ability to understand the nature and purpose of the procedure, its risks, benefits, side effects and the alternatives; 2. reasoning capacity; 3. ability to understand that there is a choice; and 4. willingness to choose. The patient’s competence required to achieve these goals needs to be considered in relation to the nature of the issue under consideration and its implications. Voluntariness to participate in research should be stressed. There should be freedom from external coercive forces, and freedom to withdraw from the study without prejudice to continuing care. Procedural aspects include such considerations as whether verbal or written consent is necessary; the nature of patient information and informed consent documentation; and the assistance of third parties in obtaining and witnessing the procedure.

13.3. Practice Theory aside, there is a need to focus on practice and to consider the gap between the moral and legal interpretations already described. The moral conception perceives informed consent as a process of consensual decision-making, and dependent on several elements: disclosure of information by the doctor, comprehension by the patient, empathetic dialogue facilitating rational and voluntary choice by a competent person, and respect for patients’ decisions. Patients need time to reflect, to liaise with those closest to them, and to overcome fear. Patience, empathy and trust are required to achieve the moral ideal of informed consent. If these aspects are neglected, and a minimalist, formal legal approach is taken, the confusion and fear that may result from poor communication could result in the process being ethically defective (3).

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13.3.1. How is Informed Consent Obtained in Practice? A major problem is the gap between the theory of informed consent and how it is actually obtained in practice! Those involved with the procedure, even in highly industrialized countries, are often the most junior staff who see the procedure as a mere formality to be achieved as rapidly as possible with little attention to the patient’s needs for reflection and family consultation. Documentation is usually written, and witnessed by minimally involved third parties, such as junior nurses. Such practice reflects the legal sense to a greater extent than the moral sense. In the research context, especially when western researchers are working in developing countries, and dealing with subjects from different cultures, it would seem that inadequate attention is paid to the complexities of obtaining informed consent. When comprehension of the research by the subject is not easily achieved, additional effort must be made to communicate across language, educational, and cultural barriers using appropriately trained assistants. Information sheets must be provided in the subject’s language, in understandable terms, and with access to assistance to any explanations required. 13.3.2. Consent from the Specially Vulnerable Consent for research on children, mentally handicapped people, mentally ill patients, prisoners, severely ill, unconscious patients, or other especially vulnerable groups, requires the special attention such as is outlined in the South African Medical Research Council’s guidelines (4). 13.3.3. Informed Consent for Research and or Patient Care In clinical practice obtaining informed consent is a somewhat informal, friendly, and unhurried procedure, in a context characterized by patients seeking out medical advice, from medical professionals whom they perceive to be concerned primarily with the best interests of patients. The process lacks rigidity, encompasses consideration of the fact that autonomy may be impaired, and makes some allowance for tailoring of treatment according to the patient’s wishes. Such a process,

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if conducted appropriately, can enhance patient confidence and the doctor patient relationship. In contrast, informed consent procedures in the research context are both formal and regulated. Characteristically the encounter is between an investigator seeking patients to include in one’s study. Within a relationship resembling a brief encounter between strangers in the pursuit of knowledge and the need to do so with scientific vigour. The information disclosed and the method of doing so are more impersonal, detailed, and harsher than in the clinical context. Professional ignorance is exposed to enable patients to understand why randomization to different forms of treatment is justified. While patient autonomy may be preserved, the rigidity of the protocol does not allow for patient choices once the research has been embarked on (other than withdrawal). Such a relationship has potentially adverse effects on researchers and patients.

13.3.4. Conflict of Obligations A conflict of obligation arises when the doctor is both the investigator and the provider of patient care. The pursuit of knowledge in the best interests of science and society may not be compatible with protecting the best interests of the patient. This conflict may be very difficult to resolve without separating the roles of investigator and practitioner to ensure both good science and non-exploitative patient care (5). 13.3.5. Can Informed Consent Really be Achie6ed? It has been argued that informed consent is a myth and that it is extraordinarily difficult to obtain truly informed consent. The potential impediments to obtaining informed consent, many of which can be overcome or minimized, include: 1. difficulties in getting patients to fully understand and accept the facts and their implications (because of language, educational, and cultural barriers); 2. patients’ fear of reproach if they do not conform to the desires of the doctor; 3. reluctance of doctors and patients to acknowledge and confront the uncertainties and fallibility that still pervade modern medicine;

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4. difficulties of transcending both patients’ faith in medicine and their (sometimes unwarranted) trust in doctors; 5. over-emphasis of legal aspects of consent; and 6. doctors’ insensitivity and authoritarian ways of dealing with vulnerable people. However with effort many of these difficulties can be minimised.

13.3.6. Alternati6e World Views and Informed Consent in Clinical Practice Despite the power of the theoretical background for informed consent within the western liberal mind-set, questions have been raised about the validity of considering sick patients as rational autonomous selves having the capacity to make the complex decisions often required in the medical context. This question asks whether rational choice theory should be applied to health care as if this was a market commodity, or whether there is something different about a person who is ill and in need of medical care. Some also argue that the rationale for informed consent is defective because it promotes a cult of moral atomism and individualism, that is insensitive to the fact that humans are members of moral communities and cannot be viewed in isolation. Despite these concerns, the power of the argument for respecting autonomy is often in favour of these choices. It is therefore very difficult to ensure that these are made by autonomous persons in the strictest sense. Beyond the modern western world-view, within those cultures in which individualism is not the central feature, it may be that all patients do not necessarily want to be informed, or if they do that this applies within a more community oriented conception of the self. While respecting this view, it is also clearly important to be aware of the dangers of group or institutional coercion, for example within religious or other hierarchical social groups. Acceptance of the need to understand cultural norms should be linked to efforts towards empowering individual to express their own choices. It would thus seem that there is a need to: 1. affirm the existence of some universal principles; 2. attempt to reconcile the desire to put universal

theories into practice with respect for the (apparent) wishes of people who live within mindsets that seem to embrace different ideas of the self, and its relationship to family, social life, and the cosmos; 3. work towards empowering individuals to make choices for themselves; 4. recognize that it is inappropriate to insist on the application of universal rules in the context of cultural differences in attitudes to life and death.

13.3.7. Empirical Data About the Use of Informed Consent in Practice Empirical studies of informed consent in practice in western or other cultures (none with the rigour of randomized control studies) surprisingly reveal a diversity of practices and attitudes. For example, in response to questions to several groups of Americans regarding informing patients about fatal illnesses, the following proportions of affirmative answers were obtained as shown in the Table below (8). Question

KAm

Should patients be: Told about 47% fatal Diseases Told About 35% Terminal Nature Involved in Life 28% support Decisions

Mex Am

Eur Am

Af Am

65%

87%

88%

48%

69%

63%

41%

65%

60%

KAm, Korean Americans; Mex Am, Mexican Americans; Eur Americans, white Americans; Af Am, African Americans.

For example, a study on Navajo Indians (personal communication with Carrese and Rhodes) revealed that the belief system in traditional Navajo culture to emphasize the importance of positive thinking. Of those questioned, 86% considered advance planning which forms part of the patient Self-determination Act, to be a dangerous violation of traditional Navajo values (7). In this culture language shapes reality rather than reflecting it, and therefore negative consider-

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ations regarding illness can adversely affect outcome. Here the moral action may be to allow Navajos to think as they wish rather than to insist on teaching them to be autonomous. We could ask them if they wish to give informed consent and respect their wish not to participate in this practice if it is alien to them. In the era in which we live, with ever widening disparities in health, wealth and power and increasing risks to all in an interdependent world, the time is riper now than ever before for westerners to strive to understand their own world view (8). Westerners should learn what it means to be human outside their privileged environments, appreciate the fragility of their own dignity in a world in which so many suffer deprivation of the basic human needs for flourishing, and participation in broader visions of sustainable scientific and social progress. It can be cogently argued that autonomous decisions by patients can never stand isolated from the whole narrative of the patient’s life, the way one has lived and is living, and the way one perceives self, family, and the community, in relation to the decision in question. A physician of integrity will endeavour not only to respect a patient’s autonomy, but also to preserve one’s integrity. This is achieved not merely through assent or dissent by the patient, but rather through an interaction between patient and doctor that preserves the integrity of both in an informed, sensitive, empathic, joint decision making process, that must include a significant element of trust. The physician must therefore be a person of integrity and cultivate the virtue of fidelity to trust (9). The following formula for morally defensible decision making has been suggested: ‘The decision should not be made by the physician in place of the patient, nor by the patient in isolation from the physician or the community. Phenomenologically these elements of a medical decision are inseparable from each other. The morally optimal condition is one in which the decision arises between doctor and patient, which is the moral sense of informed consent’ (9).

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13.3.8. Alternati6e World Views and Informed Consent in the Research Setting In the research context, even in cross-cultural settings, it can be cogently argued that research is unethical if informed consent has not been obtained. Language, educational, and cultural barriers, should not be used as excuses to undermine informed consent in research on patients who are both vulnerable and the victims of adverse living circumstance to which exploitation has already contributed so much. The correct approach is to devote more time, effort, and resources, to studying ways in which obtaining informed consent can be improved and legitimized. Alternative world-views, while relevant in the clinical setting, are less significant considerations in research. The need to avoid exploitation must ensure maximum attention to all the ethics elements of informed consent. 13.4. Conclusions The emergence of autonomy as a socio-political, legal, and moral concept, has profoundly influenced medical ethics. It has on the whole been beneficial, in protecting patients against violations of autonomy and integrity. However, much has yet to be gained from improvements in the application of informed consent in practice. Attention to the integrity of the whole person (and to that of physicians) is also necessary, although this is more difficult to define and achieve, especially in a practice characterized by multicultural beliefs (7). The requirement of informed consent reflects a recognition of the asymmetries of power and risk in the physician patient relationship. Patients seek doctors when they are sick and most vulnerable, and then entrust them with carefully guarded secrets and fears, as well as access to their bodies. Consent is an effort to lessen the asymmetries of power and risk by emphasizing the mutuality of the relationship. Consent reminds the doctor of the individuality of the patient, respects for the patient’s selfdetermination, and ultimately affirms for both parties that the physician’s authority to heal is given by the patient (6).

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The practice of caring for patients and obtaining informed consent requires empathy. Physicians should understand that the scientific frame-work within which they undertake research and practice medicine is not necessarily consonant with the existential perspective of the patient, especially when researchers come from other countries. Informed consent of a genuine moral nature, or the alternative of limited consent where appropriate will be realized only if a comprehensive approach to patient care (which is sensitive to cultural values) supplants the idea of a simplistic universal approach of a legal nature. It is also vital that exploitation be avoided and that the research undertaken has benefits both for the research subject and for the community in which the subject lives.

References (1) Faden R.R., Beauchamp T.L., A History and Theory of Informed Consent. OUP. New York 1986. (2) Beauchamp T.L., Childress J., Principles of Biomedical Ethics. 4th Edition. OUP. 1994. (3) Levine R.J., Informed Consent in Research and Practice: Similarities and Differences. Arch Int Med. 1983; 143: 1229 – 1231. (4) South African Medical Research Council. Guidelines on Ethics for Medical Research, 1993. (5) Taylor K.M., Kelner M. Informed Consent: the Physicians Perspective. Soc. Sci. Med. 1987; 24: 135–144. (6) Cross A.W., Churchill L.R., Ethical and Cultural Dimensions of Informed Consent, Annals of Internal Medicine. 1982. 96: 110 – 113. (7) Carrese J.A., Rhodes L.A., Western bioethics on the Navajo reservation. Benefit or harm? JAMA 1995; 274:826 – 9 (8) Benatar S.R. Global Disparities in Health and Human Rights. American Jounal of Public Health, 1998; 88: 295 – 300. (9) Pellegrino E D: Character, Virtue and Selfinterest in the Medical Profession. Part 1.

The Erosion of Virtue and the Use of Selfinterest. Reference Server Review. 1994. Spring; 29–44.

14. Intellectual Property Rights and Confidentiality Reidar K Lie, MD, PhD Department of Philosophy, Uni6ersity of Bergen, Norway

14.1. Introduction The two themes intellectual property rights and confidentiality, are quite different subjects. However, what they have in common is that they are relatively neglected, but quite important topics in research ethics. Intellectual property rights can be discussed within the recent controversy over the ethics issues in collaborative research between developed and developing countries. What everyone wants to avoid is the situation where research is carried out in a developing country, which for various reasons cannot be carried out in the developed country, but which at the same time is of primary interest to the developed country. The main defense of the recent controversial AZT trials has precisely been that the results would primarily be useful for the country in which the research was done. If, on the other hand, it turned out that the trials were not designed to produce results that could be used in the host country, most, if not all, would find these trials ethically unacceptable. The guiding principle is that trials should produce results that can be translated into effective treatments that can be made available to the population in which it was tested. This is reflected in the CIOMS guideline that every effort should be made to make a drug or vaccine tested ‘reasonably available’ after a trial is finished. It is precisely this clause of ‘reasonable availability’ which links research ethics with the area of intellectual property law.

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14.2. Research Agreements to Ensure Reasonable A6ailability The CIOMS guidelines 8 and 15 on research involving subjects in under-developed communities, requires investigators and or sponsors to ascertain before such research is undertaken that: 1. persons in underdeveloped communities will not ordinarily be involved in research that could be carried out reasonably well in developed communities; 2. the research is responsive to the health needs and the priorities of the community in which it is to be carried out; 3. at the completion of successful testing, any product developed will be made reasonably available to the host community; and 4. justifications of the exceptions to the above and agreed upon by all concerned parties. The guiding idea behind these guidelines is that research should be carried out in populations that can somehow benefit from the research, and that one should at least avoid doing research in one population for the benefit of another. Although it is not specified exactly what ‘reasonably available’ means, the wording of the guideline clearly states that there is an obligation for the sponsor to ensure the availability of the product, and that mechanisms for ensuring this should be set forth in an agreement before the study begins. The problem with these guidelines is that there are very few examples of research in developing countries where there has been such an agreement. This, of course, does not invalidate the guidelines, but it might suggest a lack of realism concerning what can be achieved. Examination of an illustrative case will show that there are reasons why this should not be a general requirement for research in developing countries.

14.3. Trial of Chloramphenicol for Meningitis in Nigeria In the early 1970s meningococcal meningitis was noted to be resistant to treatment with sulphonamides, a cheap and effective treatment. Another treatment, intramuscular injection of penicillin, was also found to be inapplicable, be-

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cause of its expense and difficulty of administration. The trial attempted to find out whether chloramphenicol, given alone, a much cheaper treatment than penicillin, would be effective against meningitis. The trial showed that it was indeed equally effective as penicillin (1). This relatively simple case illustrates the problems which could arise with regard to demanding a written contract of availability. Existing treatments of meningitis were unsatisfactory because of costs and logistics. The researchers therefore had a clear justification for seeking a cheaper and more practical alternative, and a reasonable expectation that the treatment would be a viable alternative if found to be as effective as penicillin. For the sake of argument, one could question a demand on researchers, prior to initiating the study, to secure an agreement with relevant authorities that the treatment will be made available to the communities in which it was tested. For one thing the demand would go far beyond the influence one can reasonably expect researchers to have concerning changes in a country’s health policy. Instead, it will probably have the effect of delaying or preventing research that might benefit the population. One should also note that there are formidable obstacles to achieving such agreements before trials start. Not only are there issues of intellectual property rights, but there are also all kinds of logistical reasons that need to be solved before a drug or vaccine is made available in the country in which it is tested. New drugs and vaccines are going to be expensive. Although there are several proposals for differential pricing schemes, they have not been successful so far. But even if drugs were free this would not ensure availability. There needs to be an appropriate health care delivery system, often absent in developing countries. The story of how hepatitis B vaccination was introduced into the EPI program illustrates the difficulty of making effective drugs or vaccines available to populations who need them, difficulties which go far beyond the reasonable responsibilities of the sponsors of the trials (2). Considerations such as these show that the CIOMS requirement of an agreement to ensure

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reasonable availability of the product being tested, is probably not a viable option. An alternative guideline that still captures our intuitive sense of justice is therefore urgently needed. In fact, a few examples will show that it is not generally the case that interventions being investigated are made available after testing is complete.

14.4. Illustrati6e Examples of Past Research in De6eloping Countries Research in developing countries is often justified in terms of a desire to make useful products available to the population in which they are being tested. More often than not, however, these justifications do not materialize after testing is completed, and this could have been known at the start of the research. I shall therefore suggest that, if one thinks availability is a condition for testing, much more explicit and detailed justifications need to be provided. The problem now is that researchers have an overly optimistic attitude towards the benefits which the research will bring. It is often simply assumed that if a treatment is found to be effective, it will be made available to the populations who need it. The examples clearly demonstrate that this is generally not the case.

14.4.1. The Hepatitis A Vaccine Trial in Thailand This trial started in Northern Thailand in 1991 and involved approximately 40 000 children, from 1 – 16 years (3). The hepatitis A vaccine was Havrix produced by SmithKline Beecham. The study concluded that ‘inactivated hepatitis A vaccine is safe and that it protects against hepatitis A for at least 1 year’. The justification for the vaccine trial in Thailand was that following the studies conducted with the Ministry of Public Health of Thailand between 1987 and 1989, it was concluded that access to a safe, affordable, effective hepatitis A vaccine, was a future public health requirement. Accordingly, an evaluation of the safety and then of the protective efficacy of hepatitis A vaccine was planned; primary schoolchildren were to be the study participants. Kamphaeng Phet Province in northern Thailand

was selected as the field site because active surveillance between 1989 and 1991, this province was found to have an attack rate of hepatitis A of 199 cases per 100 000 population. Moreover, experience in using the province as the site of a large field efficacy evaluation of Japanese encephalitis vaccine showed that the people of Kamphaeng Phet would welcome the hepatitis vaccine study. The hepatitis A vaccine has been licensed by SmithKline Beecham, and is now mainly used for travellers from industrialized countries to developing countries. Although there is some discussion about whether one should introduce routine vaccination programmes among high risk groups, it seems that the general consensus is that this is not cost-effective at this time. Thus it should not have been too difficult to predict that the vaccine would not become generally available in northern Thailand after this trial had been completed. The main reason for doing the trial was to get the vaccine licensed in industrialized countries. The population in Thailand was a convenient one, with a high incidence of hepatitis A. This trial, then, is an example of a trial done in a developing country, where it was known that the product would not be available to the population after testing, and therefore that the results would primarily benefit people in the developed world.

14.4.2. Short Course Treatment of Tuberculosis In 1972 a controlled trial on short course treatment of 6 months for pulmonary tuberculosis was carried out in East Africa (4). It had been found hard to ensure compliance with the standard 18 months treatment regimen, both in developed and developing countries. The authors recognized, that ‘it was fully appreciated that the regimens which were selected for study were not readily applicable under routine services conditions because they involved daily streptomycin for 6 months’. The study proved that short course treatment was indeed effective. However, the authors also concluded that ‘it is now important to try and find short-course regimens that readily lend themselves to practical application by routine treatment services. This is necessary not only in technically advanced countries but, even more

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important, in the developing countries where the whole organization of programmes of long-term chemotherapy has repeatedly failed and has usually proved to be beyond the capacity of the routine treatment services as currently financed, organized, equipped and staffed. Further studies are being directed to these ends’. In other words, it was recognized that this particular short course treatment would not be practically implementable in the country in which it was carried out. However, the trial was necessary to establish that short course treatment was effective, a necessary first step towards the development of applicable treatments.

14.4.3. Malaria Prophylaxis for Pregnant Women A number of studies have been carried out to investigate the effects of malaria prophylaxis during pregnancy. One of the interests has been to see whether the drug mefloquine has any adverse effects on the child. One such study was carried out at the Thai-Burmese border (5). The other one investigated such things as intrauterine growth and birth weights in Malawi (6). Mefloquine is an expensive drug that is not generally available for malaria treatment in the developing countries where malaria is a major problem. It certainly would be too expensive for routine malaria prophylaxis during pregnancy. The results from the Malawi study were used to apply for approval in the US for the use of mefloquine during pregnancy, although this application was denied (7). It is also argued that trials such as these are justified; although the treatment will not be immediately available after the trial is completed, it is a necessary first step towards the eventual availability of treatment. 14.4.4. Zido6udine Treatment for Pregnant Women in sub-Sahara Africa In a recent article on the proposed revision of the Helsinki declaration, a study involving pregnant women is described (8). The women would not receive AZT to prevent perinatal transmission, although this has been found to be highly effective. Our debate about the proposed research involving pregnant women in a sub-Saharan African country was quite animated. As the dis-

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cussion progressed, it became clear that the standard of care was changing in this particular country, where programmes to provide zidovudine were changing, and a new one which would provide zidovudine to pregnant women to be implemented in urban centers over the next 6 months. The researchers believed there was a small window of opportunity to conduct their research, because rural programmes for the distribution of zidovudine will be introduced within 2 years. A number of committee members found this argument persuasive, given the value of the proposed research. Others countered that the increasing availability of zidovudine should be a reason for not proceeding with the research. They also pointed out that the research team itself could probably provide zidovudine to pregnant women in the areas where the study would be conducted. Not to do so, they argued, would be to allow the transmission of HIV infection to children, even though it could be prevented-a violation of research ethics. The reasoning by those who defended this trial is illustrative. First it is pointed out that there is a unique opportunity to do the study in this population (the details of the study are not disclosed in this article), as it is a population which does not currently receive AZT. Second, one must take advantage of this opportunity now, as AZT is in the process of being introduced in the country. Postponing the study will make it impossible to carry out the study. The problem with this reasoning is that it gives the researchers a potential and real conflict of interest. They will be strongly motivated to delay the introduction of AZT treatment in their country until the study is finished. Given the few experts in sub-Saharan African countries, the researchers are also probably advisors to governments on AIDS treatment policies.

14.4.5. A Breast Cancer Study in Vietnam A controversial study has been undertaken in Vietnam where women with breast cancer are randomized into one group receiving mastectomy and the other group receiving mastectomy together with immediate surgical oophorectomy and tamoxifen for the next 5 years (5). Adjuvant treat-

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ment for breast cancer patients is generally felt to be superior to mastectomy alone, although there is still scientific doubt as to the benefits of such adjuvant therapy. There is no doubt that it would be useful to carry out a properly controlled trial, although as the authors point out, such trials are ‘not politically feasible at present’ in the US. The principal investigator, Richard R. Love, has extensive experience from Vietnam and knows that adjuvant therapy is not generally available in that country. He therefore proposes that such a trial should be carried out there. The trial would have the added benefit of serving ‘as a means for technology transfer, education and immediate improvement of treatment’. The women in the trial would not be denied treatment they would ordinarily receive, and in fact would have the chance of receiving a treatment that might be superior. The ethics committee in the US initially rejected the proposal because the proposed study includes two treatment approaches, neither of which is standard treatment in the investigator’s country, the US. One arm, oophorectomy and tamoxifen, at least has the virtue of being a plausible approach for adjuvant treatment, worthy of investigation under acceptable conditions. The other arm, no adjuvant therapy after surgery, should be considered inadequate anywhere. It is exploitative of the women in Vietnam not to provide some systemic adjuvant therapy. The committee nevertheless eventually approved the protocol with some modification, after the investigators had argued their case. The women in the mastectomy only group would be offered oophorectomy and tamoxifen if cancer recurred, and offered follow up visits every 3 months. This was based on the arguments that ‘a woman who was randomized to the observation group for no adjuvant treatment, would be no worse off as a result of being in this study’. The study would expose such a woman to no risk beyond that to which she would have been exposed were she not in the study. On the contrary being in the observation group offered the possibility of substantial benefit, namely more careful follow-up and planned treatment, standard for recurrence of cancer, if and when that should occur.

There is apparently some reason to believe that the adjuvant therapy in the proposed study in Vietnam are more risky than those currently regarded to be standard treatment in the US. Nevertheless, the investigators felt the study to be justified on the grounds that for a population at very high risk for recurrent disease because of the limited effective care available, higher risks might be appropriate. Given the poor prognosis of breast cancer in a country where no adjuvant treatment was available, it would not be irrational for a woman to assume a risk of adjuvant therapy that might be higher than that from a standard treatment in another country. The investigators also argued that all studies on breast cancer treatments had been done in European and American women, and there is no data on the effect of adjuvant therapy on Asian or Vietnamese women. It is argued that the goal of the trial is to investigate treatments of relevance to Vietnam. A crucial point in this aspect of the discussions with the IRB was clarifying that the research project had to be understood as part of a broader context, namely, to define an effective treatment for the most common presentation of breast cancer in Vietnam, which could be widely applied in that country. It was also important to convey the larger health priorities in Vietnam, particularly the control of communicable diseases. In this context, the investigator’s proposal was considered consistent with international guidelines for research in underdeveloped countries in that it was ‘responsive to the health needs and priorities of the community in which it is to be carried out’. It is really hard to understand this reasoning, and to evade the suspicion that the real reason for wanting to do the trial is not to benefit the population in Vietnam. There is clear scientific justification for wanting to do a clinical trial on hormonal adjuvant therapy; even though the study is done in Vietnamese women, there is no reason to expect that the results will not be seen as relevant for hormonal adjuvant therapy anywhere. It is, however, not possible to do the trial in an industrialized country. Any arguments that this trial is of particular benefit to Vietnamese women should therefore be viewed with suspicion. No data is given to sup-

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port the claim that this is a treatment that ‘could be widely applied in that country’. If the argument holds that it is necessary to do a study on Asian women to prove that adjuvant therapy is beneficial in this population, then one should choose one of the other types of adjuvant therapy, which, it is pointed out, probably carries a lower risk than the one in this study.

14.5. Short Course AZT Treatment of Pregnant Women The final example is the very controversial trials on short course treatment to prevent perinatal HIV transmission. The main justification for these trials was that they were necessary to find a treatment that could be applicable in developing countries. However, it could have been known before the trials started that even a US$ 50 treatment would be too expensive for most, if not all, countries in which these trials were carried out.

14.6. A6ailability and Intellectual Property Rights It is a reality of current drug development that most new drugs or vaccines, even against major health problems in developing countries, are going to be extremely expensive. The cost of AIDS treatment is a particularly striking example, costing US $15 000–20 000 per patient per year. The actual manufacturing cost of these drugs is of course much less. The reason for the high cost is the fact that the drugs are still under patent, giving the patent holder exclusive license to produce and sell the drugs for a number of years, and charging whatever price the patent holder thinks the market will bear. Usually the price is geared at markets in developed countries, making these drugs all but unavailable in developing countries. Let me immediately say that there are of course apparent good reasons for the high prices. Pharmaceutical companies need to recover the costs of development of the drugs, typically amounting to millions of dollars.If pharmaceutical companies are not able to invest in the development of new drugs, the drugs will simply not be available at all, neither in developed nor in developing countries. I will return to this issue below. For our purposes

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here, though, it is important to note that regardless of the reason for the high price of newly developed drugs, the fact remains that prices are going to be high. This has implications for research ethics. If we know that prices for new drugs are going to be higher than what the health systems of developing countries can afford, how can we fulfill the condition of ‘reasonable availability’? Must we not always conclude, if we are to be honest, that most if not all drugs or vaccines tested in developing countries, will not be available to the population for a long time after the clinical trial is over? If, however, we do take it to be a precondition of ethically responsible research that there is a reasonable expectation that the product tested is going to be available to the population in which it is being tested, but the current reality is that there is little reason to expect that to be the case, the conclusion must also be that those of us who work in research ethics, have a responsibility to try to do something about the current reality of intellectual property rights. This, it will turn out, is a formidable challenge indeed, as the recent controversy over the new drug policy in South Africa illustrates. South Africa has recently introduced a number of new initiatives to lower the cost of drugs. These include mandatory generic drug substitution, restrictions on inappropriate marketing efforts, parallel imports and compulsory licensing. There have been strong reactions against these initiatives, in particular from the United States, threatening trade sanctions. The United States has claimed that South Africa is in violation of international laws, although this is doubtful. Parallel importing takes advantage of the fact that drug prices are sometimes different in different countries, for a variety of reasons. A country may therefore decide to import a particular drug from another country where it is sold at a lower price than the one offered by the pharmaceutical company in one’s own country. This is, in fact, completely legal, and in fact to a certain extent encouraged to stimulate competition. Compulsory licensing is mentioned in section 31 of the TRIPS (Trade Related Intellectual Property Rights), which states that it is allowed to give

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a temporary license to somebody other than the patent holder to produce a drug, in cases of national emergency or if it is in the public interest. This would typically result in a lower price than the one asked for by the patent holder, the pharmaceutical company. Such licensing has been used in the US and Europe, for example in cases where the military would need a certain type of equipment. The US government has, however, been strongly critical of the use of compulsory licensing for drugs by developing countries. It is also important to note in this regard that new regulations in current international patent law have been regarded as controversial with regard to pharmaceutical products. Many countries used to have exemptions for drugs in their patent laws because it was felt that since drugs are necessary for health and life, ordinary patent laws, granting a particular company exclusive right to manufacture them, should not apply. Countries such as India and Brazil were particularly against the changes that took place a few years back, making drugs part of the same patent protection system as exists for other products. The main argument in favor of the change is that patent protection is necessary to stimulate innovation and investment in new promising drugs. If we do not have a system of patent protection, pharmaceutical companies will not have any incentives to come up with the high sums of money necessary to develop new products, and hence we would not have any effective medications at all, however expensive they might be. Without a patent protection system, everyone would suffer, not only developing countries. With the patent protection system, developing countries may initially find that access to new drugs is difficult, but eventually they, too, would be able to take advantage of the new drugs, when the patent period expires. This also explains why there has been such a dramatic reaction against the use of parallel imports and compulsory licensing. Although they may be allowed under current international law, it would seem that these two mechanisms are regarded as loopholes that should be closed because they threaten a system that ultimately is supposed to increase everyone’s welfare.

The only problem is, of course, that, although the system may increase everyone’s welfare in the long run, in the short run a lot of people are going to be dead, and the argument for increase in welfare over the long run is more of a theoretical argument, than one based on solid empirical evidence. Why is this recent controversy over intellectual property rights relevant for research ethics? First, as mentioned above, an important principle of research ethics is that products tested in developing countries should be made reasonably available after they have been found to be effective. It is therefore imperative to seek out mechanisms for making such drugs reasonably available, and parallel importing and compulsory licensing are such mechanisms. However, and this is the important second reason for the relevance of intellectual property rights to research ethics, the South African example clearly illustrates that there are formidable obstacles to achieving reasonable availability. When South Africa attempts to introduce changes that are apparently within current legal regulations, all kinds of obstacles are put in the way. However one may ultimately judge the legality of parallel importing or compulsory licensing, it shows that there are no simple solutions to making new drugs available to developing countries. Pious affirmations that one will do everything possible to ensure that they will be made available, will be just that, unless one can propose specific, workable mechanisms. All this has of course consequences for the approval process of research projects in developing countries. Usually one would justify such projects because the knowledge gained from the research is necessary in order to improve treatments in the country where it is carried out. If, however, there is little reason to expect that the drugs will be reasonably available for a long time after the testing, would it not be more honest to say that one simply does not know whether the drug being tested will be of any use to the host country? But if one did that, would or should the ethics review committee approve the research proposal?

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14.7. Confidentiality Let me now change gear and discuss my second topic, confidentiality, very briefly. Research projects often collect an enormous amount of data about the research subjects, and most of that data may not be particularly interesting to third parties. But some information may be of interest to others, such as a person’s HIV status. It is a generally accepted principle of research ethics that data gathered during the course of the research should be kept confidential, and should not be disclosed to third parties without the explicit consent of the research subject. Prospective research subjects are typically told that this is the case during the informed consent process. The problem is that reality is not as straightforward as the impression one might get from the informed consent form. There is the possibility that unauthorized people may accidentally access confidential information. This, of course, does happen more often than is realized in a hospital or clinic setting. But there are no ethical dilemmas involved here, other than to introduce more efficient means of keeping confidential information secure. There are also situations where the researchers are faced with a real ethical dilemma concerning what to do about information received in confidence. There are some examples. A research project may gather information about illegal behavior, such as drug use, or it may gather information that is reportable to the authorities by law. This may be information about infectious diseases, or information about child abuse. The question a researcher has to ask is what to do about that information. Should it be kept confidential, or should it be reported, as required by law, to the relevant authorities, thereby breaching the promised confidentiality provided in the informed consent process? Similarly, what should a researcher do if authorities, suspecting criminal activity for example, demand to get access to confidential information, maybe even with a court order? More importantly, perhaps, is what should be said to potential participants during the informed consent process. Should there just be a general phrase, to the effect that confidentiality will be ensured? Or

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should there be a detailed listing of the types of information that will not be kept confidential, and should there be a general phrase that there is a chance that unauthorized people may gain access to the records? If this type of information is provided to potential participants, there is of course the danger that recruitment will suffer, and that participants who would otherwise want to take part in the trial are scared off because of a misunderstanding concerning the dangers of wrongful disclosure of confidential information. These are just some of the issues raised by the principle of confidentiality. The important point is that they need to be addressed during protocol development and preparation of the informed consent form.

References (1) Barry, M., Molyneux, M., 1992. Ethical dilemmas in malaria drug and vaccine trials: A bioethical perspective. Journal of Medical Ethics 18:189–192. (2) Brennan, T.A., 1999. Proposed revisions to the Declaration of Helsinki-will they weak the ethical principles underlying human research? New England Journal of Medicine 341:527– 530. (3) East African/British Medical Research Council 1972. Controlled clinical trial of shortcourse (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet i:1079–1085. (4) Innis B.L., Rapin S., Prayura K., et al 1994. Protection against hepatitis A by an inactivated vaccine. Journal of the American Medical Association 271:1328–1334. (5) Love, R.R., Norman, C.F., 1997. Ethical and regulatory challenges in a randomized control trial of adjuvant treatment for breast cancer in Vietnam. Journal of In6estigati6e Medicine 45:423–431. (6) Muraskin, W., 1995. The war against hepatitis B. A story of the International Task Force on hepatitis B immunization. Philadelphia: The University of Pennsylvania Press.

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(7) Nosten F.F., Kuile L.M., Chongsuphajaisiddhi, T., et al., 1994. Mefloquine prophylaxis prevents malaria during pregnancy: a doubleblind, placebo-controlled study [see comments] J. Infect Dis. 169:595 – 603. (8) Steketee, R.W., Jack, J.W., Allen, W.H., et al., 1996. The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity and intrauterine growth retardation in rural Malawi. Am. J. Trop. Med. 55:33–41. (9) Whittle, H.C., Davidson, N., McD., Greenwood, B.M., et al., 1973. Trial of chloramphenicol for meningitis in Northern Savanna of Africa. Br. Med. J. 3:379 – 381.

15. Current Vaccine Research in Africa Engaging Ethics Problems Dr Malcolm Molyneux Director, Wellcome Research Laboratories, College of Medicine, Uni6ersities of Malawi and Li6erpool

15.1. Introduction Some of the ethics issues in vaccine research are common to all kinds of health research. Other ethics problems are peculiar to (or pose special challenges in) the context of vaccine research: it is these that are the subject of this paper. Vaccine related ethics issues are important because of the great need for vaccine research: immunization is a convenient measure with a track record of many spectacular successes, yet there remains a heavy burden of uncontrolled infectious disease in Africa.

15.2. Ethical Imperati6e Infections continue to account for the majority of deaths in children and adults in Africa, absences from work and school, and contribute to impaired growth in children (1). The HIV epidemic has promoted a resurgence of opportunist infections in adults and also in children. The

success of some vaccination programmes has been attributable to long-term efficacy and operational feasibility. The existence now of structures for the delivery of vaccines in the Extended Programme of Immunisation (EPI) provides a ready-made pathway for the delivery of new vaccines if these can be demonstrated to be effective. Equity in health provision and delivery is an important ethics concern (2): vaccines have a greater potential for equitable distribution than many other health interventions. In view of the importance of infections and the potential benefit of vaccines, there is a strong ethics imperative to conduct vaccine research. It would be unethical on the part of the scientific community not to promote, conduct, and teach vaccine research in the current context of diseases in Africa. Vaccine research must not only be constrained, but must also be promoted, by ethical considerations. Research unethically neglected is not as obvious or as easy to criticize as research unethically done; nor are the culprits as easily identified. All members of the scientific community worldwide share in this responsibility.

15.3. Cost, Allocation of Resources and Security of In6estment Companies face a double risk when investing in a vaccine for a disease of the poor. First, trials are expensive but necessary, and many will yield no return, because efficacy cannot be predicted. Second, populations most in need of the vaccine may be unable to afford it, even if it works. This is an ethics challenge to rich nations, who have the capacity to help but whose private industries cannot be expected to shoulder such risks. Using the example of malaria, it has been suggested that a practical solution by which companies could be spared the second of the two risks, and indeed be attracted by the potentially huge market, would be to make a firm pledge to purchase an effective malaria vaccine for Africa’s 25m newborn children each year if such a vaccine is developed (3). They would guarantee a minimum purchase price for a vaccine that meets minimum conditions of efficacy, and perhaps raise the price for a better

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one. The recipient countries might also be asked to pledge a part of the cost, depending on their incomes. But nothing need be spent by any government until the vaccine actually exists. The world’s extreme disparities of wealth underlie many of the ethical problems discussed in this conference. The above suggestion could be one way of addressing this issue in a way that is achievable and potentially highly beneficial.

15.4. Benefits to a Population During a Vaccine Trial Phase 3 trials may continue over a period of months or years, during which participants will be carefully observed. There is a need for passive case detection and regular follow-up, and usually for other assessments which may include blood sampling. To achieve this in a population who have limited access to meagre health services is likely to require the setting up of improved diagnostic and treatment facilities. There are both scientific and ethics issues around this provision. The ethics challenge is to find the right balance between inducement and reasonable compensation. If taking part in a trial provides a participant with a greatly improved health service, there may be a strong inducement to consent; failure to provide such services makes unfair demands on volunteers and anyway makes adequate assessment of the vaccine unattainable. When possible the services provided should be available to all who have been asked if they are willing to take part in the trial, whether they consent to participate or not. A scientific problem with the provision of improved services is that these may change the disease being studied. In a trial of a malaria vaccine that includes intense follow-up surveillance, including the diagnosis and treatment of fevers, the incidence of endpoints such as severe disease or anaemia may be considerably reduced by those measures alone, so that a vaccine effect becomes undetectable. Yet the value of a vaccine may be greatest if it works in the absence of efficient diagnostic and treatment services. If improved services are provided to make a trial possible, the question will arise about what should be contin-

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ued after the trial is over, and for how long. Hopefully the trial itself will have generated expertise among staff as well as some improvements to facilities, and these will remain on the ground after the investigation is finished.

15.5. Benefit to the Community if the Vaccine Works Apart from the benefits to a community through the provision of facilities and training needed to conduct a study, there is a larger question about how the study population should benefit directly from the vaccine, if it proves to be efficacious. It is generally agree that a community should benefit from knowledge or products resulting from research done on its people, and that failure to provide benefits of such research to the participants is unethical. But this principle raises several questions, especially in vaccine research. 1. How far should the benefits of a successful study be spread in the first instance – is our obligation only to the individuals who participated in the trial (eg to all who were allocated to the placebo arm of the study), or to the community from which they came, or to the entire area or country? And is it limited to the immediate future or the longer term? 2. Must research only be done on products that are now affordable, and that could be provided immediately if proved effective? At the time of testing, a product may not be in marketable form, and so has no measurable price; its price (and whether it moves to product-development at all) may depend largely on the outcome of the proposed study, and thus be unpredictable. 3. Vaccines that may have a market in both poor and wealthy nations (eg HIV) may be most quickly and easily tested in a population with the highest incidence of infection and other trial endpoints. This is likely to be a poorer community. But richer communities may benefit more quickly from the product if it proves to be effective, especially if it is expensive. How much disparity between local and distant benefit is ethically acceptable?

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4. Whose responsibility is it to provide to the community the benefits of knowledge or products gained from a study? This responsibility could lie with investigators, sponsors, manufacturers, funding agencies and governments. The different roles of each of these may seem clear, but links between them are often poorly developed. For example mechanisms for translating research findings into policy, and for translating policy into practice, are sometimes inadequate or non-existent. Each of these questions needs to be grappled with, and there are no uniform answers applicable everywhere. The most important ethics principle is that these questions should be addressed jointly, by investigators, sponsors, and trial participants, before the trial is undertaken, and agreements reached, preferably in writing, that are acceptable to each group as was the case for the consensus statement on perinatal HIV intervention (4). These agreements need to include measures to be taken if the vaccine proves effective, and also if it proves ineffective.

15.6. Consent Unlike trials of treatment for acute disease, when a patient or guardian must decide immediately whether to consent to enrolment in a study, vaccine trials allow time for the consent process to be planned and phased. This provides the opportunity, not available for trials of treatment for acute illness, to meet with the community, discuss the trial with them and learn their views and concerns. This also provides an opportunity to obtain both individual and community consent. In some cultures an individual may be reluctant to consent to take part in a study without the support of the community as a whole. Failure to seek communal consent may therefore place the individual under undue strain. There is however a danger that consent at the communal level may exert pressure on individuals, who may not feel they have the liberty to decline if they wish. A family could be physically expelled from one commu-

nity simply for refusing to take part in a trial to which the community had consented. There are other ways in which cultural sensitivity is important. In some communities individuals are reluctant to sign forms because of the fear that there may be implications they do not know about. Individual signing may either need to be dispensed with or thoroughly explained in these circumstances. The degree to which consent is ‘informed’ may be a particular challenge in the context of vaccine trials, since concepts such as immunization, randomization and placebo may be unfamiliar to participants. Misunderstandings may be dangerous, for example, if a mother in a malaria vaccine trial believes her child is no longer at risk from the disease and therefore need not have prompt treatment for fever, or if a person in an HIV vaccine trial believes that high-risk sexual behaviour is now safe. The above considerations underline the importance of a careful approach to the seeking of consent, making use of local experience and expertise. A useful enhancement of the consent process is to re-visit later in a trial the question of how well participants understand the study to which they have given consent. In phase three vaccine trials, which require participation for months or years, ‘giving consent’ need not be something done once only at the beginning, but a process to be evaluated and reinforced at intervals during the study, perhaps at times of review or cross-sectional assessments of the study subjects.

15.7. Altruism Adequate individual compensation, or personal benefits during or after a vaccine study, may not be the only reasons for people’s willingness to take part in a vaccine trial. They may wish to see benefit to the community as a whole or progress against a disease in their population, or have wider humanitarian concerns. This altruism is of great benefit to research and may be a reason for agreement to participate in trials. It adds further to the need for care on the part of investigators, to make sure that this positive

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principle is not exploited, and that people understand the balance of risks and benefits as fully as possible. Conversely, we must remember that people not only have a right to refuse to be studied; they also have a right to accept understood risks, if they wish to contribute to progress against a disease which afflicts them or the wider community.

15.8. Mechanism of Ethical E6aluation of Vaccine Studies Vaccine studies are commonly collaborative. Ethics scrutiny and clearance often need to be achieved separately by several institutions, whose priorities may be different. It may be helpful for the various ethics committees to communicate, to understand each other’s objectives, and even to produce a joint agreement about a particular research study or strategy. The way in which local, national and foreign ethics committees work together with mutual respect is as important in vaccine research as in other research topics, and is considered at greater length elsewhere in this series.

15.9. Fundamental, Basic, and Pre-clinical Vaccine Research in Africa At present the greatest capacity for basic vaccine research is outside Africa. The importance of being ‘on site’ for basic research, even for diseases more prevalent in Africa than elsewhere, is less obvious than it is for clinical and field evaluations of vaccines. There are potential benefits of investing in increased basic research capabilities in the region. Such investment is likely to improve the overall scientific ‘milieu’; to provide scientists with local opportunities; and to keep basic science ‘in touch’ with the pressing disease problems of the local population. It may also provide important advantages not available at a distance, such as the use of local parasite or bacterial isolates from well-defined clinical situations without interposing cryopreservation. This is an ethics issue because it affects the equity of distribution of opportunity and intellectual property ownership.

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15.10. Special Considerations for Field Trials of Vaccines Against HIV HIV vaccines may be directed at preventing infection or at slowing disease progression. For an infection-preventing vaccine only sero-negative subjects should be enrolled, while a disease-slowing vaccine requires only HIV infected subjects. Therefore in either case the HIV status of participants needs to be known in advance of the trial, and proper provision of pre- and post-test counseling must be in place.

15.11. Confidentiality In each case there may be difficulties over confidentiality, enrolment or non-enrolment in the study may signify an individual’s HIV status.In order to avoid this problem, it may be necessary to include other components within a trial, so that it is publicly known that enrollees may be either HIV infected or uninfected.

15.12. Clinical Ser6ices As HIV-positive subjects will either be enrolled or will be identified during the trial, disease events are likely to be frequent and may increase with time. Sufficient clinical facilities for diagnosis and management must be in place for the duration of the study, and the question of how long these will continue to be provided after the trial must be considered in advance.

15.13. Specific HIV Treatment Whether the trial will monitor individuals with existing HIV infection or identify new HIV infections that occur, there will have to be a decision as to whether specific anti-retroviral therapy will be given, and if so which drugs and whether this will be for the duration of the trial only, or over the longer-term future. Most observers now believe that the treatment offered to HIV-infected subjects in a trial should be the best available in the country where the study is being conducted, rather than the best available in the world. We can imagine a vaccine that would slow disease progress to the same extent as a drug regime but

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much more cheaply and conveniently; yet it may not provide additional benefit to a subject already taking the drug regimen. Is it possible to demonstrate this if all subjects must be taking the drugs?

15.14. Inducement Provision of both clinical services and specific anti-retroviral treatment may provide a strong inducement for individuals to participate in a vaccine trial, especially if each of these provisions is scarce or expensive in the community. This adds to the need for careful explanation and for consent to be as fully informed as possible.

15.15. Undue Expectation Because of the poor prognosis of HIV infection, especially where powerful drug regimens are not available, individuals may be keen to participate in a trial of a disease-slowing vaccine just because no other hope is available. Extra care must be taken not to exploit this predisposition.

15.16. Spread of Responsibility If an HIV vaccine is being tested in neonates (e.g. against HIV infection through breast milk), the provision of care and drugs to the mother must be considered. In trials involving adults in the general population, advice about sexual partners must be given, and investigators must decide whether participants in the trial must be encouraged to inform sexual partners about their HIV status and about the trial.

15.17. Impact of HIV on Trials of (Non-HIV) Vaccines When a vaccine against another infection is being evaluated in a population where there is a high HIV infection prevalence, the impact of HIV must be considered. The infection may affect both the disease being studied and the efficacy and toxicity of vaccines. Knowing the HIV

status of participants in a trial may be essential to the proper assessment of the comparability of groups and the interpretation of endpoints. It may also be essential in deciding the likely applicability of the results to other populations. What is the best policy about HIV testing in vaccine trials? Should consent to HIV testing always be a requirement, even if it may impair or enhance enrolment? Is anonymous unlinked testing a possibility? If so, does it require participants’ consent? Should the option of being told their HIV status always be offered to study subjects? What specific care can or should the study offer to those found to be HIV seropositive, and for how long should this continue? Should it stop with the end of the trial? These questions must be addressed in advance of the study, and guidance from the local ethics committee is likely to be necessary. The study design must include provision for the necessary counselors and the implications for care that will be required.

15.18. Study Design Bad science is bad ethics. Unfortunately the converse is not always true, for good science is not necessarily good ethics, and good ethics may not be good science. But good study design is necessary, if not sufficient, for a study to be ethically acceptable. This is especially true in the trial of an intervention such as a vaccine, which makes considerable demands on a community or population. It is an ethics requirement that the design provides an optimal opportunity for the risks and benefits of the product to be correctly identified. For this reason it is difficult to separate scientific from ethics evaluation, and commonly the same committee must assess both the scientific and ethics aspects of the proposal. Due consideration must be given to all parts of a trial: choice of comparator/placebo, criteria for enrolment and exclusion, consent procedures, sample size, randomisation, blinding, active/passive case detection, primary and other endpoints, recognition of adverse events, stopping rules, monitoring procedures, data handling, analysis, dissemination of results.

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15.19. Duration of Follow-up An aspect that is often given attention too late in the course of planning and budgeting for a vaccine trial is how long to continue observations after the administration of the vaccine/placebo. The primary and other endpoints may fall within a period of 1 or 2 years; but after that time other important questions may remain to be answered. If the vaccine works, this trial may provide an opportunity to determine how long the benefit persists; one or several more years of observation may provide invaluable information, including an opportunity to measure the boosting effect of intercurrent natural infections. This will be possible only if the placebo group remains unvaccinated. However, it may not be good ethics to withhold an efficacious vaccine from the placebo group for this added period. Prolonged and blinded placebo-controlled follow-up may also allow investigators to watch for the possibility of a delayed adverse effect of a vaccine that appears beneficial at first. For example, it is possible that a vaccine (for example against malaria or hepatitis A) may prevent infections temporarily, thus denying individuals the process of immunization by natural infections, and leaving them more susceptible to infections later, at an age when disease may tend to be more severe. Finally a vaccine may have no effect in the period studied, but might nevertheless convey a benefit later; for example a malaria vaccine administered within EPI, may not affect uncomplicated illness or anaemia, but could have a benefit against malarial coma, which tends to affect slightly older children. Again, a prolonged period of observation would be necessary to detect this.

15.20. Surrogate Markers of Efficacy A dilemma is posed in vaccine field trials, when an endpoint occurring with adequate frequency (eg uncomplicated malarial illness) must be used to assess the vaccine, while the ultimate objective of the programme is different, (e.g. to reduce the incidence of severe or fatal disease). Unfortunately efficacy against the accessible endpoint does not imply efficacy against the less common,

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more serious one. Is it ethically acceptable to use a placebo in the Phase 4 trials (which have mortality as the end-point), if the vaccine has already proved effective against uncomplicated illness in the Phase 3 trials?

15.21. Long-term Effects on Disease in a Population In many infections (eg giardiasis, malaria) intense natural exposure to the infecting agent in early life appears to convey partial protection against severe disease in later life. A successful vaccine programme could reduce this effect — e.g. converting malaria from ‘stable’ to ‘unstable’ endemicity, with potentially harmful consequences. Should this consideration affect the decision to embark on testing a vaccine in a population? How should long-term monitoring, to detect and deal with this possibility, be achieved?

15.22. Other Pre6enti6e Inter6entions A vaccine may be only one of several possible preventive measures against a disease — e.g. bednets for malaria, latrines for diarrhoeal diseases. An effective vaccine may be a potentially more manageable intervention; its benefit may be greater or less in the presence of these intervention programmes. Is it acceptable to deny a population other proven interventions while testing a vaccine? Is it ethically necessary to provide them?

15.23. Applicability of Results Elsewhere Many vaccines have been clearly effective worldwide. But vaccines may not have the same benefit in all populations. The spectrum of variants of an infecting organism, for example rotavirus, HIV, and Pneumococcus, may differ between human populations, affecting the efficacy of a particular vaccine. Or a vaccine may differ in its effects in populations with differing endemicities, in a disease where the clinical spectrum depends on endemicity, for example malaria. When does a vaccine that is efficacious in one setting require to be re-evaluated before it is made use of in another?

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15.24. Ownership of Data Many institutions and individuals may have a claim to ownership of data, especially with vaccine trials as these usually involve multiple participants, for example, sponsor, manufacturer, host field institution, and collaborating centres. Determining ownership and authorship is a complex process that is often worked out informally towards the end of a trial. Difficulties may be prevented if these questions are tackled early in the course of planning the trial.

15.25. Getting the Community’s Views The ethics of vaccine studies tend to be discussed among scientists, manufacturers and sponsors. The community seldom gets a formal opportunity to contribute to the debate. The process of obtaining community and individual consent may allow an opportunity for the community’s views to be sought on many of the ethics questions discussed in this article. Communities can provide surprising and often enlightening or challenging contributions on debatable issues. It is ethically right, and may also be valuable, to pay attention to the opinions of those who will be the subjects of a trial.

References (1) World Bank: World De6elopment Report. The World Bank 1998. (2) Gwatkin D R: Health Inequalities and the Health of the Poor. Bulletin WHO 2000; 78:3–18 (3) Sachs J. Helping the World’s Poorest. The Economist 1999; 14-20 August: 17 – 20. (4) Consensus Statement: Participants of a Workshop on Perinatal HIV Intervention Research in Developing Countries: Science, Ethics and the Future of Research into Maternal Infant Transmission of HIV. Lancet 1999; 353:832 – 835.

16. Research Involving Human Subjects: Ownership, Control, and Access to Research Medical Records Prof. Yohana J.S. Mashalla Department of Physiology, Muhimbili Uni6ersity College of Health Sciences, Dar-es-Salaam, Tanzania

16.1. Abstract For centuries the perception of research involving human subjects, has been beyond argument, and human subjects have volunteered unconditionally to participate in researches. The image of medical research has now become even more favourable because of the HIV pandemic, and demands from women and other groups that they be included in the surveys. However, researches which have not been well thought out, and or are improperly executed, may be associated with risks to the participating subjects. The risks range from possible exploitation, especially of vulnerable groups such as the sick, women, children, the poor, and other people, who for some reasons may not have the capacity to give informed consent. Research involving human subjects may also cause physical and or psychological damage to the participating subjects, especially where the integrity and cultural values of the individuals are transgressed. The Nuremberg Code, Declaration of Helsinki, CIOMS Guidelines on Biomedical Research, and other country specific codes, are among those commonly used as reference guidelines on research involving human subjects. While such guidelines have shown positive results, issues related to ownership, access, and control of research results, are still inadequately covered. It is expected that with research being associated with risks of varying severity, clear and precise guidance should be given on the rights of participating subjects to the results of the research. It should be borne in mind however, that whatever recommendations are to be made the autonomy and integrity of the participating subjects and their cultures should always be respected.

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16.2. Introduction The definition of research has been a subject of debate especially with regard to the distinction between medical practice and medical research. The distinction is derived from the intent and in medical practice it may be said that the intention is purely to benefit the patient without necessarily having to gain any knowledge of the general benefits although such knowledge might be ultimately gained from the clinical experience. On the other hand, in medical research, the primary objective is to advance knowledge so that in the end patients in general may benefit from the research, although the individual patient may not necessarily have immediate benefits. Generally, societies have benefited from advances in medical science through research, and communities are keen to see that research continues and is promoted within an acceptable framework. In elaborating such a framework, ethicists have sought to balance the desire of researchers to advance knowledge and the rights of the research subjects. In research involving medical practice, an important aspect of the balance concerns the patients’ right to autonomy and the doctors’/researchers’ duty to act in the best interest of the subject. Patients’ autonomy and choice in the context of research is debatable and in the past researchers’ disclosure of information to subjects was dominated by the notion of beneficence. The primary objective then was to maintain patients’ or subjects’ morale and sense of hope. Uncertainties were hidden from the subjects until Percival in 1803 offered an advice that ‘the balance of truthfulness yields to beneficence in critical situations’ (1). Not all research involving human subjects however, is carried out with the primary objective to benefit the patient. Research may be carried out for the purpose of generating income for further research, as part of knowledge for training medical personnel or to further the researcher’s carrier. The task of ensuring that the balance between possible risks against benefits is in many countries the responsibilities of the research ethics committees. Unfortunately, there is no legal obligation for researchers to obtain independent ethical approval for studies although in practice, it is almost impos-

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sible to obtain financial support for a study, which does not have approval by an ethics committee. There are also no binding rules to govern the work of the ethics committees especially in developing countries, which now seem to receive considerable research attention and financial support from all corners of the world. Immediate effort should be directed at ensuring that specific legislation and guidelines are put in place if research involving human subjects is to be carried out and monitored in conformity with internationally acceptable standards.

16.3. Need for Research In6ol6ing Human Subjects Studies involving human subjects have to continue if medical knowledge in the search for new cures and training are to be realized. The attitudes towards medical experimentation have for centuries been conceded to be beyond argument. In the 18th century for example, condemned prisoners volunteered to participate in medical experimentation in exchange for their freedom only if they survived the experimentation (2). In the recent years however, the HIV pandemic, pregnant women and some ‘minority’ groups in society have shaped the image of medical experimentation. Contrary to earlier studies, they have questioned why they are being marginalized, demanding they be included in studies in the search for new cure of diseases. They are prepared to share the benefits and risks associated with the studies. Such positive attitudes are pivotal in research involving human subjects for the purpose of advancing medical knowledge and management of diseases as they occur in humans. Following the Second World War, information was brought to the attention of the world community that atrocities were committed in Nazi concentration camps in the name of scientific research. This led to a serious world concern and hence the birth of the Nuremberg Code (3). From such practices and other similar experiences, scientific research has been shown to pose risks of exploitation where vulnerable groups are concerned, cause harm in the sense of causing physical damage or disadvantaging the subjects.

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Similarly, research may cause harm by doing wrong in the sense of moral or psychological harm through ignoring the respect and autonomy of the research subjects. People feel offended when their sense of autonomy, dignity or values are deprived on the assumption that the research outcomes are necessarily superior to their traditional values. Criticism has rightly therefore, been directed at researches or research proposals that ignore the rights of the research subjects, or whose methodology, execution or utility is suspect. Research subjects and the public worry that some research projects have not been well thought out and are flawed from scientific norms. Historically, there have been good grounds for such concerns, and even in the recent years examples of flawed protocols have been documented. In 1966, Beecher (4) identified 50 studies that were carried out although they qualified to be unethical, and he made reference to 186 other examples. Similar concerns led Pappworth (5) in 1967 to publish his influential study ‘Human Guinea Pigs’ which then laid down grounds for establishing review committees. It was expected that review committees would minimize or eliminate unethical and flawed research practices. This however, was not the case and the integrity of the review committees was put to question in a notable example in 1981 in England, when an elderly widow died from the effects of a drug in a randomized clinical trial which had been approved by eleven review committees. Her death was due to bone marrow suppression induced by the drug. Notable in this example was that the subject was included in the study without her knowledge. It is therefore, not difficult to understand the apprehension of the research subjects regarding research. Society and health professions have concentrated on building an ethical framework that would permit research activities to progress while at the same time maintaining the public’s confidence that individual autonomy is respected. Various efforts have been made to achieve this. In Britain, the Department of Health commissioned specific training materials for members of the ethics review committees (6). The King’s Fund Report (7) draws attention to the confusion experienced by some members of the

ethics review committees about their role and has given recommendations on both the work of the ethics review committees and on measures to be taken to facilitate good ethical practice. While various guidelines have been prepared and have set standards, unfortunately in many countries of the world such guidelines do not have the force of law. Nevertheless, even in the absence of the force of law, in some countries influential research bodies have made considerable efforts to promote good practice. One such example is the Association of British Pharmaceutical Industry (ABPI) (8) which has voluntarily adopted as a policy the European Commission’s principles of ‘Good Clinical (Research) Practice in advance of this being mandated by a European Commission Directive. While efforts to ensure that good clinical and research practices have began to have positive effects, the question of ownership, access and control of research results is still unresolved. In any case there are ethical and legal considerations to be made when discussing ownership, access and control of records. To easily understand the intricacies associated with ownership, access and control, the subject is addressed in the light of clinical practice and research.

16.4. Ownership, Access, and Control of Records in Clinical Practice The question of access to and control of medical records has a bearing on the fact of ownership. Ownership is simply defined to be the ‘state of owning something while the owner of something is the person to whom it belongs’. The concept of ownership in research is not clear, and even in law it is not well developed (9). In discussing ownership, it is important to differentiate the information that belongs to the subject, the opinion that the physician brings to the raw information collected from the subject and the process involved in documenting the information. At the common law, it is agreed that the person who writes the records should be the person who ‘controls’ the records. A good example is that a physician attending a patient, ‘owns’ the records generated in the process. In the view of the BMA, when a patient is

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registering with a General Practitioner, information is passed from the patient to the doctor in confidence. Therefore, the patient must have control of the information and both the patient and the practitioner may benefit from the sharing of the information. The pre-requisite for the patient to have control over the information one has provided, is first to have access to that information.

16.5. Patients Access to Medical Records While ‘control’ is defined as the power to make all the important decisions about the way something is run; ‘access’ is more strongly expressed to mean the opportunity or right to use or see something. In the tradition of medical practice, confidentiality is a requirement of the doctor-patient relationship and the management and security of medical information is only one aspect of that duty of confidentiality. In the past, confidentiality dictated strongly access to information, and it was stretched to mean that health records were kept confidential even to the patients who had provided the information. Nowadays, there is general support for openness and frankness between the doctor and the patient that patients should have access to information about themselves. Privacy is a fundamental right, which empowers individuals to decide the manner and the extent to which information about them is shared with other people. Such personal control is at the core of legislation enabling patients to access their health records. Self-determination in this respect is central to the preservation of the dignity and integrity of the individual. In England, the right of the patient to information about themselves is prescribed in the Access to Medical Reports Act of 1988, and the Access to Health Reports of 1990 (10). Unfortunately, the Access to Health Act does not prevent doctors from giving the patient wider access to the whole record, nor does it contain provisions that guide the doctors to only provide access to personal information upon formal application. Doctors are encouraged to give patients access to all information held about them, unless there is good course for withholding information. There are circumstances where access to infor-

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mation about the patient may be withheld e.g. when it is believed that access is detrimental to the patient’s health or when the access may lead to confidentiality of other persons compromised. In such cases, no information that identifies or relates to other persons can be revealed to the patient without the consent of the identified person. Withholding access to information by patients because disclosure might be embarrassing to the doctor should be discouraged. Access to information on behalf of others is also permissible. However, care must be exercised when dealing with persons who have ability to consent. In law, the age of an individual is not relevant to such access as long as the subject is capable of understanding what is entailed, and therefore have the right to access to information. Problems arise in the case of a minor capable of giving consent, but prefers to keep secret personal health records from parents or guardians. In such cases, parents may apply to have access to information about their children only if the minor’s consent has been given (11). Parental access to minor’s records should be discouraged where it conflicts with the interests of the minor or any other persons that fall into similar categories. There is need to ask in practice, to what extent have patients or research subjects the power to make all important decisions about the way the results of the research should be handled?

16.6. Ownership and Access to Research Results In many developing countries research is not governed by legislation, and a number of researches are carried out, and results are published without the knowledge of a national medical research council, if it exists. In some cases, where a coordinating body exists, institutional ethics committees have granted ethical clearance for research proposals without furnishing to the coordinating body the nature, procedures and the outcomes of the research. From the risks that research subjects may be subjected to during research, there is need for statutory regulation. In France, the law of 20th December 1988 ‘relati6e a la protection des personnes qui se pretent a des recherches biomedicales’ that is ‘for the protection of human research subjects’, exists and

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is much tighter. There is however a wide range of guidelines on biomedical research. The most widely known ones include the World Medical Association’s Declaration of Helsinki (12), and the International Ethical Guidelines for Biomedical Research Involving Human Subjects produced by the Council for International Organizations for Medical Sciences in collaboration with the World Health Organization (13). The latter includes guidelines for ethics review of epidemiologic studies, and takes into account needs for developing communities. Whereas, the Declaration of Helsinki provides more specific guidance on how the conduct of research should be, it does not provides specific guidance on ownership and access to research results by the participating subjects. Moreover, the Declaration lacks focus on what should happen after completion of the research. The views of the BMA is that while financial sponsors have a right to receive the full results of research, institutional or local research ethics committees have a responsibility to ensure that patient research is free from commercial bias. In studies which involve sustained cooperation, the patient as well as the sponsor should be informed of the outcome. The South African Medical Research Council (SAMRC) has made great effort to discuss ownership and control of research results. The SAMRC has in its opening paragraph stated that ‘any discovery which is potentially valuable, whether patented or not, and which is made during SAMRC supported research, must be developed in the interest of society’. In relationship to establishing titular control of research results, it emphasizes its ownership role by stating that ‘The administration of any patent rights on inventions, discoveries and improvements which originate with SAMRC supported research, the patent rights will held by the SAMRC’ (14). In terms of the Copyright Act 98 of 1978, the SAMRC agrees with the BMA views that the writer of the research report is the owner of the copyright, unless the writer wrote the report as an employee, in which case the employer is the owner. Even here the SAMRC still makes a condition of the granting of bursary or award that the copyright shall be vested in the MRC on

completion of the report. Similarly, the SAMRC is in agreement with the BMA views on the rights of financial sponsors on the research reports that financial sponsor may have the right to receive the full results of the research. However, it should be the responsibility of the investigator to ensure that there has been prior agreement with the sponsor that the results of the research may be submitted to journals of the investigator’s choice and that the sponsor should not influence publication of the results. The SAMRC falls short of clear guidelines on the rights of the patients to research results. For example, the guidelines state that ‘in studies that in6ol6e sustained cooperation on the part of the patient, it is good practice to make agreements to inform participants of the outcome of the research in broad terms and to combine this, with a letter of thanks or a small gift in the case of children’. In the SAMRC context, the rights of participants to research results have been reduced to ‘mere information of the research outcomes in broad terms’. There is no mention of the rights of participants to information generated from their participation in the research or not. In this case the letter of thanks is probably meant to replace that right and in the case of children a small gift. Critical analysis of the words ‘good practice’ raises conceptual questions on the rights of participants to research outcomes by the SAMRC. If good practice has to be meaningful, there was need to have it defined and stating clearly what constitutes good practice. ‘Good practice’ may bring interpretation challenges where ‘innovative research’ is concerned because in innovative treatment or therapy, the practicing physician may depart significantly from standard or accepted practice for the benefit of a particular patient.

16.7. Participation in Health Research by Non-medical Personnel In 1964, the World Medical Association (WMA) drew up a code of ethics on human experimentation. This code was amended in 1975 and 1983. On section 1 (3) of the Basic Principles, it states that ‘Biomedical research involving human subjects should be conducted only by scien-

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tifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with the medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent’. The guidelines show the true medical nature of the WMA and that, for years there have been little interdisciplinary collaborative activities between social science and medicine, a reflection of the bureaucratic barriers to interdisciplinary collaboration inherent with problems of professional territoriality found worldwide. As a result, medical scientists and social scientists saw themselves as independent groups with little in common. Things have now changed and it is becoming increasingly recognized that illnesses and diseases have social roots and the need for interdisciplinary collaboration between the two groups is being given priority both at international and regional levels. Some of such initiatives are the long involvement of social scientists in the work of the WHO’ Special Programme for Research and Training in Tropical Diseases (TDR) through its social and economic programme, and the INCLEN’s decision to include social scientists in their programmes. The rising numbers of international social science and medicine associations with particular reference to Africa, such as the SOMA-NET, International Forum for Social Science and Health, Pan African Association of Social Anthropologists, African Association of Medical Anthropologists, and SOSMED, reflect strong support for interdisciplinary collaborative activities. In the light of such developments, there is equally need to address the roles of non-medical persons in research involving human subject and answer some of the following questions: 1. Should non-medical persons carry out research involving human subjects without the supervision by clinically qualified persons? 2. Should the responsibility for the human subjects in medical research rest on other than medically qualified persons? 3. Should non-medically qualified persons have the right to access medical records for the purpose of research?

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These are by no means easy questions to answer, particularly considering the contributions of non-medical persons such as social scientists to the current in-depth knowledge of the concepts and perceptions of diseases in different communities, more so in the developing countries.

16.8. Storage of Research Results There are no universally accepted guidelines on who should keep storage of the research results and the duration for which identifiable research results should be kept. However, it is general practice that any research information that is likely to have immediate benefit to patients should immediately be made known to the public. Research results should be kept in such a manner that the identity of participants is coded and the key to the code kept secure by the investigator. When the research is completed, the need for continued security and confidentiality should remain for a minimum of 5 years. Confidentiality of identifiable records should be maintained even after death and where the researcher wishes to access such information arrangements should be made to obtain consent from close relatives or the institutional research review committee, where it exists.

16.9. Conclusions This has been an attempt to highlight some of the gray areas in this large subject and by no means exhaustive. There is therefore an urgent need to define ownership, access to research results, discussion of the legal and ethics issues related to the subjects, and reaching consensus on these and other related issues. Finally recommendations should be made which will guide researchers, more so for those working in developing countries.

Acknowledgment I wish to thank the AMVTN Task Force for the honour of inviting me to make this presentation. Many thanks also should go to all organiza-

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tions that have devoted great effort to publishing guidelines for biomedical research, and also to those who have contributed their thoughts and time in making this presentation a success.

References (1) Lake CD, (Ed). Perci6al’s Medical Ethics. Williams and Wilkins, Baltimore, 1927. (2) Wells F. Bioethics and Industry. International Journal of Bioethics, Paris, 1993. (3) Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law, No. 10, vol. 2. Washington, DC: US Government Printing Office, 181: 1949. (4) Beecher. Ethics and Clinical Research. New England Journal of Medicine, 274, 1966. (5) Pappworth H. Human Guinea Pigs. Routledge and Kegan Paul, London, 1967. (6) Royal College of Physicians. Guidelines on the Practice of Ethics Committees in Medical Research Involving Human Subjects, 1991 (7) Neuberger J. Ethics and Health care. The Role of Research Ethics Committees in the United Kingdom. King’s Fund Institute, 1992. (8) Association of British Pharmaceutical Industry (ABPI). Guidelines on Medical Experiments on Non-patient Human Volunteer. London, ABPI, 1988. (9) BMA Ethics Division. Rights and Responsibilities of Doctors. BMA, 1992. (10) Mitchels B and Prince A. The Children Act and Medical Practice. Family Law, 1992. (11) World Medical Association. Handbook of Declarations. World Medical Association, 1985. (12) Council for International Organizations of Medical Sciences. International Guidelines for Medical Research Involving Human Subjects. Geneva, 1993. (13) Council for International Organizations of Medical Sciences. International Guidelines

for Ethical Review of Epidemiological Studies. Geneva, 1991. (14) South African Medical Research Council. Guidelines on Ethics for Medical Research, pp. 44–47, 1993.

17. Equitable Sharing of Research Burden and Benefits Adetokunbo O. Lucas, MD Visiting Professor, London School of Hygiene and Tropical Medicine (Read on behalf of Prof. A.O. Lucas by the late Robert Mshana, MD, PhD)

17.1. Abstract The ultimate objective of health research is to generate knowledge for improved health. Research projects involve investments by research scientists, their sponsors and the subjects of the study. All the contributors to the enterprise should derive appropriate rewards proportionate to their respective contributions. The subjects of the study and their communities should be potential beneficiaries of the expected outcomes of the study. Ideally, useful products from the research should be accessible and affordable to the participating communities. All the sponsors of the study should be acknowledged in publications and in sharing the fruits of intellectual property generated from the study. Collaborative research involving scientists from the same or different departments, institutions and countries should be designed to recognise the respective contributions of all partners. National governments should empower African scientists by giving adequate support to their institutions so that their scientists can negotiate agreements with their colleagues from developed countries on the basis of peerlevel interaction. They should also support regional networks thereby strengthening their relationships with colleagues who are dealing with problems that are similar to theirs in comparable circumstances.

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17.2. Introduction The ultimate objective of health research is to generate knowledge that would promote good medical practice, personal health care, as well as health-related community and environmental interventions. The ethical justification of health research is the expectation that the findings can contribute to the pool of knowledge that will guide health policy and practice. The ideal design would include strategies that minimize risk to the subjects and maximize the chances of generating useful new knowledge. We should adopt the slogan for health research: ‘knowledge for impro6ed health’.

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studies are being assessed. This is particularly relevant in the design of clinical research. Subjects should not be exposed to frivolous investigations which cannot be expected to produce useful knowledge. It is sometimes more convenient to do some clinical studies in developing countries because of the large load of cases or sometimes because of somewhat more tolerant ethical review committees. African researchers should ensure that proposed research projects are related to the priorities of the communities and nations in which the studies are being conducted. One group of individuals should not be made to bear the burden and risks of research that is not relevant to their own situation but is designed solely for the benefit to another community.

17.3. In6estments in Research Even the simplest research project usually involves significant inputs from various partners: 1. Subjects of the study: individuals, families and communities; 2. Sponsors of the study: government(s), institution(s), donor(s); and 3. Research scientists: medical and health related disciplines. Natural justice demands that all the contributors to the project should derive appropriate recognition and rewards proportionate to their respective inputs.

17.4. Subjects of the Study The contributions of individual subjects of research, their families and the communities in which the studies are conducted must be fully recognised and rewarded. Short-term immediate benefits could include the free treatment of unrelated medical conditions, or the improvement of community infrastructure such as water supply. Longer-term benefits could include privileged access to the beneficial results of the research as well as new products derived from the study.

17.4.1. Risks and Benefits As far as possible, the critical issues should be carefully examined at the planning phase of the study when the possible risks and outcomes of the

17.4.2. Access to and Affordability of New Products One commonly discussed issue is the expected cost of the new technology. For example, is it ethical to do research on a drug that would be too expensive for the local community to purchase? There is no simple stereotyped answer to this question but the issue should be addressed upfront. 1. The cost and price may change. For example mefloquine was very expensive when it was first discovered, but later a new chemical synthesis process made it more affordable. 2. Special pricing could be negotiated. WHO/ TDR negotiated tiered pricing for mefloquine when it was first registered; the lowest price was for bulk purchase by the public sector in the least developed countries where malaria was endemic. The highest price was for sales in the private sector in developed countries, for example for tourists and other travelers to malaria endemic countries. 3. The drug may be donated as in the cases of ivermectin, azithromycin; or philanthropic donations from private foundations and other donor agencies as in the case of leprosy control programmes. The cost of the drug is however, not the only barrier to access since there are other factors in the health system that may account for the failure to reach target populations with affordable reme-

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dies. Access to anti-retroviral drugs for the treatment of HIV/AIDS is often presented mainly in terms of the price of the drugs. The use of the triple drug combination requires clinical and laboratory services that are not available to populations in most developing countries especially in sub-Saharan Africa. Even if the drugs were donated free, the health services cannot deliver them except to the relatively small number of urban elite who have access to tertiary health care. Scientists in developing countries have the special responsibility to ensure that they do not collaborate with outside agencies in unfair exploitation of their populations. The design of studies that are funded by external agencies or that involve the testing of foreign products should include careful negotiation that would ensure that the test populations and their communities share equitably any rewards that are derived from the research.

17.5. Sponsors The various sponsors of research deserve recognition of their inputs. Usually, donors stipulate conditions for the award of grants to research scientists including: acknowledgements of their input in all relevant publications; and conditions for the management of patentable products. The contributions of national authorities are sometimes overlooked. Often, research scientists who are salaried employees of universities, research institutes, and other public institutions, fail to acknowledge the inputs from their national government. They seem to take for granted their salaries, the capital investment in the infrastructure of their institutions and other inputs into the running of their institution. They make formal acknowledgement of their foreign donors but make no reference to the national input.

Increasingly, however, in order to provide the full range of expertise that is required, research projects often involve teams of researchers and technologists. Furthermore, the members of the team may not belong to the same department but are engaged in inter-departmental, inter-institutional and international collaboration. Thus, the team could involve individuals from: “ the same department, “ different departments in the same institution, “ different institutions in the same country, and “ different institutions in different countries. In setting up such collaborative projects, the partners should identify all major issues about the design and implementation of the programme. With careful attention to detail, the responsibilities of each partner should be defined. There should also be agreement up front on how they will share the rewards. There should be prior agreement on such issues as: “ the overall plan of the project including the statistical design; “ the design of the protocols of the component parts of the project; “ mobilisation and management of financial resources; “ the performance of specific tasks in the clinical and laboratory settings; “ data handling and processing; and “ drafting reports and formal publications. “ In the same way, there should be agreement about the sharing of the rewards: “ authorship of formal publications, “ acknowledgement of minor performers, “ patents and other intellectual property, and “ disposal of residual resources such as funds, equipment, and consumables. Even with the best will in the world, it is not possible to anticipate all possible eventualities. The partners should therefore, make arrangements for future negotiations and in complex projects, for arbitration mechanisms.

17.6. Research Scientists 17.7. Empowering African Scientists It can be relatively easy to recognize the contributions of an individual research scientist working alone on a subject of his or her choice.

One common problem is the variation in the amount of power that individual members of

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partnership can wield. African scientists often have to work in collaboration with foreign colleagues who have access to relatively large resources. This disparity may put the African scientist at a disadvantage in negotiating the terms of the collaborative study. Some of these collaborative ventures have been designed such that scientists in developing countries obtain significant benefits from the relationship. Such benefits include the training of local staff and the conscious transfer of technologies and expertise leading to significant strengthening of local research capability. On the other hand, there are cases in which unscrupulous scientists from developed countries have exploited their financial power to the disadvantage of their African partners. In order to protect national scientists, and to make sure that health research in Africa is organized in the best interests of local populations, national governments should provide adequate resources ensuring that local scientists, are not too dependent on financial grants from external agencies (‘He who pays the piper calls the tune’). Regional and sub-regional research networks can empower African scientists and institutions by enabling them to develop peer-level relationships with colleagues who are dealing with common problems in situations that are similar to their own. Major international donors both multilateral and bilateral agencies as well as private foundations, should ensure that their grants promote equitable collaboration among partners without cynical exploitation of the weak.

17.8. Conclusions Health research often involves collaboration among partners from different disciplines, different institutions and different nations. In addition to the work of the research scientists, one must recognize the inputs from donors and sponsors of the study. Most important of all, the burden and risks borne by the subjects of

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health research such as individuals, families, and communities, must be recognized and rewarded.

18. Archived Specimens: Ethics Concerns Dorothy C. Wertz, PhD Senior Scientist, Di6ision of Social Science, Ethics, and Law, The Shri6er Center

18.1. Abstract The aim of this paper is to facilitate discussion. It describes various types of collections of specimens, their uses in research, types of identifiers, requirements for informed consent, third party access to samples, recontact, and controversial ethical and social issues. There is need for research on public opinion and people’s views on these issues, with particular attention to those of the minority groups.

18.2. Archi6ed Specimens To most people, what happens to blood or tissue discarded in a hospital or donated for research is an abstruse question, since the ‘sample’ is no longer part of their bodies. Starting with 18th century British surgeon John Hunter, collections of stored specimens have existed in hospital pathology departments for at least 200 years without arousing ethical or social concern [1]. In the last few years, however, with technologies of DNA extraction and the possibility of pre-symptomatic and susceptibility testing, the uses of these collections have raised complex ethical issues and some heated discussions [2–11]. What follows is an introduction to these issues, based on practice and law in the US.

18.3. Types of Collections In the US, there are basically eight types of collections of stored specimens, listed below. Many of these would not call themselves DNA banks, even though they function as such.

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18.3.1. Pathology Samples Retained by Hospitals after Surgery Regulations require that these be kept for a certain period of time in order to check accuracy of diagnosis. Unusual or ‘interesting’ samples are often kept indefinitely. Sometimes cells are kept alive in laboratory cultures for many years. These are called ‘immortalized cell lines’. The best known examples are the HeLa cells, named for an African – American woman called Helen Lane [a pseudonym] and kept alive for about 50 years. Most pathology samples, however are dead cells kept in paraffin blocks. 18.3.2. Newborn Screening Samples Starting in 1962, all states have offered screening of newborns for in-born conditions called ‘errors of metabolism’, where early diagnosis and treatment benefits the newborn. In 48 states, screening is mandatory; two (Maryland and Wyoming) require parental informed consent [12]. The newborn’s heel is pricked, and a spot of blood is placed on a special paper and dried. States vary in the length of time for which they keep newborn blood spots. Some states destroy them after 90 days, others keep them indefinitely. 18.3.3. Forensic DNA Databanks Over 450 000 blood or saliva samples have been collected and kept on file from persons charged with or convicted of felonies, especially murder and sex crimes [13]. All states are moving to establish forensic DNA databanks [13,14]. As technologies become faster and cheaper, law enforcement authorities may seek to collect DNA from all persons who are arrested, regardless of whether they are charged with or convicted of crimes. This is already done in the UK. In the US, the practice could lead to enormous databanks, because about 30% of all American males have been arrested by the age of 18, and about 60% will be arrested over a lifetime. In 1996 alone, over 15 million persons were arrested [15]. According to the Bureau of Justice Statistics Clearinghouse, 9% of all US males will be incarcerated at some time during their lives [16]. Usually the samples are destroyed if the arrest does

not lead to conviction. If there is a conviction, the sample itself and the computerized data from it are kept on permanent file.

18.3.4. The Armed Forces DNA Bank All members of the armed forces are required to provide DNA samples in order to identify casualties, so that ‘there will be no more Unknown Soldiers’. This requirement has been upheld in military courts. However, people may request return of their samples after leaving the service. Otherwise, samples will be kept for 20 years and then destroyed [17,18]. 18.3.5. DNA Collected for Clinical Care These samples may be collected as part of clinical care and kept in the clinical laboratory. 18.3.6. Commercial DNA Banks This is DNA that individuals have chosen to store at their own expense on behalf of their descendants, to make diagnosis easier in the future. There are few such banks. 18.3.7. Blood Banks Sometimes donated blood or blood cells are frozen and stored before being used in transfusions. Cord blood banks, which store blood from a baby’s umbilical cord, are a special type of blood bank. Cord blood contains ‘stem cells’ that can be used instead of a bone marrow transplant if the individual needs them later in life for cancer treatment. Sometimes people also donate portions of their own or their child’s cord blood to save the lives of others. 18.3.8. Research Collections The National Institutes of Health (NIH), the Centers for Disease Control (CDC), the National Science Foundation (NSF), and many individual research laboratories funded by these agencies have collections of DNA. Some projects, such as the Women’s Health Initiative, have stored hundreds of thousands of samples for future, unspecified ‘genetic testing’. The Human Genome Diversity Project (HGDP) proposes to collect and store samples from a variety of ethnic groups around the world [19].

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18.4. Identifiers on Samples Identifiers are of three main types:

18.4.1. Actual Names 18.4.2. Identifying Numbers which Can be Linked to Names Only the number is on the sample. In order to protect confidentiality, usually access to the code linking numbers to names is restricted to a small number of people. If portions of a sample are used for research, researchers receive only the numbers, not the names. Various terms are used to describe samples identified by numbers. These terms may be confusing: they include ‘identified’, ‘coded’, and ‘anonymized’. The latter term is especially confusing because it is sometimes also used to describe samples that cannot be linked to names, as under ‘No Individual Identifiers’, below. 18.4.3. No Indi6idual Identifiers (Anonymous) These are samples from which all identifiers have been irrevocably stripped. No one can trace a sample to an individual. There are no numbers, no codes, no list of names. Sometimes, however, socio-demographic identifiers (age, sex, race, ethnic group) may be attached to make a sample more useful to researchers. This raises the possibility that genetic differences between groups may be found, for example the relationship between Ashkenazi (Eastern European) Jewish ancestry and a gene for breast cancer. Knowing sex or ethnicity may make it easier to identify high-risk groups and recommend preventive measures, or, eventually, treatment. On the other hand, relationships between ethnic groups and genetic predisposition (for example, to mental illness) may raise concern about stigmatization, especially in behavioral genetics. Most research uses samples with identifying numbers only. These could, in extraordinary circumstances and presumably with the approval of an IRB (institutional review board that oversees the ethics of federally funded research with human beings), be linked to names.

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Ordinarily, researchers themselves do not have the list of names, which remains in a secured file in the lab that supplied the samples. Researchers can, however, request medical information about the individual who supplied the sample. Research that is not federally funded does not require the approval or oversight of an IRB. However, most research takes place in hospitals or laboratories receiving government funds (even if not for this particular project) and thus must have IRB approval. Infertility research, which is usually done at private labs, is an exception. Many researchers think that samples lose their value if rendered truly and irrevocably anonymous. They cannot be compared with the medical history of the individual. It is also impossible to provide information to people in the rare instances when research findings may be of immediate medical value to individuals and families. However, many research projects, including those to sequence the human genome, use totally anonymous DNA, which carries no identifiers, including sex or race. Newborn blood spots, forensic DNA (except for unidentified material found at a crime scene), Armed Forces DNA bank, DNA samples in clinical laboratories that are linked to medical records, commercial DNA banks, and cord blood banks, all have the names of individuals attached to or easily linked to the samples.

18.5. Uses in Research 1. Pathology samples have been used for hundreds of years. Slices from the paraffin blocks are routinely sent out to colleagues at other institutions, in other countries, and sometimes to commercial companies. 2. Newborn blood spots are used in some states, [20] including California, which conducted research on possible genetic causes of sudden infant death syndrome (SIDS) [21–24]. 3. Forensic DNA banks are, at present, restricted by state regulations so as to allow use of DNA for identification only. The information kept in state crime lab computers will enable identification of individuals but will not provide any information about genetic

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disorders or susceptibility to common diseases or behavioral disorders. Totally anonymous samples, with no codes or identifiers that can ever be linked to individuals or groups, may be used in research. Current regulations forbid use of the Armed Forces DNA bank for research. The DNA is for identification only. DNA in a clinical laboratory, commercial DNA bank, or blood bank, may be used only with the informed consent of the individual.

18.6. Informed Consent Some collections are mandatory. These include forensic DNA for various kinds of suspects as specified in state regulations and DNA collection from members of the Armed Forces. Collection of newborn blood spots is mandatory. Only two states, Maryland and Wyoming, require informed consent from parents. Permission is required for any research use of DNA, including newborn blood spots and pathology samples. However, many people are unaware that they gave ‘permission’. It is often a simple notification that samples may be used in research, with an opportunity to ‘opt out’. Individuals must take the initiative to prevent use of their samples in research by writing to a special office. Hospital admission papers usually specify that any human material left behind after surgery is ‘abandoned’ or ‘discarded’ and becomes the property of the hospital unless an individual objects within a specific period of time. In states that use newborn blood spots in research, the information provided to parents before newborn screening usually says that the blood spot becomes the property of the state within a certain time (in California, 90 days) unless the parents object in writing. The ‘opt-out’ procedures are very general and do not specify who will use the samples or for what research purposes or how long they will be stored. Most people entering hospitals or giving birth may not notice the statements about possible research uses of samples, because they have more urgent matters at hand. The only instances when a full, written informed consent document is used are (1) when

specimens are collected specifically for research, and (2) when DNA (or data from it) is requested from a medical record or from a sample that an individual has stored at a commercial DNA bank.

18.7. Access to Stored Specimens Access to stored specimens is restricted without the individual’s consent, except for forensic purposes, when a court order may be obtained. Insurance companies, employers, schools, adoption agencies, and other institutions have no access to any of the collections of specimens described above. Insurers may, however, ask for an applicant’s medical record as a pre-condition of providing insurance. For a specimen stored in a clinical laboratory and computerized information about DNA in a medical record as part of clinical diagnosis and treatment, the individual has to consent for an insurer to have access to these. Attempts have been made to set up separate genetic records (called shadow charts) aside from medical records, but this is legally questionable. If the specimen was collected for purposes of research, it is usually kept separate from the individual’s medical record. The problem is that it is sometimes difficult to draw a firm line between research and health care. Most insurance companies get all the information they need from the applicant’s family history (parents’ health and causes of death). In applying for insurance (unless covered through an ‘employer package’ of benefits) applicants are required to tell the company whatever they know about inherited conditions in the family. If an applicant knows a fact and does not disclose it, the contract with the company is void. At this point in time, insurers are not particularly interested in applicants’ DNA, but this could change. According to federal law, employers cannot ask for medical records or medical tests until after a person is hired, as long as the individual is able to do the job. After hiring, any employer can only require medical examinations which must be directly related to current performance in the workplace, and should not include pre-symptomatic or carrier testing.

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Government agencies (with the exception of those allowed to collect and store samples, such as the Armed Forces, state crime labs, and newborn screening programs), may not have access to samples in other types of collections, even to samples held by other government agencies. For example, the Welfare Department cannot use samples in a state crime lab to check the identities of applicants for welfare. Relatives and spouses (or partners) may not have access without the consent of the individual. Law enforcement agencies may gain access to all types of stored DNA, but only with a court order, if necessary to solve a crime or identify remains. Civil suits, for example for questions of inheritance, usually require permission of the individual, or if deceased the next of kin.

18.8. Issues of Concern 18.8.1. New research on samples taken for other purposes. Will the sample be used for purposes beyond those stated in the informed consent document, or in new projects that may arise? This issue came to the fore when it became known that research on prevalence of the BRCA1 gene in the Ashkenazi Jewish population was conducted on samples collected years earlier for research on Tay – Sachs disease. Will donors be notified of any new uses and asked to give a new consent? Is the cost of this re-notification a worthwhile use of public funds? Some projects, such as the Women’s Health Initiative, have very general consent forms, saying only that blood will be kept for a specified number of years and then used in ‘genetic testing’. Is this type of ‘blanket consent’ ethical, or does it fall short of ethical requirements for informed consent? If a blanket consent is used, is there any way to screen out potential uses of a sample that members of particular minority groups may find objectionable? 18.8.2. Identifiers Will a name be on the sample, or a number that can be traced to a name? Or will the sample be totally anonymous, with no one able to link it to

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an individual? How can researchers avoid confusion in using the words ‘anonymous’, ‘anonymized’, or ‘identifiers removed’? Will samples be identified according to race or ethnic group, even if names or code numbers are not on them? Sometimes published results point to a particular group as having a different genetic make-up or different chances of developing a particular disease. Should these groups be identified? There may be health advantages to identification, but also risks in terms of possible stigmatization.

18.8.3. Use of Samples by other Researchers Will samples be shared with other groups of researchers at other institutions? Shared with researchers in other companies? Shared with researchers at commercial companies? 18.8.4. Length of Storage What will happen to the samples at the end of a research project or after the researcher moves? How long will the samples be kept and where? Will identifiable samples be kept after the donors die? Will blood relatives then be able to gain access to them? 18.8.5. Contacting Donors about Important Results Will donors be contacted if researchers find something that is important for the individual’s or family’s health? This is rare in most genetic research, because many studies have no clinical application or are difficult to interpret. Occasionally, however, a finding may have implications for diagnosis or treatment. Should people be notified only if a condition is preventable or treatable, or should they be notified in all cases? Should donors have a ‘right not to know’ research results, even if these would be useful for prevention or treatment of disease? Will donors receive a short, readable summary of the overall research findings if they want one? 18.8.6. Access for Blood Relati6es or Spouse (Partner) Should blood relatives be able to get access to a sample without the individual’s consent if they

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need the information for their own genetic diagnosis? Should a spouse/partner get access to a sample, without consent, if it is needed to help diagnose a couple’s child?

18.8.7. Compensation Will donors receive compensation for any profits from commercial products developed from a sample? Monetary compensation is usually impractical because thousands of samples may be used, and any one individual’s share would be a matter of a few cents. However, individuals, ethnic groups, or communities who participate in research may in some circumstances be entitled to benefits if their samples were the source of a commercial product or procedure. The benefit could be in the form of priority access to new drugs or treatments, free of charge or at reduced cost. This idea, while accepted by international bodies, has yet to be worked out in practice. In a proposed study in Iceland, however, a pharmaceutical company has agreed to compensate participants by providing them with free access to any tests or pharmaceuticals developed from the study, during the life of the patients [25]. This may not be enough, in view of the length of time that may elapse between the initial research and development of useful treatments. Researchers on asthma in Tristan de Cunha gave the islanders a refit to their three-bed hospital, exercise machines, and asthma testing equipment [26]. There are many statements from professional bodies about the use of archived specimens [8,10,27– 35]. Ethics commissions, including the US National Bioethics Advisory Commission, have also researched the problems [36]. 18.8.8. Informed Consent Some international bodies, including WHO [37] and HUGO, favor use of blanket consents as the most efficient way of conducting multiple research efforts on a sample without having to seek out and recontact individuals for consent to each new project. In the US, national research projects, such as the Centers for Disease Control’s National Health and Nutrition Examina-

tion Survey (NHANES) or the Women’s Health Initiative, may be very large. The Women’s Health Initiative includes 160 000 women ages 50–79 and has drawn blood samples from each for possible ‘genetic testing’ in 2005. As researchers do not know at present what kinds of genetic tests may be available or informative in 2005, the informed consent for this project makes no specifications about the kinds of testing that may be done. If specifications are made in the informed consent, as was done for NHANES, researchers may find that the specified research leads to avenues of other research not included in the informed consent. NHANES III currently has over 17 000 stored blood and urine samples and 8000 cell lines. Returning to each participant and requiring a new informed consent specifically for the new research could become quite costly to the taxpayers. Many of the older participants in the Women’s Health Initiative may not be available to give consent in 2005. Therefore, it is important to develop consistent policies that protect individuals while also allowing potentially useful research to proceed. It is believed that the fairest approach is a ‘‘line-item’’ informed consent. Such consent allows people to express their wishes about various alternatives, such as retaining coded identifiers rendering a sample totally anonymous; recontact and no recontact; access and no access for spouses, blood relatives, other researchers; permission and no permission for use in future, unspecified research projects. Several authors have already suggested such an approach [4, 6]. Although blanket consent for future projects may be desirable, donors should have the opportunity to specify, in the informed consent, any uses to which they do not want their sample put. Any ‘blanket consent’ for future uses should be limited to diagnosis and treatment of disease, and should exclude research related to reproduction or to behavioral genetics such as crime and risk-taking, these being areas that are highly controversial. Unfortunately, line-item consent requires thorough knowledge about the different alternatives

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and their possible consequences. Most people have not considered these issues before and tend to become confused about the alternatives and their potential importance. Many people, especially members of minority groups that have been victimized by past research, do not believe that informed consent offers them any protection from unscrupulous researchers [38]. A massive public education program may not be enough; evidence must be forthcoming that researchers are responsible and deserving of people’s trust. Most of the discussion has occurred in the absence of research on the concerns of the public. There has been no research on the opinions the public at large or of minority groups with regard to use of archived specimens. Although many people may feel little attachment to the fate of a blood sample or a tissue specimen removed in surgery, blood has a religious or quasi-religious meaning for some groups. Research will be necessary to elicit people’s concerns and to establish full and fair practices for use of samples.

Acknowledgments This paper was originally presented at the National Dialogue on Genetics, College Park, MD, March 20-22, 1998. The author would like to thank Philip R Reilly, Marvin Natowicz, and the New England Regional Genetics Group Social and Ethical Concerns Committee for reviewing an earlier version of this manuscript.

References (1) Lyons, A.S., Petrucelli R.J. Medicine: An Illustrated History. New York, Henry N Abrams, 1978, p 482. (2) Annas, G.J. Privacy rules for DNA databanks: protecting coded ‘future diaries’. J. Am. Med. Assoc. 1993; 270: 2346 – 2350. (3) Clayton, E.W., Steinberg, K.K,, Khoury, M.J., et al. Informed consent for genetic research on stored tissue samples. J. Am. Med. Assoc. 1995; 274-: 1786 – 1792.

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(4) Gold, R.L., Lebel, R.R., Mearns E.A., et al. Model consent forms from DNA linkage and storage. Am. J. Med. Genet. 1993; 47: 1223–1224. (5) Grody, W.W. Molecular pathology, informed consent, and the paraffin block. Diag. Mol. Path. 1995; 4: 155–157. (6) Knoppers, B.M., Laberge, C.M. Research and stored tissues: persons as samples, samples as persons. J. Am. Med. Assoc. 1995; 22: 1806–1807. (7) Knoppers, B.M., Caulfield, T., Kinsella, T.D. Legal Rights and Human Genetic Material, Toronto, Emond Montgomery, 1996. (8) Stephenson, J., Pathologists enter debate on consent for genetic research on stored tissue. J. Am. Med. Assoc. 1996; 275:504. (9) Sugarman, J., Reisner, E.G., Kurtzberg, J. Ethical aspects of banking placental blood for bone marrow transplants. J. Am. Med. Assoc. 1995; 274: 1783–1785. (10) Therrell, B.L., Hannon, W.H., Pass, K.A., et al. Guidelines for the retention, storage, and use of residual dried blood spot samples after newborn screening analysis: statement of the Council of Regional Networks for Genetic Services, 1996. (11) Weir, R.F., Horton, J.R., DNA banking and informed consent. Part I, IRB, 1995; 17: 1–4. (12) Hiller, E.H., Landenburger, G., Natowicz, M.R. Public participation in medical policymaking and the status of consumer autonomy: the example of newborn screening programs in the US. Am. J. Publ. Health 1997; 87: 1280–1288. (13) McEwen, J. Forensic DNA data banking by state crime laboratories. Am. J. Hum. Genet. 1995; 56: 1487. (14) McEwen, J.E., Reilly, P.R. A review of state legislation on DNA forensic data banking. Am. J. Hum. Genet. 54: 94. (15) US Federal Bureau of Investigation: Crime in the United States, 1996. Washington, FBI, 1997. (16). US, Department of Justice, Bureau of Justice Statistics: Lifetime Likelihood of Going to State or Federal Prison. Washington, US

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Government Printing Office, March 1997, pp. 8–10. US, Assistant Secretary of Defense (Health Affairs) Memorandum and Policy Statement. Establishment of a repository of specimen samples to aid in remains identification using genetic deoxyribonucleic acid (DNA) analysis. Washington, DC, January 5, 1993. US, Assistant Secretary of Defense (Health Affairs), Memorandum. Policy refinements for the Armed Forces Repository of Specimen Samples for the Identification of Remains, April 2, 1996. Greely, H.T. The Ethics of the Human Genome Diversity Project: The North American Regional Committee’s Proposed Model Ethical Protocol. In: Knoppers, B.M., Laberge, C.M., Hirtle, M. (Eds.) Human DNA: Law and Policy. The Hague, Kluwer Law International, 1997, pp. 239 – 256. McEwen, J.E., Reilly, P.R. Stored Guthrie cards as DNA banks., Am. J. Hum. Genet. 1994 ; 55: 196. Gozal, D., Lorey, F. Incidence of sudden death syndrome in infants with sickle cell trait. J. Pediatrics, Feb 1994: 211 – 214. Shaw, G.M., Todoroff, K., Finnell, R.H., et al. Infant methionine synthase variants and risk for spina bifida. J. Med. Genet., in press. Shaw, G.M., Rozen, R., Finnell, R.H., et al. Maternal vitamin use, genetic variation of infant methylene-tetrahydrofolate reductase, and risk for spina bifida. Am. J. Epidemiol. 1995; 148: 30. Zhang, Y.-H., Ybarra, A., McCabe L.,et al. Frequency of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency among California children dying of Sudden Infant Death Syndrome (SIDS) or liver disease. Two-tiered analysis of newborn screening specimens. Pediatric Res. 1995; 37: 167A. Tapping Iceland’s DNA. Science 1997; 278:566. Strauss, S. A tiny island yields a key to asthma. The Globe and Mail (Toronto, Canada), 11/27/97, page A12. American College of Medical Genetics, Stor-

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19. Optimum Ethical Standards Dr George Ulrich Senior Reseacher, The Danish Centre for Human Rights

19.1. Introduction What is it, fundamentally, that we are trying to accomplish? What are the critical issues that ethics regulation mechanisms ought to address? The strictures and imperfections in real life research apart, what are the ideals that biomedical science is committed to? What would a system of high ethics standards look like, if it were fully functional? What are the central challenges in approximating this? Questions of this nature are particularly relevant to discussions like those of this Seminar seeking to define standards of research ethics that are appropriate in an African context. Naturally this endeavour has to build on international standards as they have emerged since antiquity, and especially since the end of the Second World War. We must acknowledge that existing ethics guidelines (such as those of the CIOMS) represent a tremendous accomplishment, and that they are in many respects the result of a genuine global effort. But they do not present us with a ready made model that has come into place once and for all, and for adoption everywhere. To the contrary, there is a need for continuous checks and improvements. We would also do well to acknowledge that there are certain fundamental insufficiencies and causes for concern in the current orthodoxy on research ethics. A familiar concern has been the question of universalism and cultural diversity: are the current international standards consistent with local values in all parts of the world, or are they ‘western values’ that are being imposed on the rest of the world? Although this question is no longer experienced to be quite so urgent as it once was, it needs to be taken seriously considering the divergent regional values, universalism, and globalization. The more critical concern is whether the established norms and procedures actually address the

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pertinent issues. This too can be relativized in terms of whether they are responsive to local circumstances in the various areas in which research is conducted. An indication that this may not always be the case is found in the common perception that actual ethics standards often remain low despite the implementation of rather rigid regulation mechanisms. A further concern is that contemporary professional ethics, including research ethics, has become something merely formal, as a set of routine procedures that look good but have little to do with genuine ethics conscientiousness. This is demoralizing, and no profession can afford to expose itself to this ridicule, and suspicions of hypocrisy. Every effort must be made to avoid a situation of rules being put into place that are then subsequently routinely violated. The upshot of these considerations is that while there can be no question about the need to build on what has already been accomplished, it is advisable to resist the temptation to simply adopt and adapt existing models, particularly the North American and European models of ethics regulations. It can neither be assumed that the familiar principles are fully adequate nor that formal regulation always improves the ethics standards of what is going on the ground. There is ample reason to occasionally pause to reflect on the overall goals and how closely we are approximating them. To take up this challenge is not an easy task. Many of you have had extensive experiences in African research communities, and therefore aware of the shortcomings of contemporary research ethics, even if there is involvement of donor agencies such as Danida funding research internationally. What do we understand by the notion of standards in the first place, and what are some of the criteria for a set of ethics standards to qualify as optimum? The salient issues can be grouped into three distinct types of ethics issues to focus on protection, communication, and rele6ance. Each group of issues involves a separate underlying rationale and gives rise to a set of strategic considerations about how best to optimize standards in a given area.

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19.2. Concept of ‘Optimum Standards’ The notion of ‘standards’ tends to be used in a dual sense. In a formal or prescripti6e sense, the phrase ‘ethics standards’ indicates the requirements defined by a profession or an authoritative agency, as necessary for conducting professional activities in a given context in an ethically acceptable manner. For an institution to formally specify its standards is also a way of announcing publicly what the minimal expectations are that every member of that institution, or anyone wishing to work with the institution, must be prepared to honour. This is essentially what we have in mind when setting about to define a set of ethics standards of relevance to biomedical research in an African context. These are to function as the minimum requirements that anyone wishing to conduct biomedical research involving human subjects in Sub-Saharan Africa will have to observe. However, in common parlance the word ‘standards’ is also widely used in a less formal, descripti6e sense. It then serves as a measure of the degree to which individuals or members of a given institution conduct themselves in an ethically commendable manner. For an institution to maintain high ethics standards in this informal sense, means that its members are motivated by ethics concerns and give priority to these other interests associated with research. Needless to say, the two uses of the word are closely related. Under ordinary circumstances, the descriptive use of the notion ‘ethics standards’ may be interpreted as an indication of the degree of compliance with established formal standards. If the latter function as the yardstick by which we agree to be measured, then our ‘standards’ in the former sense denote the measurement itself. Furthermore, it may be assumed that to adopt exacting standards in the narrow sense is a means of ensuring, or at least promoting, high ethics standards in actual professional conduct. But this should not be regarded as a foregone conclusion. It is possible that formal standards fail to translate into actual ethical behaviour, and there might be other ways of promoting a high level of ethics conscientiousness. Viewed in this light, a central challenge consists in making the two senses of ethics standards work

together. This is important when it comes to determining what it would mean for a set of ethics standards to qualify as optimum. In the broad, informal sense, an optimum ethics standard may be defined as a pattern of professional behaviour that is maximally responsive to the various relevant parameters including economics and other strictures. Optimum ethics standards in the narrow, prescriptive sense may then be defined as a set of formal ethics standards that are optimally suited to facilitating this.

19.3. Characteristics of Optimum Ethics Standards They should be clear, relati6ely simple, and meaningful to the people concerned. This may be interpreted as a stipulation that these standards in a given area must be consistent with local values in order to be valid. However, while a high degree of compatibility in this respect is commendable, it is not always possible to attain, and should probably not be advanced as an absolute requirement. An important reason for this is that society is dynamic and research itself is in many contexts an alien component that introduces new social dynamics, and therefore requires new standards of normative regulation. Regional standards must be consistent with current international ones. It has been convincingly argued that global double standards are unacceptable in principle and dangerous in practice. While research ethics should seek to accommodate regional values and beliefs, it must at the same time retain a universal core. Standards of research ethics must be pertinent in a local context. They must effectively address the actual ethics problems associated with research in the given area. This requirement demands special attention because it is only partially met by current ethics standards. As is well known, established procedures do not always work in practice. There is also a wide range of important ethics concerns that are not adequately addressed in contemporary research ethics. The key problem here is not non-compliance, but rather a failure to acknowledge certain ethics concerns as pertinent.

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Should formal ethics standards be always enforceable? We may wish this was possible knowing that systematic non-compliance to established ethic standards is demoralizing. Nevertheless, the expectation of full enforceability is neither realistic nor desirable, since it would leave us with much too limited a conception of what ethics is about. Ethics is in several respects fundamentally different from law. Aside from functioning as a vehicle of formal regulation of behaviour, ethics standards also serve an important critical function of providing a reference point for what we think are wrong and right practices. However, for some wrong practices so recognized, we may not be in a position to change them. Formal ethics standards should indeed be expected to fulfil various practical functions, and should enhance ethically motivated conduct among the various parties involved in research. How this may be envisioned to happen in practice is a matter of central importance to contemporary research ethics. One area that should be given increased priority, is strengthening accountability in a variety of different settings, including comparatively informal settings involving civil society and representatives of the communities hosting research. In such contexts, ethics standards function not primarily as determinate enforceable rules, but rather as parameters of public justification.

19.4. Identifying the Issues An important first step towards developing a regional set of ethics standards consists in delineating the field in need of attention. What types of ethics issues are there? Which acts and relations are experienced as ethically significant? What are the expectations with which researchers are met? In beginning to clarify this, one soon finds that the domain of ethics is quite complex and differentiated. Moral philosophers have traditionally sought to delimit the realm of ethics in terms of one foundational principle. It is now increasingly being recognized that ethics or morality, needs to be thought of as a system regulated by multiple values, norms, and interests, and involving several different types of issues at

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different levels of ethics consideration (1). Different types of ethics issues, in turn, require different forms of intervention, and are subject to varying degrees of formal regulation. The task of identifying the relevant issues can be done in two stages. The first stage addresses a small number of different conceptions of what ethics is all about. At the heart of each such fundamental account of the nature of ethics one usually finds a certain basic 6alue that is paramount, and for which ethics standards and principles are designed to promote. In practical ethics interaction, basic values are usually articulated as obligations or claims to be acknowledged as legitimate and binding. Even if they are typically associated with (perhaps derived from) competing schools of moral philosophy, it is by no means necessary to view divergent obligations and claims as mutually exclusive. In keeping with the notion of a systems approach to ethics, we may well choose to embrace a broad range of values and claims eclectically as part of a differentiated ethics vocabulary. Upon examination one finds that different basic approaches to ethics often target different levels of ethics consideration, and therefore complement each other nicely in an integrated ethics framework. The second phase involves identifying, describing, and categorizing the specific ethics issues that confront researchers. This is a more concrete endeavour than the identification of basic values in light of competing conceptions of the nature of ethics. It is, on the one hand, a matter of applying the general ethics principles to the research activity, and on the other, to conducting research in different social groups. This is of direct use for researchers (individuals or working in groups) in forming an overview of the ethics considerations that ought to be taken into account in the course of their daily activities. It is also highly useful in contexts such as the present one, where we are assembled to define a set of authoritative ethics standards that will form the basis for the approval of research proposals. For the purpose of clarity, the range of specific ethics issues could be grouped into a small number of categories, each defined by a common theme and a set of characteristic features. Three categories of ethics issues have been

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proposed addressing protection, communication, and relevance. The discussion of each of the above broad issues should take several different aspects into account. Firstly, it involves describing the basic responsibilities of researchers. This, in turn, points to what practical measures are suitable for increasing the compliance of researchers with reasonable expectations of the nature of the ethics responsibilities, and to what degree they lend themselves to monitoring and formal regulation? Another central aspect has to do with the negotiation of ethics dilemmas. Sometimes basic values conflict, and concrete obligations have a tendency to pull in different directions. This is particularly liable to happen considering the nuances of the ethics vocabulary accommodating a broad range of ideals and concerns. Genuine ethics dilemmas are characterized by not having a simple solution. The challenge for research ethics is, therefore, specifying the appropriate manner of balancing conflicting interests. This too involves an important strategic or pragmatic aspect: who is to be involved in ethics decision making, and in which formal settings are difficult decisions to be justified? However, not all perceived dilemmas are genuine. Often alleged conflicts of interest function as poor excuses for lowering ethics standards, even in situations when it is not necessary. This tendency can, and should, be curbed to the maximum extent possible. As a general rule ethics dilemmas are usually best resolved by searching for positive synergy effect between the apparently conflicting interests. Although this is not always possible to achieve, alleged dilemmas should be examined if these are indeed genuine. Often in situations of perceived conflicting interests, it can be shown that staunch promotion of one set of ethics concerns is also capable of enhancing the other set of concerns when the relation between the two is properly construed. This is in most cases true of perceived conflicts between protecting the individual and serving the broader public interests. Similarly, in most cases it is possible to establish constructive synergy between on the one hand pursuit of vested research interests such as career and status,

and on the other the commitment of science to serving the general good.

19.5. Nature and Scope of Ethics How to go about defining the scope of relations that are ethically significant, and the basic human values to which all professional activity, including biomedical research, must be committed? A central difficulty lies in the fact that today research is an inherently international activity, which by its very nature transcends existing cultural and religious boundaries. Neither the practitioners of research nor the many subject groups involved, can be assumed to share a set of common moral references. Therefore, today research ethics must somehow be responsive to a broad range of different normative expectations and sensitivities. What are the most pressing areas of concern? Is it possible to identify a set of basic parameters of ethics deliberation that can meaningfully define the scope of relevant issues? Ideally speaking, this ought to be approached as a matter of empirical investigation. A suitable starting point would be to examine the operative expectations in various different research situations. Examples of situations when expectations are frustrated, would especially provide an indication of the types of acts and relations that are experienced as ethically significant in the given context. This, in turn, could be subjected to comparative examination: do we experience the basic ethics issues in the same manner, and is the current conceptual vocabulary of professional ethics able to capture the actual issues on the ground in different parts of the world? When it comes to articulating a set of regional ethics standards, such as standards for biomedical research in sub-Saharan Africa, a paramount requirement is that the operative ethics principles must be generally consistent with existing regional values. As long as there is doubt about this, the need for empirical studies in the area of research ethics should not be underestimated. Having planted a flag, as it were, to identify an important area of future investigation, we could for our present purposes take a shortcut to taxonomy of the central ethics issues by taking cues from the western philosophical tradition. The pur-

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pose for doing this is not to advocate any particular school of moral philosophy, but rather to record several different visions of what ethics is fundamentally about. Such visions can be combined eclectically, not as foundational principles, but rather as indicators of relevant levels of ethical consideration. Once a set of core values has been identified, the subsequent discussions should be on these, and could be promoted and protected. In keeping with the maxim that our conceptual vocabulary should be kept simple, the discussion could be restricted to four basic accounts of ethics (2).

19.5.1. Respecting the Integrity of the Person An important level of ethics consideration has been defined by the German moral philosopher, Immanuel Kant, in the maxim ‘to treat others not only as means but always also as ends’. This maxim is generally interpreted as an injunction to respect the integrity of the person. It can be broken down into two distinct obligations: a duty not to expose others to harm be physical, mental, or material, and in a wider sense to protect subjects in our care from harm. But it also implies a duty to treat others with dignity, which is to recognize the competence of others and interact in a respectful manner. This is very much a matter of the quality of communication, not only what we do to others but also how we relate. Widespread frustrated reactions among research participants, is a reliable indication that this is indeed a universally recognized parameter of ethical behaviour. 19.5.2. Responding to Human Needs While not necessarily the intention of Kant, it is possible to interpret the maxim of respecting the integrity of others (especially in the sense of not doing harm) as a purely restrictive ethics principle. This defines certain types of behaviour as unacceptable. It can also be used to derive certain basic rules that we must honour if we wish to engage others, but it does not imply a general obligation to serve or respond to the need of others. Nevertheless, this has perennially been a central focus of ethics thought, and is probably indispensable to any comprehensive account of

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what ethics is about. The idea of an emphatic duty to serve and care for others could be attributed to countless different moral philosophers. In contemporary western philosophy, it is often associated with the name of Emmanuel Levinas, and following the biblical parable, it is sometimes described as a Samaritan duty. The basic idea is also familiar to all major religious and cultural traditions.

19.5.3. Promoting the General Good In addition to the ideal of caring for others in immediate, face to face situations, the significance of ethics is often attributed to one’s ability to contribute to the general good of society. This, of course, is the primary focus of the school of moral philosophy known as utilitarianism, which defines utility as the one principle from which all moral obligations can be derived. Even if one does not accept this sweeping claim, one may still recognize a moral value in responding to needs at the social level and a duty to assume responsibility for the long-term and largescale consequences of one’s acts. The standard approach in terms of ethics cost benefit analyses, is that the cost benefit ratio should be maximized to achieve a reasonable degree of proportionality between either allocated resources and the anticipated results, or the anticipated risks and the potential benefits of the proposed interventions. A different way of accommodating the principle of utility within our conception of optimum ethics standards, is to include a criterion of rele6ance as an important parameter of ethics consideration. This criterion considers a proposed intervention relevant, if it is meaningful, useful, and capable of making a positive contribution. The notion of relevance so qualifies if it includes at least two distinct aspects. In terms of its direct utility, or in other words, the applicability of the anticipated results. This is usually a reasonable expectation, especially in situations where resources are scarce, yet it should probably not be advanced as an absolute requirement since it would then have the unfortunate effect of disqualifying the entire endeavour known as basic research.

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The other parameter of relevance incorporates a broad range of what might be described as secondary or deri6ed effects of good science. These include capacity building for further research being conducted in the area, and those other research and other scientific effects which in several ways contribute to social development, not only in a narrow instrumental manner but also in terms of shaping our general outlook and understanding of the world. Upon examination, one finds that it is possible to list many other legitimate advantages of hosting and participating in research. In fact, one could go so far as to include personal vested interests such as career concerns, status, and monetary benefits. The underlying ethics ideal would then consist in maximizing the relevance of research at all of these levels, but only to the extent that this can happen in accordance with the principle of proportionality, and without sacrificing other fundamental ethics standards.

19.5.4. Promoting Justice The vocabulary of ethics is not complete without a notion of justice. To a considerable extent, the principle of justice covers the same territory as other basic ethics principles, such as that of doing good whether at the individual or the social level, and has the character of something optional. Concerns about justice can be articulated in the form of a claim. Thus, viewed from the vantage point of the recipient, it may be said that one may be fortunate to benefit from the benevolence of others, but our general feeling is that everyone is entitled to be treated with justice. Justice is a complicated principle to work with because it can be construed in numerous different ways. In an emphatic sense, it may be interpreted to mean that everyone deserves to be treated equally. This might be taken to imply that everyone deserves equal access to existing resources. In comparison with the actual distribution of resources in the contemporary global order, this is a radical proposition. In a somewhat less radical sense, the idea of justice could be interpreted to mean that everyone should be treated according to merit. This is highly relevant in many research contexts, not least when it comes to forging func-

tional and mutually satisfactory relations of collaboration. Nevertheless, in research ethics the notion of justice is most often interpreted in the distributi6e sense meaning that there should be an equitable distribution of burdens and benefits from the point of view of any party involved in research. This is a relatively weak interpretation of justice, since like the maxim not to do harm, it functions predominantly as a restrictive principle stipulating that if individuals or groups are to be engaged, then certain obligations follow. But if the world’s privileged groups simply continue to neglect the dispossessed and marginalized, then there is strictly speaking no breech of justice in the distributive sense. A further complication in working with the principle of justice, is that the endeavour to balance inequities at one level very often goes hand in hand with exasperating inequities at another level. Justice usually takes the form of a compromise between competing legitimate claims, and is for that reason generally open to dispute. An intuitive commitment to justice is a strong motivating factor for most researchers, and even at its weakest interpretation. It places the interests and needs of the least privileged high on the international agenda without merely presenting this as a matter of charity.

19.6. Types of Ethical Issues Having identified and grouped the key ethics concerns, the next step is deriving the practical implications of the basic values that we establish to constitute the foundation of contemporary biomedical research ethics. As suggested above, this step involves several distinct questions: 1. What are the reasonable ethics obligations and claims? 2. How urgent are they in the given context that we are addressing? 3. How well are they reflected in current international research ethics? 4. What measures could be taken to enhance ethics standards in a given area? 5. How do the pertinent obligations and claims occasionally conflict with the characteristic ethics dilemmas confronting researchers?

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6. What are the characteristic ethics dilemmas in research and how are they to be addressed? Questions of this nature comprise the central ethics issues, which for our present purposes can be grouped as involving protection, communication, and relevance. A thorough understanding of the rationale and characteristic difficulties associated with each of these key areas, should be of paramount importance to the endeavour to draft a set of functional ethics standards, and establishing relevant and effective regulation procedures.

19.6.1. Protection Issues If there is one ethics principle that we can all agree upon, it is undoubtedly the principle of non-maleficence. This is certainly one of the areas receiving most attention in contemporary biomedical ethics. This is often attributed to the invasive nature of medical procedures as well as to the degree of efficiency attained by the profession. With every scientific advance, the medical profession increases its ability to manipulate the human body, and entails an exceptional ability to do good, as well as increased capacity for inadvertently inflicting harm. From a practical point of view, what is particularly appealing about the principle of protecting research subjects against harm, is that it is a determinate principle. Harm can usually be established in fairly definite terms, and risks for harm can be anticipated, at least to a considerable degree. This general ethics principle, therefore, translates readily into a set of specific obligations, which can be clearly stated, monitored, and enforced. These include an obligation to: 1. design or re-design one’s research methodology so as to minimize the risk of harm; 2. carefully monitor the effects of one’s interventions throughout the research process; 3. promptly interrupt any study that reveals adverse effects, and 4. ensure compensation packages for research participants in case something does go wrong. The monitoring of compliance with such obligations is one of the primary tasks of ethics review committees, and other public authorities responsible for regulating research. Added to the standard protection mechanisms, research ethics

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today also invariably incorporates a set of special considerations pertaining to the protection of various 6ulnerable subject groups. Among the most obvious groups in this category are children, the mentally disabled, refugees and other various ‘‘captive’’ groups such as prisoners, and large impoverished populations found in all parts of the world. In so far as the world’s poorest generally lack access to primary health care, they are highly exposed to health research, and are therefore in need of additional protection which contemporary health research ethics have not been able to provide. A common solution has been to restrict the population access to research. While this approach serves to shield vulnerable subjects from such harm, it also excludes these marginalized populations from the benefits accrueing from participating in relevant research. What we might call risks of intrusion, have to be balanced against risks of exclusion, and it is not always clear which are worst. In light of the seriousness of this area of ethics consideration, a crucial question that needs to be considered at the present seminar is whether current protection mechanisms are adequate and effective? Are invasive research procedures in fact being properly monitored? Are some research initiatives able to by-pass standard screening procedures? Are review boards adequately composed and sufficiently equipped to fulfil their important tasks? Is the high prevalence of donors sponsoring research in Africa compromising the basic protection standards? Are the vulnerable subject groups adequately and properly protected? It is likely that most of the seminar participants are informed about what is happening on the ground, and where the central difficulties lie in ensuring a high standard of protection of research subjects. However, it must be emphasized that the questions raised are highly pertinent, especially in connection with establishing ethics standards for vaccine trials but in fact in connection with any discussion of ‘optimum ethics standards’ for biomedical research involving human subjects in Africa. One of our primary duties must be by all means to avoid the scenario of impoverished population groups in developing countries being ex-

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posed to substandard research (and being used as the so-called human guinea pigs). If we are to be honest with ourselves, there are widespread suspicions of such exploitation, and for this reason alone it is exceptionally important that monitoring mechanisms are put into place that both function and are seen to be effective. Since the Nuremberg trials after World War II, informed consent has been virtually universally recognized as a cornerstone of international research ethics for the biomedical sciences (3 – 5). The principle is also being increasingly embraced by other less invasive sciences, such as the behavioural and social sciences. In this manner, informed consent is close to attaining the status of the paramount principle of ethics regulating all research involving human subjects (6 – 7). A central reason for the prestige of informed consent is that it is viewed as a powerful instrument of self-protection, the assumption being that given adequate information and the option to make an uncoerced decision, no one will voluntarily subject oneself to unreasonable risks of harm. And if competent subjects do choose on a voluntary and fully informed basis to accept a certain risk of harm, then the common perception is that this should be respected. It is, after all, a central premise of science to encourage individuals to make a reasonable and balanced contribution to the common good. In real-life research, however, informed consent does not always function as an effective protection mechanism. The theoretical legitimacy of the principle aside, there are numerous factors that compromise its application in practice. The communication gap between researchers and research participants is sometimes too wide for genuine informed decision-making to be feasible. Research activity tends to be tangled up with local authority structures, and decisions are in reality often made under considerable duress. In situations without basic access to health care, it is highly questionable whether research participants have the necessary alternatives that would make the very idea of free decisions meaningful. Researchers working in all parts of the world, are familiar with problems of this nature. They are certainly common in Africa, and it is

therefore important at seminars such as this one, to devote special attention to the difficulties of working with informed consent and the practical limitations of the principle. As long as there is doubt about the effectiveness and meaningfulness of informed consent in a given social and cultural context, it should only to a very limited degree be relied upon as a vehicle of self-protection. This means that there is an added need for review boards and other agencies monitoring research to assume a protective role. And consent alone should not be viewed as sufficient indication of high ethics standards. But this reservation must not be taken to imply that the underlying rationale of informed consent is irrelevant. In essence, informed consent may be interpreted as a principle of respectful communicative interaction, which on the one hand translates into a requirement for maximum openness in research, and on the other as an obligation to respect and heed the expressed will of prospective research participants. Both of these ethics requirements are pertinent in any context, be it any branch of science and in any part of the world. It is just that these requirements are not always subject to the degree of monitoring and enforcement that we demand from the basic protection of research subjects. The crux of the matter is therefore that informed consent belongs (primarily, or at least in part) to another realm of research ethics, namely to the level of ethics consideration that is associated with what could be called communication issues. This is an area of ethics consideration that is less determinate than protection issues, but it is not for that reason less important.

19.6.2. Communication issues As previously suggested, the basic value of respecting the integrity of the person entails the principle not only of protection against harm, but also of respectful communicative interaction. Whereas the former principle concerns what we do to others, the latter concerns the quality of our relations. It may also be described as a question of how our attitudes and acts reflect on others. In many circles of scientists and professionals, there is a widespread perception, that while ethics considerations of this nature may be valid in princi-

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ple, they are not particularly important. If respectful interaction is occasionally neglected, so be it; ‘‘soft’’ ethics concerns should not be allowed to interfere with the more serious business of conducting research, and attending to urgent social problems. There are numerous ways in which common ethics standards of communicative interaction can be applied to research. Foremost among these is the basic requirement to address others in a respectful and dignified manner. This is something we are all very aware of in our ordinary human interaction, and something we are very sensitive to. Affronts to our dignity are often experienced as even more offensive than unintentional physical or material harm. A variation on the same theme has to do with recognizing competent subjects as such, and this in turn entails an obligation to respect autonomy, as is stipulated by the principle of informed consent. In order for this to be meaningful, researchers should honour the principle of maximum openness in research; otherwise by not observing this principle research subjects would be deprived the chance of making their own informed decisions. In practice, the principle of openness in research is demanding. It means taking the time to carefully explain one’s research intentions and the consequences they will have for each group of participants. It also means providing this information in a manner that is intelligible while striving for a reasonable degree of completeness of information, or at least not withholding any central information. A striking indication of the importance of this is found in the strong manner in which most research participants react to being misled, and even more so to being deliberately deceived. This is almost invariably experienced as a serious breech of trust, affront to one’s dignity, and has far-reaching consequences for the overall reputation of science. Another key aspect of the ethics of communicative interaction, is respecting personal and cultural sensiti6ities. This is particularly relevant when research is conducted in a situation of pronounced cultural differences. The principle is immediately applicable in situations of face-to-face interaction, but it also ex-

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tends further to one’s general relation to the community hosting the research, and to the manner in which people and groups are subsequently portrayed in publications that ensue from one’s research. The latter area is sometimes called the ethics of representation. It is increasingly being recognized as central to contemporary research ethics, and it is often coupled with the more general requirement, that research results be returned to the communities hosting research. This is in recognition of the entitlement of participants to benefit from the results of research, and also as a preventive mechanism against gross misrepresentations. Having established the basic principle of respect for personal and cultural sensitivities, it is appropriate to note that an attitude of respect does not preclude the possibility of challenging cultural differences. Being involved in a genuine moral relation always means being able to challenge the other, and express both approval and disappointment. In fact, not to do this is implicitly condescending and paternalizing, in that it implies not actually expecting fully responsible behaviour of the other or having given up on the other in advance. Thus, we shall have arrived at a situation of respectful interaction only when we have forged relations in which personal and cultural differences can be candidly broached. However, the requirement remains that this must happen in a respectful manner and in a spirit in which the behaviour and values of the professional are equally subject to critical scrutiny and evaluation. The latter stipulation is indispensable, the underlying point being that high standards at the level of communicative interaction, are unattainable without a fundamental reciprocity of expectations and demands. The ethics considerations presented here are of critical importance to research for a number of different reasons. What is essentially at stake is the dignity of research subjects, and this is a fundamental value in its own right. It is also a value that has been grossly neglected throughout pre-colonial and colonial history. Systemic dignity violations for example in the form of slavery, racism, and apartheid, have left deep scars, and

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we would be deceiving ourselves if we were to pretend that this has no impact on present-day research, particularly on donor sponsored research in developing countries. Future generations of researchers will not be able to redress the wrongs of the past, but as a minimum requirement we must be committed to not repeat the transgressions of the past. This places a central emphasis on the principle of respect for dignity. The principle is also important due to numerous practical implications. It has a bearing on the basic protection of research participants in so far as full openness about research procedures and aims may be assumed to be one of the best insurances against substandard research. Almost all serious breeches of ethics happen covertly! Another consideration, which should not be underestimated, is that respectful communicative relations strongly support our impulse to care for others and our aversion to inflicting harm. This becomes apparent when one looks at the characteristic scenario accompanying atrocious violations of humanity. From the slave trade, through the cynical experimentation on humans in the concentration camps of World War II, to the crimes committed in present-day ethnic warfare, gross violations of humanity tend to be invariably preceded by a failure to recognize the victim of crime, as fully human (8). One of the most powerful ways of countering this is by fostering relations of respectful communicative interaction. Not all scientists appear to take respectful communication seriously. One need only inquire into the public perception of scientists in many parts of the world to ascertain that it is an area in which ethics standards are definitely lacking. The common notion of ‘‘over-researched areas’’ marks another discouraging example of deep-seated frustrations. Thor Theander once suggested that a simple test of the overall ethics standards of one’s research, would be to inquire whether one would be welcomed once again by the host community, and whether the research subjects would once again volunteer to participate. This is a test that many of us would fail due to inadequate standards of communication and follow-up.

A primary reason is that ethics deliberations in general, and especially the so-called ‘soft’ concerns to which respect and mutual understanding pertain, are widely viewed as a nuisance making the research process more cumbersome. Sometimes these actually inhibit the access of scientists to vital research data. Ethics procedures are invariably time consuming, and it is often assumed that if prospective research participants were fully informed about our intentions, they would refuse to volunteer. Then society would be deprived of information that is necessary for addressing urgent social problems. The paramount argument against excessive ethics ‘fussiness’ is, in other words, expediency. In the real world, this carries considerable weight. Most researchers operate in a competitive environment. They are fundamentally at the mercy of academic institutions, funding agencies, and publishing houses. These agencies are prone to demand frugal budgets, tight research schedules, and prompt delivery of data. So by simple natural selection, the most ethically conscientious researchers are liable to perish. When it comes to research in developing countries, the same basic argument is often given the added twist, that the urgency of needs, and the chronic imminence of social disasters justify a temporary suspension of ethics requirements. This is invariably presented as an exceptional circumstance, but the appeal to the urgency of social problems is so common that it comes to function virtually as a carte blanche excuse for lowering ethics standards, and precisely in situations where vulnerabilities are most prevalent, and public protections are weakest. Yet these are the situations where high ethics standards of research are therefore most needed. The tendency of suspending ethics commitments on account of expediency is entirely unacceptable, both on moral and on practical grounds. Even if high ethics standards were a luxury, researchers and research participants cannot afford to renounce them. In fact high ethics standards are not a luxury, and it is not true that lowering of ethics standards expedites attainment of knowledge, and the applicability of research results to urgent social problems. The picture can in fact be reversed: exacting

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ethics standards as a general rule, enhances the ability of science to fulfil both its theoretical and practical mandate, and must therefore be regarded as integral to ‘good science’. This is certainly true when it comes to the ethics of respectful communicative interaction, which in a very immediate sense enhances our access to viable and reliable research data. This also benefits the public reputation of science, and of which the long-term implications should not be underestimated. Under exceptional circumstances, it may be justified to temporarily lower the ethics standards. Even then this should neither be a decision made in private nor a licence that researchers can grant themselves. One of the central challenges of contemporary research ethics consists in specifying the criteria and formal procedures for obtaining exemption from otherwise operative ethics expectations. This should always require some form of public justification, even when it comes to the soft ethics standards related to respectful interaction. Communication ethics issues are difficult to subject to formal regulation. Respect for dignity, cultural sensitivity, and the cultivation of reciprocal relations etc, are more a matter of modifying one’s general attitude than of observing a limited number of specific obligations. They are also more a matter of degree than of either complying or not complying with set rules. They have a process in the course of which genuine ethics relations gradually emerge, while previous transgressions are continuously corrected. This makes the ethics of respectful communicative interaction difficult to monitor and even more so to enforce. If it is agreed that the above considerations deserve a central place in the conception of optimum ethics standards, then it should be acknowledged that not all 6alid ethics principles can be enforced. The fostering of high ethics standards therefore requires complementary intervention at a broad range of different levels. Some ethics concerns can be met by improved formal regulation, raising demand awareness and education among researchers, targeting the policy making level, and strengthening various sites of informal ethics accountability. This latter level of intervention is exceptionally important. It should be ac-

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knowledged that the entire area of ethics associated with reciprocity and respectful communicative, stands in need of continued exploration with respect to both the specific implications of the general principles, and models for how to respond to these in practice. This is an area of biomedical ethics where experiences in the social sciences and in the emerging area of participatory research methodologies, may prove to be highly relevant. It is also conceivable that probing studies of how to make informed consent procedures more effective and meaningful, will enhance our overall understanding of how to handle communication issues in practice.

19.6.3. Rele6ance Issues When combined, the ethics principles of utilitymaximizing the common good-and that of justice (taken in the distributive sense), yield a requirement that research should be rele6ant in the context in which it is conducted. Utility on its own stipulates that there should be proportionality between risks and anticipated benefits, but this can be stated in anonymous, impersonal terms without regard for the good of the particular stakeholders in the research process. The principle of distributive justice, however, adds the stipulation that there should also be proportionality between burdens and benefits from the point of view of any party directly involved in, or in other ways intimately affected by a given research initiative. It may be too strong a demand that all parties involved should directly benefit from research; for first and foremost research is justified by its ability to make valuable contributions to the common good. However, this does not preclude recognition of on the one hand, an obligation to make some returns to individual participants and host communities, and on the other, an entitlement for all of the main stakeholders to regard the activities involving themselves as meaningful and relevant from their own particular point of views. Simple though this principle sounds in theory, it is quite complicated in practice, and is subject to considerable controversy. The demand for relevance is articulated in numerous different ways by different groups of lay critics of research. It is

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quite often raised by members of the public with a hint of hostility towards academics and scientists. Many research interests appear obscure to ordinary people, yet they are costly, invasive, and perhaps even put the public at risk in various ways. It is therefore felt that the general utility of the research ought at least to be beyond question. This is especially urgent in situations where needs are overwhelming and resources scarce, as is the case in all developing countries. Thus tax payers in donor countries are particularly prone to demand proof of relevance from scientists engaged in development-related research. The same demand is regularly made by representatives of the countries hosting research, both out of concern for maximizing the use of available funds, but also in order to avoid a situation of impoverished population groups being exploited. At the ground level in developing countries the picture often looks somewhat different. Here research is typically perceived, not primarily as a contribution to the common good, but rather as a self-interest activity (providing its practitioners with career, income, and status), and it is therefore frequently met with some variation of the question: ‘what is in it for us?’ This sometimes takes the form of ‘crude’ demands for monetary compensation for research participation. But the question is also often expressed in more subtle terms in the form of hesitations about whether one is willing to participate, or in that of misgivings about certain aspects of a given research proposal. In all such cases, public and private demands, misgivings, hesitations, and suspicions-no matter how seemingly ‘unreasonable’, may be taken as an indication that the local relevance of a given research proposal is not immediately apparent. Although there is a pressing need to devote more attention to this level of ethics consideration, researchers are prone to resist this demand for relevance. It is naturally viewed as a bonus if one’s research activity is beneficial in the context in which it is conducted, and even more so if one’s results have important practical applications. The dominant view among scientists is that this cannot be a universal demand, and not one which can be made on ethics grounds.

Research is essentially a non-self interest activity devoted to the pursuit of truth and the common good. In this light, the majority of practical and material claims that are regularly made on research are simply unworthy. This argument is misguided, weak, and rings hollow in many concrete contexts in which research in conducted, not least the research undertaken in developing countries. First of all, as research participants are keenly aware, research is indeed an activity associated with multiple vested interests, and we would do well to openly acknowledge this as a factor which is not necessarily illegitimate, but which needs to be properly balanced against other reasonable claims on research. Moreover, the appeal to science as a universal good, rings hollow because many of the people and population groups that we invite to contribute to our research, have an experience of being excluded from the common good. It is, of course, fully conceivable that disadvantaged individuals or entire communities may choose to make a contribution to science without regard for immediate personal benefits. The critical point, especially given the world’s systemic inequities, is that this has to be a decision that is freely made by the research participants themselves in each specific situation. It can neither be assumed nor taken for granted. Researchers therefore need to approach lay subjects with a humble attitude, and the expectation of having to make a good case for the relevance of one’s proposals. As for the idea of remunerating research participants for their time and contribution, the central objection to this (aside from the general reluctance to mix up research with material interests) rests on the concern that monetary compensation will compromise the notion of voluntary research participation. This, paradoxically, is especially pertinent in impoverished communities where even a small token of appreciation could mean a lot. Therefore the international scientific community tends to adopt a particularly severe stance against payment for research participation when it comes to research in developing countries. Certainly the idea of being able to pay impoverished population groups small money for exposing themselves to high risk research procedures

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that other groups would flatly refuse is a slippery slope. Nevertheless, we recognize the legitimacy of the request for some immediate, tangible benefits from research activities to which one makes a contribution, then the onus is on us as researchers to find acceptable alternative solutions. This could take the form of a mix between compensation for actual expenses (transport, meals, etc) and lost income. In addition to this, a more substantial contribution that is made, not to the individual research participant, but rather to the entire community or group hosting the given project. In this manner it should be possible to minimize the connotation of pressure for continued cooperation. The general perception of the relevance of the research may be further enhanced if the returns made to the host community, are thematically linked with the object of the study in question. A further reason why scientists are prone to resist relevance as a core ethics standard, has to do with the perception that it is a requirement that much valuable research is simply not capable of honouring. To be more specific, relevance is widely viewed as an extra-scientific criterion which stands in danger of excluding the entire range of basic research from the company of legitimate scientific activity. If there is something that needs to be strengthened in most research environments around the world, it is precisely basic research. This priority can be reconciled with the criterion of relevance by adopting a more comprehensive view of the nature of science. It should be noted that science is not only about advancing our knowledge, or merely about producing data that may be useful for some practical purpose. It is always also about enhancing the conditions for further scientific activity within the same general area, be this through building intellectual capacity, resource base in the form of libraries and institutional infrastructure, and publications that identify questions in need of further examination. Furthermore, the very fact of hosting scientific activity shapes the public’s underlying view of the world. Modern society is dependent on the continuous production of knowledge, not only in a narrow

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instrumental sense but also for the manner in which we interpret our natural and social environment. Articulated in general terms, scientific activity by its very nature always reaches beyond itself, and it is in this perspective that the question of the relevance of science has to stand its test. Historically, foreign sponsored research in Africa has not performed well on this count. Common practice during colonialism and well into the postcolonial era, has been for research data to be expropriated without any significant returns being made to local research environments and without the outlook of science enriching the on-going process of social development. Data have, in other words, been mined like other raw materials intended to be refined and consumed elsewhere, and which to say the least is ethically unacceptable. It is therefore with good reason that it is now a standard requirement that all donor sponsored research in developing countries, should be defined from the outset as collaborative, be committed to local capacity building, and social development. Research is now expected to justify relevance not only in terms of its direct applicability, but also in terms of its secondary or derived effects. In this respect the so-called basic research has at least as much of a contribution to make as research that is linked to specific practical functions. Thus, relevance when properly construed, is an entirely reasonable demand to place on all research. It forms an indispensable part of our ethics vocabulary, and must figure prominently as part of any comprehensive vision of ‘‘optimal ethics standards.’’ However, like respectful communication, the standard of relevance is difficult to monitor and enforce. The general requirement does not readily translate into determinate obligations that one can feel assured of having met, given a reasonable effort. In many circumstances the notion of relevance rather functions as an ideal to be approximated, and it is far from always clear what it would take to meet this ideal or who is to make the critics decisions about when to deem a given research proposal relevant.

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The question of how best to promote the relevance of scientific activity clearly exceeds the purview of individual responsibility. As individuals we are generally powerless, for social justice motivating the ethics standard of relevance, is predominantly a matter of institutional, national, and international policy, and upon which the individual researcher has a very limited impact. Social justice is addressed at a higher level of authority in charge of planning and co-ordination of research, allocation of funds, decision making about what should be researched, which proposals to approve, and organizing collaborative initiatives. The demand for relevance is nevertheless sufficiently determinate to function as an ethics standard, which can meaningfully be applied to individual researchers in a variety of different ways. It is already common in the ethics section of research proposals to include an assessment of anticipated benefits and harms. This in effect functions as a justification of research in terms of its contribution to the overall good, and it would not be complicated to add to this the expectation of a statement on the relevance of the proposed research in relation to the primary subject groups affected. Aside from justifying one’s research in terms of its relevance before an ethics review committee or permit granting agency, it is also reasonable that the same justification should be made in a less formal manner before representatives of the community hosting research, and even before individual research participants, when requested. In this manner, the criterion of relevance can be a routine part of research evaluation and project description, not merely as a selling point, but as an indication of preparedness on the part of researchers to honour a reasonable ethics expectation. Questions of equity, social justice, relevance, the applicability of research, the feedback of research results to host communities, the distribution of secondary or derived benefits of research, and the contribution of research to basic academic capacity-building mark an area of ethical concern in which there is room for considerable improvement. It is therefore also a primary area

in which contemporary research ethics needs to break new ground. While this requires intervention at many different levels, inclusion of a criterion of relevance among the core standards of research ethics may help to modify the basic attitude of researchers, and to strengthen the expectations with which researchers are met by the general public and individual research participants.

19.6.4. Strengthening Accountability The enhancement of ethics standards in the broad sense is something that can neither happen in a vacuum nor be ensured by public authorities and ethics review committees alone. In order to be effective, professional ethics must be embedded in popular perceptions of what is right as well as in the manifold institutions of civil society. A key formal principle is that ethics decision making, always requires public justification at many different levels. While it is paramount that decisions are in conformity with established ethics standards, this is not sufficient by itself. Researchers must also assume responsibility for making their premises and choices apparent, and for responding to any ‘serious’ parties that may wish to examine and question these premises and priorities. The obligations and claims established at the various levels of ethics consideration, function as parameters of public justification. The concomitant strategic observation is that a key practical challenge in contemporary research ethics consists in strengthening ethics accountability. This entails, on the one hand, identifying a number of appropriate sites of accountability (of which ethics review committees is only one among several), and on the other raising what might be called ethics literacy among researchers and the general public. Along with the extent to which strengthening of ethics accountability and expectations are met by researchers and professionals, there will be a growing need to expand our conception of the relations that are ethically significant. There may be some ethics standards appearing to be far beyond the limits of rules and requirements, and yet strictly enforceable.

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References (1) Gert, B., 1988. Morality: A New Justification of the Moral Rules, Oxford University Press. (2) Beauchamps, Childress, 1994: Principles of Biomedical Ethics, Oxford University Press. (3) Abdussalam, M., 1992. Application of Ethics Guidelines in Non-Western Communities. In: Ethics and Research on Human Subjects: International Guidelines, CIOMS, Geneva, Pages 65 – 69 (4) Osuntokun, B.O., 1993. An African Perspective. In: IBID CIOMS, Geneva, Pages 173 – 76 (5) Loues, Okello D., Kawuma, M., 1996. Research Bioethics in the Ugandan Context. A Programme Summary. Journal of Law, Medicine & Ethics 24: 47 – 53. (6) American Anthropology Association, 1998. Code A4 (7) Fluehr-Lobban, C., 1994. Informed Consent in Anthropological Research: We are not Exempt. Human Organization 53(1): 1 – 10. (8) Rorty, 1993. Human Rights, Rationality, and Sentimentality. In: On Human Rights, Editors Shute and Hurley, The Oxford Lectures, Basic Books.

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of identifying such variable conditions and needs in Africa, reviewing available ethics guidelines for meeting these needs, and making appropriate recommendations. The current international ethics guidelines as well as those developed for South Africa, are already specifically addressing health research ethics issues in developing communities found in Africa and elsewhere. Such issues include communication with illiterate research subjects, procedures for obtaining and documentation of informed consent, compensation for participation and injury, sensitivity to community ethos, customary collective decisions vis-a-vis self determination, consenting age, obligations of sponsors and hosts, and composition and responsibilities of ethics committees. However, there are areas which still require discussions and consensus, such as participation equity for women and vulnerable populations, promotion of priority research on otherwise neglected communicable diseases endemic in Africa, research capacity building, dissemination, and utilization of research results. It is hoped that the proceedings of this Seminar, consisting of commissioned presentations, discussions, and recommendations, will be published for implementation by African countries.

20.1. Introduction 20. Health Research Ethics for African Countries Joas B. Rugemalila, MD, MPH, PhD, Chief Seminar Rapporteur Hakika Medical Centre, Dar es Salaam, Tanzania Abstract Health research is a very important developmental activity undertaken primarily to provide solutions to perceived problems. However, it is equally important that research should abide to ethics ensuring respect for autonomy and self determination, beneficence, non-maleficence, and justice. Although these ethics principles are universal, the monitoring guidelines are required to respond to some conditions, which may vary from one research community to another. It is in this context that this seminar is being held with the objectives

20.1.1. Health Research Health research is systematic collection, analysis, and interpretation of data, aiming at providing an answer or solution to a stated question or problem relating to human health, and whose locus therefore goes beyond medicine. It includes all other aspects involved in health promotion, has inputs not only from clinicians, but also from other professionals, and the lay public. Although health research may be undertaken for such other reasons as to get publications for professional advancement, the primary aim should be to provide solutions to problems, and thereby promote development. 20.1.2. Health Research Ethics These aim at safeguarding the human rights of persons participating in research, particularly respect for autonomy, self determination,

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beneficence, non-maleficence, and justice. Although ethics are universal to all persons and communities, the implementation guidelines are expected to be pragmatic and sensitive to community specific ethos and needs. It is in this spirit that some of these factors have been addressed by the latest editions of the Helsinki Declaration, International Ethical Guidelines for Biomedical Research Involving Human Subjects developed by the Council for International Organizations of Medical Sciences in collaboration with the World Health Organization (1) and the South African Medical Research Council (SAMRC) Guidelines on Ethics for Medical Research (2). The factors which have been of latest concern relate to developing communities in both developing and developed countries.

20.1.3. Health Research Ethics in Africa All African countries have developing communities, and some of their ethics concerns to that effect, have been lately addressed (1 – 2). However, there are some African countries which have no officially recognized mechanisms for reviewing and monitoring health research ethics. For the countries already doing so, there have been no opportunity for stock taking of their experiences. Furthermore, Africa still has its specific needs, some of which are discussed elsewhere in this presentation. 20.1.4. Seminar Objecti6es and Strategies This Seminar has been convened, therefore, to provide a forum to receive and discuss presentations focusing on Africa for: 1. Health problems and research needs; 2. Socio-cultural profiles; 3. Current universal, regional, and country specific ethics guidelines; 4. Country experiences regarding supervision and monitoring of health research ethics; and 5. Recommendations addressing current ethics issues in African countries. The deliberations were undertaken in plenary and group sessions. A draft of the recommendations along with the presentations and discussions were circulated to the Seminar participants and health research institutions within and outside

Africa for editing and consensus, before their publication as proceedings of the Seminar. It is expected that the recommendations will be implemented by African countries, and that in the future, seminars like this one will be held regularly to review and update health research ethics issues affecting the region.

20.2. Africa Highlights 20.2.1. En6ironment Most of the African countries are in the sub-Sahara region, experience a tropical climate which is particularly favourable for transmission of communicable diseases. In many African communities, there is defective environmental sanitation and human excreta disposal, thus further exacerbating transmission of communicable diseases. There are also many arid areas with prolonged droughts, and therefore rampant for nutritional deficiency disorders. 20.2.2. Population Profiles Africa has an estimated population of about 634 million people, constituting about 10% of the world total population (3). Adult literacy is low, particularly for women with an estimated rate of 60%. Most of the populations are therefore expected to have limited capacity for understanding complex health research concepts, low levels of awareness for their human rights, and are therefore vulnerable to abuse by health research. The economic front is also very unfavourable for promoting human rights, justice, and self-esteem. The annual GNP per capita is about US$ 340, and the population dependency ratio is very high at 93%. Most populations, therefore, are economically deprived, hungry, dependent, and displaced as either refugees or prisoners of war, all of which are risk factors for exploitation. 20.2.3. African Cultures Cultural beliefs and practices or customs, besides being sensitive issues, are not uniform across Africa, but vary widely between countries, and even within countries. Besides national languages, which for many countries may be more than one, there may be several ethnic dialects. Mother

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tongues are often easier and therefore preferred for thinking out, receiving, and presenting ideas. On the other hand, a foreign language may be less embarrassing for discussing sensitive issues such as those relating to sexual matters. However, using a foreign language may not convey the message adequately, particularly if the ultimate aim is to elicit informed consent. Although most African countries are secular and accommodate many religions, some states experience threatening religious fundamentalism. Yet there are some religions whose basic beliefs and practices are opposed to scientifically proven health concepts. Fortunately, there are respectable local persons who are knowledgeable about their community ethos, and willing to discuss such issues, and provide advice.

20.2.4. Burden of Disease African countries have heavy disease burdens afflicting mostly young age groups, and thus causing premature deaths and or protracted disabilities. Over 60% of this burden of disease (BoD) is estimated to be caused directly by communicable diseases, and a further 10% by nutritional disorders. Communicable diseases exacerbate not only nutritional disorders but also all other non-communicable diseases being brought into increasing prominence by demographic and epidemiologic transitions. Furthermore, the disease aetiologies on the continent appear to be more multi-factorial than in developed countries. 20.2.5. Health Research Needs Notwithstanding the dire need for health research, local capacity in the form of expertise, technologies, and financial resources, is far more constrained than in developed countries. There is therefore need for commitment by research hosting countries and sponsors alike, to respectively provide and receive and put to good use training to potential local researchers and technology transfer. Researchers from both host and sponsoring countries should be committed to equitable sharing of research burdens and benefits. There is also need for fostering collaboration between local beneficiary populations and sponsors, as well as between various disciplines, local and external

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researchers, and institutions. Communicable and nutritional deficiency diseases are not expected to be accorded research priority by developed countries which have research capacity. Most of these conditions have long been controlled in these latter countries. Furthermore, the above diseases mostly affect economically deprived populations, and would therefore not be expected to attract research investments. Nonetheless, it should be realized that with the ever increasing globalization, some communicable diseases remain a real threat to both developing and developed countries. Some useful and implementable research findings do not often reach their beneficiaries, and are therefore not utilized. There are research findings which are published in scientific jargon, and in foreign journals of limited circulation in Africa. Such reports are incomprehensible and inaccessible to the lay beneficiaries, as are those presented at foreign scientific meetings. Sometimes even the research may have been undertaken without the beneficiaries being aware, and therefore without any inputs from them.

20.3. Currently A6ailable Guidelines 20.3.1. Uni6ersal Ethics Guidelines All available ethics guidelines have undoubtedly been enriched by among others, the Socratic Oath, Nuremberg Code, Helsinki Declarations, Proposed International Ethical Guidelines for Biomedical Research Involving Human Subjects, and the International Guidelines for Ethical Review of Epidemiological Studies. The above guidelines have been superceded by the International Ethical Guidelines for Biomedical Research Involving Human Subjects (1). The latter guidelines have particularly considered ethics issues affecting health research in developing communities, and countries. All African states are grouped among the world’s developing countries The above guidelines particularly address: 1. Communication between researchers and research subjects; 2. Documentation of elicited informed consent; 3. Compensation for participation and injury; 4. Accommodating community ethos;

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5. Collective decisions vis-a-vis individual self determination; 6. Obligations of research sponsors and hosts; and 7. Constitution and responsibilities of ethics review committees.

20.3.2. South African Ethics Guidelines Although South Africa is more advanced than most of the African countries, it still has sufficiently large developing communities to be classified as developing. Through its medical research council, the country has developed and regularly revises its own Guidelines on Ethics for Medical Research (2). The preface to the latest publication acknowledges that these guidelines have been specifically adapted to among other situations, the customs of the predominant African ethnic populations, and the minorities, and to have drawn on the experiences of among others, WHO CIOMS and the Royal College of Physicians (3-6). Unfortunately Some of the quoted references misleadingly refer to medical research and physicians. The guidelines actually address health research which is more encompassing, and recognize that besides physicians, health research is increasingly involving the participation of other professionals including biologists and social scientists, and multidisciplinary collaboration. However, the guidelines are not explicit on the means for promoting and monitoring multidisciplinary collaboration. 20.4. Seminar Recommendation It should be noted that to some extent all African countries, have similar health research ethics problems, and that some of these are also found in other developing communities worldwide, and have therefore been addressed by either one or both the International Ethical Guidelines in Biomedical Research Involving Human Subjects and the South African Medical Research Council Guidelines on Ethics for Medical Research. Key terminologies in the above and other relevant publications, such as bioethics, ethics, and ethical guidelines, medical, biomedical, and health

research, should be reviewed to achieve harmonization and avoidance of confusing jargon. For each ethics problem affecting African countries in the context of being developing communities, available guidelines should be compared to facilitate the selection of the one providing optimum solution for either adoption or adaption. The problems of interest in this context include: “ language of communication between research investigators and subjects; “ documentation of informed consent; “ compensation for participation and injury; “ sensitivity to community ethos; “ customary collective decisions vis-a-vis individual rights; “ age of consent; “ obligations of sponsors and hosts; and “ composition and responsibilities of ethics review committees. The ethics guidelines for African countries should also consider and cover among other issues, mechanisms to be adopted by national ethics review committees to ensure: 1. research participation equity for women; 2. promotion of priority research for control of communicable diseases; 3. capacity building through training and technology transfer; 4. sharing of research responsibilities and funds; 5. dissemination and utilization of research findings; and 6. co-option of lay public knowledgeable in community ethos.

References (3) CIOMS and WHO (1993). International Ethical Guidelines for Biomedical Research Involving Human Subjects, Geneva, Switzerland. (4) SAMRC (1993). South African Medical Research Council Guidelines on Ethics for Medical Research. (5) World Bank (1994). Better Health in Africa: Experience and Lessons Learned, Washington DC, USA.

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(6) Royal College of Physicians (1986). Research on Healthy Volunteers. London: Royal College of Physicians. (7) Royal College of Physicians (1990). Research In6ol6ing Patients London: Royal College of Physicians. (8) Royal College of Physicians (1990). Guidelines on the Practice of Ethics Committees in Medical Research Involving Human Subjects. Second Edition. London: Royal College of Physicians.

21. Opening Speech

21.1. Vote of Thanks In the vote of thanks to the guest of honour, Mr Rugumyamheto, was commended for the speech which clearly highlighted pertinent health research ethics issues in contemporary Africa. The continent was particularly noted for having: 1. The greatest need for health research; 2. Communicable diseases as the major proportion of its burden of disease; 3. Very limited capacity for undertaking the required research; and 4. Inequitable research partnerships with developed countries.

21.2. Recommendations The speech required the health research fraternity to: 1. Foster partnerships between researchers and research institutions in developing and developed countries; 2. Making the partnerships do away with donor driven research; 3. Putting in place mechanisms to monitor and evaluate the partnerships for openness, transparency, and accountability; and 4. Ensure active participation of host populations, communities, and institutions right from setting the research agenda to its implementation, dissemination, and utilization of the research findings.

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22. Country Reports on Supervision of Health Research Ethics

22.1. Questions and Answers 1. What areas of legislation in Tanzania are specifically outdated and need to be addressed? Answer: The legislation relating to the enforcement of the regulations and to coordination of the various national institutions undertaking health research, does not empower the committee to effectively do so. 2. Is there any participation from the grassroots in Tanzania in the National Medical Research Coordinating Committee (NMRCC)? Answer: NMRCC has a professional secretariat and membership from national institutions involved in health research, as well as lay representation through non-governmental organizations, and has mandate to co-opt ad hoc membership when need arises. 3. Does Zambia have plans for developing a national health research ethics committee? Answer: Yes, there are plans to that effect. 4. What are the minimum qualifications in Zambia for the lay representatives on the existing ethics committee, and how are they selected? Answer: The minimum qualifications are ability to read and write in English. These representatives are usually chosen by the University Department of African Studies. The Department knows who the leaders are. 5. Is there any conflict in the Sudan between the international health research ethics and Islamic guidelines? Answer: There has been no conflict between the two. 6. How is money raised to support the running of ethics committees? Answer: Tanzania budgets funds for the committee through the National Institute for Medical Research (NIMR). 7. In addition NIMR charges US$ 100 for each ethics cleared externally sponsored research if this does have a budget for overheads for the Institute. Zambia charges externally and locally funded proposals US$ 50 and Kwacha 20 000, respectively. The University of Zambia School of Medicine managing the ethics committee, charges as overheads 10% of the research budget. Malawi

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also charges 10% of the research budget. The charge has to be paid when the proposal gets ethics clearance, and defaulting investigators are blacklisted. In the Sudan institutional ethics committee do not impose any charges. However, the are intentions of asking the national government to fund a national ethics committee when it is formed. 7. What has been the public reaction in Kenya to the HIV vaccine trials? Answer: It is the Chairman of the Kenya National AIDS Committee who has the mandate to answer that question. However, information on the intended trials given at the UNAIDS sponsored meeting in South Africa in July 1999, showed that similar trials have already started in Uganda. The Kenya trials would be undertaken with collaboration between the Universities of Nairobi and Oxford, and would be based on the findings showing that some prostitutes in Nairobi resisted challenges with HIV infection. There has been an information, education and communication (IEC) campaign to sensitize the public as groundwork for obtaining volunteers for the trial expected to start in February 2000. 8. What is the situation with the public and private universities in Kenya? Answer: All universities whether public or private have to be accredited by the Ministry of Education. For health research ethics clearance, investigators have to submit research proposals for review and approval through institutional departments, ethics committees, and the university senate. At present the recognized ethics committees are at the University of Nairobi, Moi University, and Kenya Medical Research Institute (KEMRI). 9. Are there any other mechanisms for monitoring the conduct of health research, other than reviewing research proposals for ethics clearance? Answer: Investigators of ethics approved research have to submit to ethics committees notifications of any major changes in approved proposals, progress and final reports, publications arising from the research, and have to obtain permission to publish findings. 10. Do other countries besides Kenya have separate scientific and ethics review committees? Answer: The country presentations from Tanzania,

Malawi, Sudan, Cameroon, and the Democratic Republic of Congo, showed that research proposals were simultaneously reviewed for both scientific and ethics issues by the same committees.

22.2. Comments There was need to define who was the community when talking about community participation, and to play down politics when selecting lay representatives for ethics committees. Funding of ethics committees which may undermine their autonomy should be avoided. Charging proposals by percentages of research budget for funding ethics committees, may create tendency to have these deflated. For some countries charges as high as 10% of research budget may discourage investigators from applying for ethics clearance. Research budgets including institutional overheads could be a possible source for funding ethics committees. However, there were some research donors such as the National Institutes of Health (NIH) who refuse to allocate money for overheads for institutions in developing countries, and yet will allocate as high as 50% of the research budget to institutions in developed counties.

23. International Guidelines for Health Research Ethics

23.1. Questions and Answers 1. Were the Prussian and German guidelines initiated by government or professional bodies? The essence of the question is that the initiating agent has to be known in order to evaluate or appreciate the motive for the guidelines. The Helsinki Declaration was initiated by the World Medical Association which is an organization of physicians, and the declaration therefore focuses on the ethics of the research undertaken by physicians, and to whom these are also more binding. This declaration and others appear to be less rigorous when it comes to other professionals undertaking health research involving human sub-

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jects. Answer: Both the Prussian and German guidelines were initiated by governments in response to the research that went afoul. 2. Considering the terminologies that ethical and unethical refers to what are acceptable and unacceptable respectively, can the terms ethical and ethics be used interchangeably, for example when qualifying ethics/ethical guidelines or committees? Answer: This is a question of semantics, and it does not really matter which one of the two is used.

23.2. Comments 1. Although most guidelines provide for the protection of individual subject rights, they do not sufficiently do so for communities. A good example is that of the International Conference on Harmonization (ICH) guidelines which do not have an eye for communities. 2. In the African context, this is particularly upsetting because many of the individual rights are derived from the community, and biomedical research is part of community life. However, in Europe and America biomedical sciences are integrated in communities. 3. The Helsinki Declaration which was initiated by the World Medical Association focuses almost exclusively on research undertaken by physicians, and to whom these appear to be more binding. This declaration and a few others ignore the fact that other professionals also do undertake health research. However, the CIOMS WHO 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects, to some extent address other professionals engaging in this research.

24. Burden of Disease in Africa in Early 21st Century

24.1. Questions and Answers 1. Is there adequate capacity in African institutions for utilizing the concepts of burden of disease (BoD), disability adjusted life years (DALYs), and years of life lost (YLL)? Answer:

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There may exist no adequate capacity now to understand and apply the concepts. However, the usefulness of the concepts should be appreciated, and capacity strengthening including technology transfer and training made available through research collaboration between institutions in developing and developed countries. 2. Is there data supporting the occurrence in Africa of demographic and epidemiologic transitions, other than that published in the World Development Report for 1993 and for which reference period there was scanty data for sub-Sahara Africa? Answer: It is true that the predictions relating to the demographic and epidemiological transitions in Africa are based on the World Development Report for 1993. With the trends of urbanization, industrialization, and the almost unchanging fertility rates, it is unlikely that health status in Africa will remain static in the next 30 years. The continent is likely to undergo an experience similar to that of Latin America in the 1960s to 1990s which included increasing life expectancy, an aging population, and increasing non-communicable diseases. 3. How will maternal, perinatal, and childhood mortality decrease given the increasing HIV/ AIDS pandemic? Answer: Notwithstanding the increasing HIV/AIDS pandemic, the above mortality rates are expected to decrease as a result of socio-economic development, improvement of health services, and decreasing communicable diseases. Furthermore, the control interventions against AIDS are expected to improve which will slow down HIV transmission. 4. Notwithstanding the relationship between poverty and disease, are we sure that if poverty decreases disease will also decrease and vice versa? Answer: It is expected that with socio-economic development, poverty will decrease, and there will be better living conditions, improved hygiene and sanitation, better health services, and that therefore disease should decrease. Improved health care by itself may produce marked reduction of diseases. This has happened in Cuba, which is a relatively poor country. Also with decreased disease, populations become healthier and more economically productive.

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5. Given the direct relationship between longer life expectancy and incidence of non-communicable diseases, would it not be expected that with the life expectancy dropping from 53 to 49 years the incidence of non-communicable should decrease rather than increase as it is now being predicted? Answer: An adult morbidity and mortality study on populations either predominantly rural or urban in three districts in Tanzania, and representing different levels of socio-economic development, showed that the epidemiologic transition was taking place with the more socio-economically developed populations showing increasing non-communicable diseases, notwithstanding the relatively similar life expectancy.

24.2. Comments 1. Sometimes the terms communicable and non-communicable diseases may not be clear because some conditions and cancers such as peptic ulcers and cervix cancer which were previously classified as non-communicable, are now known to have infectious aetiological agents. 2. Access to improved health care by itself may produce marked reduction in communicable diseases. This has happened in Cuba, which is a relatively poor country where the problem of non-communicable diseases, outweighs by far that of communicable ones. 3. In order to deal with the high burden of disease due to HIV/AIDS, there should be deliberate ethics guidelines to expedite availability of an affordable vaccine.

25. Traditional African Perception of a Person

25.1. Comments 1. There was disagreement with the statement that the West has a headstart in long distant survival, well being, and prosperity. Furthermore, there was an over-emphasis on the role of western technology. The western development was propelled by the ideal that knowledge is power, coupled with the motive for commercialization. If

these were taken away, the technology would not have developed that quickly. However, every successful venture has in itself the seeds for its own failure, and this could account for the destruction of some civilizations. 2. The concept of African culture was questioned because this actually represented several cultures. However, this could be accepted because even the western culture comprises several cultures such as French and German. The cultures comprising either the African or western cultures have several commonalities justifying their grouping together under a single term. 3. The ideas of western culture empowering the African culture, and the African culture humanizing the western culture, and that of the two cultures helping one another through some processes such as globalization, were noted to be impressive. Such processes are increasingly being recognized to bring about dialogues such as the present one, and facilitating cultures to open up to others. 4. There was confusion as to whether the African perceptions of a child and foetuses, were at the same level as that of an adult human being, person-hood, and whether these put emphasis on age and experience, as appeared to be the case in the western culture. With emphasis on age and experience, there must be a cutoff level at which person-hood assumes moral responsibilities, and becomes liable and answerable. 5. It was observed that just as community life is different from collective life, western pursuit to find technological answers to human questions cannot always be expected to succeed. Although highly criticized, the Engelhardt philosophy concurs with the African culture, at least on the issue of the human egg not having the moral obligations of an adult human being. 6. It was considered that the presentation should have highlighted in the context of the African culture, such issues as beneficence, autonomy, self-determination, informed consent, and confidentiality. These are important concepts within the western culture. However, these appear to have no comparable contexts within the African culture.

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26. Traditional African Perception of Illness

26.1. Comments 1. It was reckoned that the issues raised by the presentation have parallels in western culture, and that there are universals which express themselves in local ways in Africa, for example the household remedies. Modern medicine is also filled with such rituals as indiscriminate X-rays. It is also not hard to see differences in rituals by western and traditional healers. One major limitation of western medicine is that it does not convincingly describe why people have become ill. When we discuss with people about illness, we should go beyond symptoms and signs, and cover the whole story of how the illness fit into the person’s life. Dr Kleiman has cited a story of a small girl who was badly burnt, and no matter what was done to her she never stopped screaming until she was asked to tell her story of what it was like to be so badly burnt. 2. An experience from Cameroon concerning witchcraft, and published by a Jesuit priest from the same country, was cited to illustrate an African concept of a person. Whereas the West has a dualistic concept of a person, Africa has the singular concept. An anthropological concept of the human being as muntu, refers to wholistic being in time and space, and goes on to the material concept of the soul. This is where our concept of witchcraft comes in. Most of us regardless of status, would therefore prefer wholistic care, and this gives an advantage to traditional healers. This fact should be taken into consideration if we want ro reduce the cost of medicine in this epidemiologic and demographic transitions. 3. It was observed that there were convincing evidence that for any disease there were social and environmental roles. Yet most of the presentation was on the perceptions of witchcraft and illness. The presentation was expected to provide an indepth analysis of what witchcraft does, and what we should do in Africa, such as including in the medical training the teaching of African ideals such as African religion, law, and medicine. 4. There was a need to know at what level traditional thinking should be introduced into

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practice. There was some feeling that Tanzanians were ahead in the way they use Kiswahili as a medium of interaction among them. In the area of controlling HIV/AIDS we have probably wrongly adopted the western style in that we are dealing with a disease without illness. We also pursue the concept of illness without disease, of which the good examples are HIV positive status and hypertension (raised blood pressure). We have to have one common language of approach in medicine in Africa, and should not act according to what others think but to what we think ourselves. 5. A study which was undertaken in the Democratic Republic of Congo on the parents’ interpretation of their children’s illnesses, was quoted to have shown among other findings that, 26% of the parents felt that their children were ill because of bad fate. The majority of the parents in this group were relatively more economically poor, had made more consultations within the family, and with more religious sects. 6. It was observed that there has always been a tug of war between doctors and lawyers in the area of witchcraft, and this becomes a problem when it is associated with crime such as homicide. Witchcraft is a distinct attitude found in both African and Western cultures. Western thinking tend to equate it as a disease of the mind or insanity. However, because of the legal consequences, western thinking backs off, and call it a non-reasonable belief. In the context of guilty of having committed murder, a reasonable person in the western thinking is not the same as a reasonable person in the African mind. Belief in witchcraft could be something real, and even if it is imagination, witchcraft still has an influence on the mind of the person who believes it. Definition of African witchcraft is appealing. Belief in it does suggest that there must be a psychological aspect of disease that must be considered, and urge us not to disregard it as being useless. Most African countries have law against witchcraft, which is wrong. A lot of witchcraft may be myth, but you find that harmful medicine is always involved. Rather surprising in witchcraft, there is no term for poison. It is only harmful medicine, which is used to harm an individual.

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7. The Seminar was reminded of the past ritual of taking out tonsils which fortunately, is no longer practised; and of the unnecessary surgeries on stomachs occasioned by the beliefs in acids as the cause for peptic ulcers, before the virus cause was discovered.

27. The Regulatory Review Process in the Licensure of Biologicals

27.1. Questions and Answers 1. What are the reasons for the differences in the regulation of drugs and vaccines, and for ethnic suspicion that a drug that works in Europe would not do so in Africa? Answers: Drugs and vaccines are regulated differently, and ethnicity matters especially for biologicals. 2. For the HIV/AIDS problem which is much more important in Africa where it is decimating the economically productive populations, and urgency for controlling its further transmission, are these factors not enough warrant to influence the regulation processes to expedite the availability of drugs and vaccine for controlling this disease? Answer: Things have been moving fast, and rules have been bent for this particular disease under the influence of activitists. 3. Does the Food and Drug Administration have an eye for the rest of the world, especially with regard to how Africa can use the US Code of Federal Regulation? Answer: It is important that every country should have protection ensuring that products are safe, efficacious, and serve the interests of the country. The US CFR can be adopted whenever it is feasible, but it is up to the individual country. 4. It was announced in 1983 that the drug AZT was capable of inhibiting HIV. Since it takes at least 5 years to go through the regulatory process, and the incubation period of 5 to 7years, should the interpretation of the above announcement, be that the manufacturer of AZT started working on the drug as early as 1973 when HIV was non-existent, or that the regulatory processes were expedited, and or that some facts are being hidden? Answer: As there was no

body in the audience who has worked on this, there was no answer to this question. 5. Is there concern that one of the unintended effect of the US CFR protects a monopoly? Answer: It depends on how one looks at it. The US Congress mandated the Food and Drug Administration and CFR to ensure safety and efficacy of the products to be used for management of human health. 6. Who handles the issues of drug expiry? Answer: The policing of drug expiry is done by other agencies. 7. Is it not true that due to excessive regulation, the playing field for producing products for promotion of human health and management of diseases becomes too expensive, so that it excludes Africans, and leaves the game to be played only by the big boys? Answer: In the free market economies, the decision would depend on the risk and benefit cost ratio.

27.2. Comments It was noted that although the regulatory authorities are often considered to be obstacles, they are there as part of the ethics processes to provide quality assurance for product manufacturing, testing, and licensing. Regulatory authorities are therefore there to protect the individual and community, by ensuring that the products marketed are safe and efficacious as intended. They are not there to control industry, but to provide protection against semi-professional entrepreneurs having either inadequate experience or financial support. In Europe the regulatory authorities do not provide the same standard of guidance and help as that provided by the US Food and Drug Administration. The European Commission member states receive from the EC Working Parties directives which they gradually adopt. Although some EC member states are very speedy in this, some will delay the process for many years, sometimes up to 5–7 years. The presentation has exposed very stringent requirements. If these are fulfilled by those working on vaccines, disasters would be avoided, however, with the disadvantage that availability of the vaccine would be delayed.

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28. Composition and Responsibilities of Ethics Committees and Investigators

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come up with too many different forms. There must be a frame-work which is equally acceptable in the North and South.

28.1. Questions and Answers 1. It seems most African ethics review committees are institutional rather than national based. Should this be endorsed especially considering the independence of such committees? And should national committees serve many clinical trials? Answers: National and institutional ethics review committees are both important to have, and should co-exist particularly for large countries with many institutions undertaking health research. The national ERC will have the additional responsibilities of setting the standards and guidelines to harmonize the review process. Scientific and ethics review of proposals, can be undertaken either by the same committee or separate ones. Each approach has its own advantages and disadvantages. The committees should be free to ask for advice from non-members, because it is not possible to have all the required expertise in the regular members only. 2. What is the relationship between Data Safety Monitoring Boards and Ethics Review Committees? Should they be combined or left as separate entities? Answers: These should be kept separate because their logistics of operations and functions are different, and the independence of each should be maintained.

28.2. Comments 1. It was observed that the interaction between the different parties with health research interests as demonstrated in the presentation, was not always the case. Although all have the common goals of doing research, obtaining data, and results, some interactions between these parties have to go through a neutral intermediary, and this should be transparent. 2. It was noted that biomedical research is becoming globalized. There is need for collaborative research which implies that there must be in place ethics review committees that are harmonized with and across countries, otherwise we will

29. Informed Consent in Health Research

29.1. Comments 29.1.1. Discussant 1 It is rather strange that the concept of informed consent, did not arise from within the medical profession but as a consequence to the Nuremberg trials, and later to court actions against physicians in malpractice cases, particularly in the US. The Nuremberg Code, which followed the trial, contains 10 principles. Principle 1 requires informed consent and principle 9 allows the participant to withdraw from participation in an experiment any time if so wishes. In 1961 the World Medical Association drafted a code to distinguish ethical from non-ethical research. Before these milestones and for more than 2000 years, the Oath of Hippocrates or one of its variations guided the practice of medicine. It was an ethical code or an ideal, an appeal for correct conduct but not a law. It was no guarantee against malpractice or violations of the principles embodied in the oath. Patients trusted physicians and in many societies they were regarded with great esteem. In the Middle East the physician was and is still known as the Hakeem an Arabic word meaning the wise. The theory and practical aspects of informed consent are clearly discussed in the paper. It is agreed that health care professionals tend to both dislike and be suspicious of informed concent. Patients in many parts of Africa are not aware of the concept. This is an appropriate opportunity to specifically discuss the procedural matters in obtaining informed consent as it applies to the African populations of today. These populations have social and cultural values that have to be take into consideration and respected. In western culture informed consent targets individuals. The level of education, which has been proven to be one of the important factors that influence the outcome in obtaining informed consent is higher

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in industrialized than in developing countries. Understanding the concept of autonomy is also higher and decision making by individuals is less influenced by the rest of the family. Even in the developed world understanding of the contents of informed consent forms is becoming increasingly difficult because these documents contain increasingly complex legal, technical, insurance, and financial information. In a paper published as recently as 1993, it was stated that many Americans have difficulty integrating and synthesizing ideas, and that approximately half of the population struggle with basic computational and reading skills. In developing countries where illiteracy is high and for cultural reasons experience tells us that obtaining true informed consent from individuals is almost an impossible task. Furthermore, most of us working in Africa engage in field trials involving large numbers of individuals, which adds to the complexity to an already difficult situation. Under these circumstances an alternative but morally acceptable approach is needed. It is believed that the alternative, is communal informed consent provided the necessary safeguards to be mentioned are undertaken. Communal consent may be obtained from trusted and respected community leaders rather than from individuals. In Africa there is a tradition of respect for senior citizens in the community who are usually consulted on every issue pertaining to individuals, family, or the community at large. Although the concept of communal consent is unacceptable in western culture, it is certainly compatible with the cultural norms in most developing societies. Where individual members of a community do not have the necessary awareness of the implication of participating in an experiment to be able to give adequate informed consent directly to the investigators, the decision of whether or not to participate should be elicited through the intermediary of a trusted community leader. However, the consent should not be through a single community leader, but by an adequate number of chosen individuals who represent the community. This presupposes that the investigators must have enough prior knowledge about the community

and their culture. There is of course the danger that individuals may decide to participate not because of their own free will but out of respect for the leaders. While this cannot be eliminated completely it can be minimized. Essentially the same procedure outlined in the paper under discussion should be followed. The information should be given in both written and oral form in a language comprehensible to the community leaders. In Africa oral communication is more important than a written document, but the latter should always be included and signed by the community leaders. Because there are many languages and dialects in Africa, it will be an advantage to include among the investigators, individuals who are familiar with the local language. Before the consent form is read before the community representatives, it has to be tape-recorded and retranslated by an independent person to make sure that the correct information is given. The leaders should be given the opportunity to ask questions and adequate time to explain the contents of the document to the participants The nature of the communal consent procedure places a particularly heavy responsibility on scientific and ethics committees that review a given proposal. They have to be extra careful and meticulous about details of the science and ethics of a given project because of the unconventional manner in which the study is to be conducted. An independent committee should be established to monitor the execution of the study.

29.1.2. Discussant 2 It is rather doubtful whether if informed consent was really possible in clinical research. Obviously informed consent is important. For example the disclosure of information on the research to be undertaken, and often other processes of eliciting informed consent, are usually delegated to junior staff who may not be that much qualified. There is the need to balance the need for giving the patient adequate time to assimilate the information and to ensure that enrollment continues at an acceptable pace. In some situations, it may not be really for most patients to have adequate competence to make decisions about their care. The environment such as the hospital may be too

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inhospitable for the patient to assimilate the information being given. In Africa many health services are under-funded with the effect that for most patients to be enrolled in a study, may be an undue incentive to get standard treatment. When you have low levels of literacy, the fact sheet for the patient could become a problem for such concepts as a placebo. For many studies in Africa, there is very little if any monitoring done to ensure that informed consent is really informed and voluntary. It is suggested that this monitoring be done by the investigators themselves as a form of self-assessment, and that the whole concept of informed consent be viewed from a moral rather than legal standpoint.

29.1.3. Other Comments 1. Often people understand something better if they are asked to be part of the process. This is being taken into account by an ongoing study in the United States of America, which is also rating top risk and benefit to the study subjects themselves, their spouses, and the community. It seems people really see informed consent in a family context. 2. It was pleasing to note that the distinction was made between informed consent in the moral and legal contexts. If exploitation can be avoided then informed consent would not be that important. Generally in the West, informed consent has been used to protect investigators. Things would also be different if there was complete confidence in clinical care and or health research, and doctors and or investigators had epistemiological humility. 3. Having junior staff eliciting informed consent may be a good thing for after all patients appear to trust them more than senior staff. However, they should be appropriately trained. It is also important to distinguish between coercion and inducement. Coercion at whatever level is unacceptable. Inducement becomes unacceptable if it reaches a level were the subject either consciously or unconsciously is prepared to forego autonomy and rights. The ideal of informed consent is seldom achieved as a goal. It requires more skills and efforts.

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4. Sponsors of health research in developing countries should be willing to build capacity of the people in those countries to do those things. A study has been published recently in the Lancet by an Oxford team, showing that people are quick to criticize a problem study in a developing country and much less inclined to do so for a similar study in a developed country. 5. On the one hand we have a principle that is not working, and on the other hand we want to affirm the principle. There are two avenues for this situation: (1) try to fix it or (2) the rationale for the failing principle is different from what we would expect. The question is how far do we want to go in this other direction. We should meet the legal requirements but also have to go beyond this and meet the moral requirements. 6. It is important to improve communication skills especially for eliciting and documenting informed consent. Also studies should be undertaken to check how genetic counseling is done. There have been protocols rejected for ethics clearance, and yet the proposed studies were undertaken. In Spain, investigators of those studies are liable by law, and yet these have not been prosecuted. 7. Communal consent could be a trap for the African community. This has been abused in the past, especially for people who have spoken for others. Each person knows what is good and bad for self.

30. Intellectual Property Rights and Confidentiality

30.1. Comments

Discussant The subject constitutes an ethics crisis at an international level. There are many different interests to be observed including those of researchers, research subjects, communities, companies and or those sponsoring research, home countries of communities or institutions hosting research, companies, and or research sponsors. Drugs or

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other products must be made available to the research communities, and governments may intervene on behalf of their communities or companies. Researchers on one or both sides may advocate for more support. The situation could be eased by arrangements at state levels between countries where the testing is done and where the test product comes from. This arrangement will shift emphasis from researchers to policy makers, for example prohibiting research being undertaken in the country, and then taking the results out and using the results elsewhere. There could be a realistic agreement that a certain percentage of profits subsequent to the research, should go back to the country which hosted the research. Dealing with two world views such as was exemplified by the US Vice President putting pressure on the South African President, may set a precedent which could threaten the idea of a free market. There is certainly something wrong with the system either the emphasis on free trade or the monopoly to produce the drugs, which justifies changing the trade rules. The problem of confidentiality is not only in medicine but also in the social sciences. Researchers have an obligation towards people on whom they do research. The question is whether this obligation is sustainable. Certain categories are recognized to have rights to confidentiality. In terms of legal compensation when it comes to giving evidence in court, the first question is whether you are competent or not in terms of age or sanity. Some people may not be competent because they are in a confidential relationship with the person. For example would researchers in this kind of relationship, feel morally bound to divulge confidential information on a person for the benefit of public good.Confidentiality may or may not have a time frame beyond which the information may no longer be considered to be confidential. Confidentiality is also a moral and legal issue. It becomes a moral dilemma when you have conflicting legal debates. Researchers may have to deal with this at the level of the consent process.

30.2. Other Comments 1. It was observed that it is not clear whether the AZT trials involved mother, child, and any other protocols. The discussant also observed that there were on the ground dilemmas regarding confidentiality and HIV infection status, and the interests of the individual and those of the community. There are times that lawyers have said that one could use loopholes if the dilemma involved community interests. 2. The concept of property rights goes beyond patenting which is too narrow to focus on here. Property rights includes among other things publications, manufacturing, and copyrights. Intellectual property law cannot be used to argue for co-authorship, which is a question of research ethics. 3. The concept of intellectual property could appear as a contradiction of terms. It arose with the concept of private property in western culture. In most African communities the idea of intellectual property does not exist, and one wonders whether we can do without this concept, but rather state what this is meant to achieve in other ways. What is legal and what is ethical in terms of confidentiality? We can give various reasons for doing or not doing something. It is easier to get rich by stealing than by working very hard. Since stealing is morally wrong we cannot calculate the benefits of stealing to decide if we should engage in it or not. Which is the ethical duty and what is the moral duty? 4. In some countries such as the U S where the law is so important we should first determine what is ethical before what is legal. 5. In reference to the discussions of the difficulties with the CIOMS guidelines, one may reach the conclusion that the issues should be sorted out at the state level, and that efforts are best spent on discussions on patenting. These may misleadingly lead to the conclusions that the relevant articles should be dropped from the CIOMS guidelines. However, these are the articles that make concrete the idea of distributive justice. We need them to show whether trials have ethical problems or not, rather than saying the standards being violated should be dropped which actually is the reverse.

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6. It was observed that sometimes it may not be clear as to how far should reasonable availability of the test product go in the terms for research sponsors? You could say the grant from the sponsors should cover the reasonable availability of the product. We should not forget that often the host countries do contribute substantially to research costs. One could draw on the experiences of a study undertaken in Mwanza, Tanzania, on syndromic approach to management of sexually transmitted diseases. The findings of the study showed that through this approach transmission of HIV could be reduced by 40%. The sponsors of the study (the European Commission and Tanzania) declared that they would make the product reasonably available to study communities in Mwanza. Thus linking the research arm with the development arm of the sponsoring country, may make the product available since the development arms usually have greater resources at their disposal than the research arm.

31. Current Vaccine Research in Africa: Engaging Ethics Problems

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the time of eliciting informed consent three to four specific questions were asked, and the child was only recruited if the questions were answered correctly. Discussant 2 Altruism from an African perspective can be linked to the concept of autonomy. There are a number of circumstances where altruism can be exercised, for example the ongoing malaria vaccine research in West Africa being undertaken in adult populations, which are unlikely to benefit from the vaccines. Altruism can work both ways in contracts which a researcher makes with the research community, and for vaccines developed at high costs. The costs may come down. The vaccine may be highly efficacious at reducing deaths from the target disease, but the company may not want to get involved in reducing the costs. Issues like these are not unique to vaccine trials. However, vaccine trials are being singled out because the follow up period has to be very long.

31.2. Other Comments 31.1. Comments Discussant 1 Altruism (willingness to do things which benefit others even if this will be a disadvantage to oneself) is generally none existent to biologists. Although we may seem to be altruistic, we only do things to promote our own ego. Volunteers to Phase I and II trials of vaccines can be said to be altruistic because they may be injected with a malaria innoculum. Researchers based in countries where malaria is not endemic, could also be said to be altruistic if they are developing and evaluating vaccines for this disease. It was observed that a high proportion of the women whose children were involved in the vaccine trials, did understand the concept of a placebo. This was achieved because there was adequate communication with the community at the time of recruitment, and enough time was given for the information to be assimilated. Furthermore, at

1. The ethics of both activity and inactivity must be considered. However, the problem of inactivity or failure to act is that we do not know who is responsible. The language in guideline 8 in the CIOMS guidelines dealing with under-developed communities, suggests an element of overprotection. One should formulate guidelines for high risk research rather than putting damper on research. Capacity building is a reasonable requirement. The tendency of high level African researchers to disappear into high level position should be rectified. 2. Inactivity may be caused by poverty, and causes of poverty are mostly problems of ethics. 3. The teaching of ethics in African universities should be emphasized. 4. There are several examples of drugs such as ivermectin and praziquantel, which were initially very expensive, but with time the prices came down. There are new mechanisms such as drug donations and others being initiated by the World

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Health Organization, which are now being used to make drugs and other medical products become available to those who most need them. What we may consider today to be unaffordable, things may change and make these affordable in the future. 5. Illnesses arising from situations related to growing poverty should not be overlooked. These situations have been likened to a glass of champagne. Everybody’s life is warped when you consider that 95% of the money being generated is from the money itself and not labour.

32. Research Involving Human Subjects: Ownership, Control and Access to Research Medical Records

32.1. Comments 32.1.1. Discussant The presentation has rightly emphasized the resolution of the questions of ownership of discoveries made from access to indigenous knowledge, the role played by the indigenous population, and proposes conditions for future use of stored research materials. 32.1.2. Other Comments 1. There was need for detailed considerations to be given to what to do when the study is over, particularly with regard to dissemination of results to different target groups, and how this should be done to other than peer scientists. Such groups would include communities, policy and decision-makers, and relevant non-governmental organizations. The application of research results was also a concern as were the questions of intellectual property, and place of regulatory bodies. 2. There was a need for strict guidelines specifying what to do with the specimens once the research is over, particularly with regard to research sponsors, overseas, and local institutions. 3. Which legislation supercedes whose in the case of conflict between countries, which earlier

had a research partnership? One such conflict has involved a country which had contributed to banked specimens, and three years later that country on being blacklisted as terrorist, was denied access to the banked specimens. This is clearly unethical because the one who provided the specimens should have the upper-hand. 4. If you own something you should have access to it. The use of data is a most important thing in research. If you are not using it then there is no impact in terms of ethics. Guidelines must specify the use of data, not just the ownership. When the study is over how do you disseminate data for decision making. 1. It was observed that we live in the information age when lots of power is connected to information. Sharing could play more active role in discussion in addition to ownership. 2. The three key words ownership, control, and access involve ethics and jurisprudence. There is the source of information to be considered. A doctor has in possession trust against which nobody has a better title. The title is also in the hospital management committee. There should be a written agreement between the investigator and sponsor about dissemination of knowledge about and arising from the research, access to data at the end of the study, and on anything to be done with the specimens. 3. Dissemination and utilization of research information should be followed up closely as is done by the ministries of agriculture, which use the extension units not only to disseminate information to farmers, but also assists farmers to use new knowledge. We are familiar with complaints against histopathologists for refusing patients access to slides which they have paid for. 4. The guidelines by the World Medical Association put emphasis on biomedical research being undertaken only by scientifically competent investigators and under the supervision of a clinically competent person. However, the role of social scientists in biomedical research, need to be reviewed and defined, especially with reference to supervision by clinically competent persons.

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33. Equitable Sharing of Research Burdens and Benefits

33.1. Comments 1. The question of patents depends on basic research being undertaken. If Africa wants to get patenting income, it has to invest more heavily in basic research. The field research being undertaken at the moment is not going to generate much in terms of intellectual property rights. 2. Some field research may generate indigenous knowledge which by itself may be worth patenting, or greatly contributing to a new invention. For example, in the course of interviewing people, a new medicine may be discovered. It is in situations like this that intellectual property rights and patenting should be reviewed to benefit the communities involved in the research. 3. A genome ethics committee in the US has had a problem of defining a research community, especially when it comes to giving back research benefits. There is also the problem of how much of the profits should the companies give back as benefits. Anyway what is a research benefit? Should the benefit be distributed to everyone having malaria in the participating community, or only to people who participated in the trials? 4. The Organization of African Unity (OAU) has been taking up the issue of indigenous knowledge since many African countries have been affected by this issue. There are two contradictory agreements. The World Trade Organization intellectual property rights agreement does not recognize indigenous knowledge at all. The World Trade Organization is the only United Nations body which can punish any country with sanctions. Although the American concept is that indigenous knowledge is not science, they are known to have patented this in various forms. There is a need to define what is basic research, and what of this can be undertaken by African countries. 5. South Africa has about 25 000 western trained doctors and 200 000 traditional healers. There are some key traditional healers who have agreed to work with pharmacologists. There is a systematic examination of the herbs, and grantee

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that profits will be shared. There is recognition of the importance of traditional healers, sharing of information with them, and they have been made to recognize their limitations and when they should refer patients. Given the history of exploitation on this continent, ways have to be sought to enable sharing of the research benefits, and not just the money but the symbolic meaning of that. 6. It was noted that there was the risk of viewing research benefits only in terms of money. We appreciate the accessibility of communities, their solidarity, and their initial inputs into research. 7. Although the Chinese have the claim for discovering artemether, they did not patent but sold for profit. The Vietnamese are now producing more artemether than the Chinese. 8. The sharing of research benefits has to be equitable, consideration should be given to who should be involved, what is to be shared, and the outcome of the sharing. Information has become power, and this has to be translated into money. It should be a principle to scientists not to publish until what is to be published is really known. 9. In order to make sharing equitable, we should objectively quantify the values of the inputs and outputs, so that what one puts in gets an equivalent from the total outputs.

34. Archived Specimens: Ethics Concerns

34.1. Questions and Answers 1. How far has the human genome project reached? Is it true that the US green card lottery and the human genome projects are linked as has been indicated by journalistic sources? Answers: The human genome will have been sequenced by the end of December 1999. However, the National Institute of Health expects to have a more complete map by March 2000. There are estimates that in about 100 years it will be possible to design individual drugs for each person. The green card procedures have no relationship to the human genome project, which is being done on 10 individuals.

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2. Is it ethical to use specimens for any other research that was not originally planned and consented for by the owners of the specimens, especially considering that publication of this other research will have to state the origin of the specimens? Answers: There is no need to go back and get consent of individuals. However, if there is a determined risk to the research community, the new use of the specimens has to get ethics review in the country of origin. This also applies to hospital records, which for a long time have been used for retrospective studies. 3. On the distinction between identifiable and non-identifiable data, is it possible to convert a bank of data from identifiable to non-identifiable? Answer: You simply take all identifiers off the specimen. However, the expense could be enormous. It is an alternative if you do not want to go through ethics review for the new research.

34.2. Comments 1. The importance of having researched information was noted. How do we get this information if people simply refuse to participate in the research? Should we insist that consent be given? For issues related to the community and protection of minorities, who should decide, how should committees be constituted, how should editors and publishers be made to be sensitive and or responsible to contents of research publications? Are there situations when to some degree individual rights have to be over-ruled? Should giving something back to the donor not be considered as an incentive? 2. Here we are really faced with certain problems, just as one encounters a catch in answering the question ‘have you stopped beating your wife’. We find ourselves at a stage where we have to go back to the beginning or origin. What Africans need most is building and maintaining capacity for doing basic research. There is something called the biodiversity convention and the human genome project. Some third world countries went into this project. It may turn out to be calculated to put a human face on exploitation. Countries like the U S would not ratify because they did not

want to accept even minimal guarantees to what third countries were asking for. 3. Through a national health service, genetic testing and genome mapping will be undertaken on large Icelandic populations. Although the testing may involve miscarriage of justice to individuals, there has to be public trust because the results will serve national interests. 4. One of the central issues is the use and reuse of specimens. For example in the efforts to find out where HIV came from, blood specimens collected years ago were tested from various areas. This is likely to continue happening. The issue is less sharing of the benefits, rather it is sharing the risks. These benefits are difficult to share. 5. Have human samples been patented in the U S? For example the U S has patented agricultural products whose raw materials came from Africa, and in return Africans are paying expensively for the products. 6. Generally, it is said that one cannot patent something in its natural state. You can only do so for something that is non-obvious. You cannot patent a gene in a person or blood, but you can do for isolates from the gene, blood, and the process used to extract things. We know there are cell lines that have been patented. You can take gene sequence and patent it for a purpose. This argument can be used to bend rules when it comes to genetics. One shudders to think about what has been done in the seed industry being done in human beings. However, it is consoling to hear that the genetics group is opposed to patenting. Nevertheless, in reality no government will do this research without the help of private industry, and therefore patenting. It should be ensured that patenting does not interfere with research, and that people are not exploited as a result.

35. Optimum Ethics Standards

35.1. Question and Answer 1. The distributed paper talks about three types of ethical issues as opposed to the three levels in the presentation. Are the issues and levels being

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used interchangeably? Is there any ranking of the issues/levels? Answer: Protection issues are the most important.

35.2. Comments 1. Respecting the integrity of a person, sensitivity to human needs, culture, relevance, and capacity building, have all been rightly emphasized. 2. It would appear that the reference individual that is being talked about is the adult. The concept of children is brushed aside. Children do not have the capacity to consent, and in Africa these are the most affected by health problems, and most of the trials have therefore involved children. Yet the issues have not extended to children. Furthermore, the rights of children need to be considered. 3. If we are unable to show respect to adults, it should be more difficult to do so to children. 4. Human rights issues are problematic in Africa. Human rights violations are increasingly being revealed and documented. Constructive interactions need to be undertaken with governments that may seem repressive.

36. Group One Discussions

36.1. Subjects 1. International Ethics Guidelines; 2. The Regulatory Review Process in the Licensure of Biologicals and; 3. Optimum Ethics Standards.

36.2. International CIOMS Ethical Guidelines The definition of underdeveloped community in Guideline No 8 is not clear. It seems that economic values are considered as the backbone for the moral value of the society. This needs to be defined clearly. The phrasing in the guideline and commentary imply that a project designed or originating in an underdeveloped community can only be researched upon in a developed community. There is need to rephrase the text and com-

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mentary to give an opportunity for issues identified in any one community to be researched in that given community. The projects that are not originating in the underdeveloped community and whose use may be for a developed community should not be burdened to the underdeveloped community as expressly stated in the text. Equity is covered by Guidelines No 10 and 13 in terms of the individual and community sharing fairly in the benefits, burdens, and being able to be compensated in the event of damage. However, the place of the collaborators is not apparent in the text and there is need to include them expressly and explicitly. Capacity building and prioritization of research are amply covered in Guideline No 15. Informed consent is covered in Guidelines 1, 2, 3, 4, and 9. The importance of consent which is the hallmark of acceptance of research, is covered by a third of the guidelines in various shades. This was considered adequate. Vulnerable groups are covered in Guidelines 5, 6, 7, and 11. Coverage of population groups in which informed consent cannot be procured, are considered as being extensive enough as safeguards for the disadvantaged. The coverage of ethics committees, regulatory authorities, and sponsored research in Guidelines 14 and 15, are accepted as adequate. Regulatory authorities are recognized in USA and Europe as legally constituted institutions, based on an adequate comprehensive infrastructure, with adequate financial and human resources for their operationalization. Such institutions cannot be established in that format in African countries considering their economies. It was observed that alternative medicine practices were not equally regulated where they were not publicly advertised. India and China have their own standards, some of which are considered to be internationally competitive. In Africa the system of drug and vaccine certification can be established at national, or even better, at a regional level. It was considered worthy considering the ratification of whatever has been approved by countries which have vigorous and stringent regulatory authorities, in particular USA and Europe.

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It was unanimously proposed that Africa should adapt international ethics guidelines with a sui generis system of regulation. Ethics Committees should be established, but their operationalisation depends on political will, public awareness, and accountability. It is further proposed that a system of public enquiry be evolved in which society concerns can be the subject of an Ombudsman. There is need to establish a forum in Africa which will enable the exchange of experiences, harmonization of practices, and the establishment of a network of biomedical ethics committees.

37. Group Two Discussions

37.1. Subjects

1. Burden of Diseases in Africa During the Early 21st Century; 2. Traditional African Perception of a Person; 3. Traditional African Perception of Illness; and 4. Traditional African Health Seeking Behaviours

37.2. Burden of Disease The discussion focused on the size and distribution of the burden of disease, and factors contributing to the disease burden. It was emphasized that the size, and trends in size of the disease burden, overshadow the distribution of the burden. In 1990 the burden of disease on the population in Africa was 580 disability adjusted life years (DALYs) per 1000 lives compared to 100 and 250 DALYs per 1000 lives respectively in industrialized countries and for the world as a whole. Clearly the burden of communicable diseases will continue to be a major component well into the 21st century. However, the burden of non-communicable diseases such as diabetes, malignancies, cardiovascular diseases, and substance abuse, will increasingly be added. A complex set of interacting factors have contributed and will continue to contribute to the above. Poverty is a central issue, resulting from, and perpetuated by such diverse factors as envi-

ronmental conditions favouring vector borne diseases, droughts and famine, population growth, and changing spatial relations of people. There are also the effects of urbanization, war, conflict, migration, displacement within and outside countries, and the humiliating effects of colonialism. These have adverse effects on energy, initiative, and sprit of indigenous people. The intense social disruption in the lives and traditions of Africans resulting from these processes should not be underestimated. The impact of neo-colonialism in the post independence years, has in recent years been amplified by the effects of globalization of the economy, and severely eroding the economic base of the continent. At the end of the 20th century, sub-Saharan Africa contains 10% of the world’s population, carries 68% of the world’s burden of HIV/AIDS, but has access to only 1% of the world’s economic resources. These statistics starkly reveal the plight of the continent, and expose the need for empathy for those living under such conditions.

37.3. Traditional African Cultures The African worldview is communitarian in contrast to that of the West which is individualistic. These different worldviews have both positive and negative values. It is important to draw from both cultures and to combine the positive values in western individualist set-up, and African communitarianism. Examples of positive values within African culture and worldview that are relevant for bioethics are things like respect for persons, human beings who by the western concept may not qualify as persons, non-human animals, other living things, and inanimate nature. These are within African culture a lot of awe, respect, and caution. Within the traditional African communitarian setting, there was also an egalitarian impulse, and leveling tendency aimed at reducing individualistic inequalities to the barest minimum. Another positive value from African culture, would be the perception of the child within the culture. A child is usually considered to be the responsibility of all adults in the community to which it belongs. Hence the common saying that a

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child belongs to a single person only when it is still in the womb; once born, it belongs to all persons in the community. Another aspect of African culture that is important for bioethics, is that actions of an individual are perceived as affecting the whole community. Taboos, for instance, are imposed on certain things with the belief that, if they are broken, the consequences affect not only the individual but the whole community. This has benefit of helping individuals within the community to help each other to stay on the path of moral up rightness. Examples of positive values within western culture are such things as efficiency, punctuality, attention to details, science and technology, and individual initiatives. There are historical conditions and explanations that are responsible for the different worldviews. These conditions are such that it would be possible with the ways the western and African societies are developing, and given globalization, to really profit from adopting and applying what is best from both systems. What is true of the individual in the way one can select targets for self-improvement, is also equally true with communities, states, and societies. What we are seeing with globalization is a combination of values from individualistic and communitarian societies. All this is related to the bioethics of informed consent, confidentiality, justice, autonomy, and human dignity, voluntariness, community solidarity, beneficence, and non-maleficence. Some of these principles which have been most discussed in western discourse, would not appear to be so important in the African context. If we take autonomy, for instance, it would appear much less important because the individual within the African context normally sees oneself as linked to others, and does not consider one’s actions as being purely individual and autonomous. However, that does not mean that autonomy is not important. The trajectory of emancipation of the individual from the community has been taking place in different forms at different paces in all human societies. There is need to encourage autonomy while at the same time respecting the community links which would enable the emancipation of the individual to continue to take place

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while maintaining the important aspects and values of community. Conflict in the invidualistic and communitarian attitudes may be more apparent than real. Take the example of a married African woman who may not want to give informed consent before consulting her husband. It would be quite wrong to think that she can therefore be bypassed and the consent taken directly from the husband. What seems to be important here is to respect the individual’s freedom of choice, even if that individual may perceive that freedom differently, as for example linked with the approval of others. What is important is that the process should not involve coercion or exploitation. Another important point is combining western biomedicine which gives no explanation beyond the purely scientific matters, with the African practice providing both treatment and explanations. When this is done, it seems more satisfactory from the point of view of the patient, whether in African or western world. It is important not to get bogged down with disagreements arising from ethics theories. It seems more important to concentrate on the basic foundation of ethics and morality involving the principles of good will and the desire of not doing harm to others. From these basics, one can very easily deduce or develop ideas of caring, trustfulness, and respect, all of which are indispensable to any system of ethics. The concept of individual and community at the personal level is analogous to that of individual nations and the world community. Just as there is increasing acknowledgment that we are all world citizens of our own nations, and that we are interdependent, so there should be a resurgence of the understanding that respect for individuals, should not eclipse the interdependence of individuals within the communities from which they arise and live.

38. Group Three Discussions

38.1. Subjects 1. Composition and Responsibilities of Ethics Committees and Investigators;

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2. Informed consent in Health Research; and 3. Current Vaccine Research in Africa: Engaging Ethics Problems

38.2. General Obser6ations Since there already exists many international, regional, and national health research ethics guidelines, the concern should not be to replace these, but to adapt those optimally serving African specific issues and interests. The guidelines to be adapted should be improved to be user friendly, and preferably published in a simple booklet for use by groups and individuals, either on its own providing comprehensive information on key ethics issues, or limited to guiding users to sections of different manuals providing guidelines and other information on health research ethics.

38.3. Ethics Committees 1. Countries can have ethics committees at either or both institutional and national levels. It is preferable that each country should aim at having operational and communicating institutional and national ethics committees. 2. The national ethics committee should set the standards for the institutional committees as well as monitor and supervise their activities. 3. Ethics committees are primarily concerned about ethics principles namely respect for human autonomy and self determination, beneficence, non-maleficence, and justice. However, any one of these principles may be violated if the science underlying the research is wrong. 4. Research ethics and science are therefore almost inseparable, and ethics committees should be equally concerned about the underlying science. 5. Ethics and scientific principles underlying proposed research can be considered together by an ethics committee deliberately selecting appropriate reviewers per se for ethics and science. This arrangement will save on financial costs and time thus expediting approval of good research. However, this arrangement may be less

thorough for either ethics or science. Countries should therefore choose the arrangement, which suits them best between one committee addressing both ethics and science, or two separate committees for ethics and science. 6. Although data safety monitoring boards (DSMBs) may not necessarily be part of ethics committees, they complement the latter by ensuring that the research is undertaken according to the approved protocol and quality control of data collection and analysis. 7. Ethics committees have the dual roles of promoting and restricting good and bad research respectively. Examples of promoting research is to facilitate the teaching of ethics as part of a relevant university curricula, and organizing workshops on ethics for scientists and others. Bad research should be restricted by policing all research being proposed as well as that in progress. 8. The quorum for ethics committees should not be fixed in terms of numbers of members, but in representative memberships, which should include a range of specialties, and definitely lay people. 9. Investigators and ethics committees should use a checklist ensuring that African specific ethics issues and interests are addressed. 10. The checklist should evaluate research proposals for provisions for: “ Capacity building of collaborating national instructions; “ Obtaining and documentation of informed consent not only from the study individuals, but also from communities such as schools, hospitals, and villages; “ Sensitivity and respect to local cultures and welfare of vulnerable populations such on children, women, and prisoners; “ Dissemination of findings to the study communities, ministry of health, policy, and decision makers; “ Current, immediate, and future use of data being generated and stored human specimens and tissues; and “ Mechanisms for research monitoring and evaluation by investigators and any one else wanting to do so.

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39. Group Four Discussions

39.1. Subjects

1. Opening Speech by the Guest of Honour; 2. Intellectual Property Rights and Confidentiality; 3. Ownership and Use of Research Outputs; 4. Equitable Sharing of Research Burden and Benefits; and 5. Archived Specimens: Ethics Concerns

39.2. Opening Speech The salient points raised by the speech were: 1. It is important that the research agenda must be decided by all partners together; 2. The research priorities must really address the needs and interests of the host community, district, nation, and region; 3. Research collaborative partnerships must build up mutual trust and demand transparency in all dealings; 4. The participating parties must share equitably responsibilities and benefits; 5. Research partnerships need periodic monitoring and evaluation; 6. Investigators must see to it that the study results are widely distributed and utilized; 7. Research results and other outputs constitute intellectual property and must therefore be equally shared among the partners; 8. Partnerships should contribute towards research capacity strengthening of individual selves and their home institutions.

39.3. Intellectual Property Rights and Confidentiality 39.3.1. Confidentiality 1. Permission must be requested with informed consent to publish study results in order to increase knowledge and benefit society as a whole. 2. Normal conditions of patient physician confidentiality apply in most cases. 3. Research and publication should not lend to a situation where a population which has agreed

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to enter a study becomes stigmatized by any perceptions that it has particular disease problems or undesirable genetic predispositions.

39.3.2. Intellectual Property Rights 1. The fundamental principle should be that knowledge sharing benefits all. Knowledge ownership is a hazy and probably undesirable concept and the current fashion for ‘intellectual property rights’ (IPR) may not particularly benefit Africa whose resources are rarely considered to be intellectual property’. 2. Under current global patenting and licensing arrangements, there is little or no opportunity for the research being carried out in Africa benefiting from the ultimate profits generated. African is IPR-poor because of a lack of basic research and patentable inventions. This situation could certainly change by increasing the basic research capacity in Africa and possibly via mechanisms similar to the Costa Rican experience, through which negotiations could be made for commercial licenses to exploit national ‘biodiveristy’, permitting future revenue sharing from any commercial products discovered. 39.4. Ownership and Use of Research Outputs 39.4.1. Ownership 1. The question of who among the research subjects, researchers, sponsors, host institution, owns data and other research outputs is complex and controversial. 2. Some sense the study subject ‘owns’ one’s data and gives it to the researcher in confidence and trust, that it will only be used for the purposes consented to.However, control and ‘ownership’ in some senses are then passed on to the researcher. 3. Whilst researchers and host institutions should not forgo their ‘right’ to publish, they should not abdicate their duty of protecting the research subject’s confidentiality. 4. Since publication normally requires copyright to be ceded to publishers, who then have some ‘ownership’ rights. Data ownership is in some senses a partnership in which equitable treatment of all parties should occur.

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39.4.2. Use of Data 1. Data should be used only for the purpose for which consent was sought. New use and users require new ethics review and permission. 2. Sponsoring bodies should not consider that financial sponsorship ends all responsibility to provide access to data and other research outputs to the partners originally generating it. 3. Sponsoring institutions should in fact obtain permission from host institution to use research data.

39.4.3. What to Do When the Study is O6er Some problems will remain after the cessation of study, and may involve two types of ethics issues applying to either all trials or trial outcome, and whether this is a success or discouraging. For studies with a successful outcome, there should be: 1. Targeted and wide distribution of information in appropriate formats as executive summary, newsletter, brochures, video, and meetings. 2. The audiences should include peer researchers, journals, conferences, policy and decision makers, operational staff, relevant non-governmental organizations (NGOs), study subjects, study communities, and mass media. 3. Appropriate promotion of utilization of the results by involving government, NGOs, and commercial enterprises. 4. Provide successful product for at least the placebo group. 5. Provide letters of thanks to adults, and small gifts to children. 6. Implement plans for continuation of staffing of the facilities used for the study, definite improvement of the community health and welfare, and building of integrated and sustainable benefits to the study community. 7. Continuation of capacity building at the African partner institute. 8. In the case of discouraging study results, there should commitment to undertake the appropriate above post-study procedures. 9. In any event it is the onus of the researchers to ensure that there is a national response for the major study results.

39.5. Future Access to Archi6ed Specimens 1. Samples should be stored in such a way as to ensure good standards of coded storage, confidentiality and data management. 2. Line-item informed consent that would allow people to express their wishes about various alternatives should be developed. For example these could include coded identifiers on totally anonymous samples; recontact/no reluctant access/no access for spouses, blood relations, other researchers; permission/no permission for future use in unspecified research projects. 3. Any ‘blanket consent’ should be limited for diagnosis and treatment for disease, and should exclude research in contraversial areas such as reproduction or criminal risk taking behaviour. 4. Such ‘complex informed consents’ will require public education on such issues, without this a ‘simpler’ informed consents confirmed to specific research projects should be used.

39.6. Equitable Sharing of Research Burdens and Benefits 39.6.1. General Principles 1. There should be an equitable sharing of the burdens and benefits when research is performed. 2. The sharing involves research subjects, researchers as well as sponsors or donors. 3. There should be a reasonable degree of proportionality between the allocation of resources and the anticipated results or between the anticipated risks and the anticipated benefits of the proposed research. 39.6.2. Burdens and Benefits for Research Subjects, Communities and Society 1. Subjects should not be exposed to frivolous investigations, which cannot be expected to produce knowledge, and impoverished populations should not be exposed to substandard research and ethics. 2. A group of individuals should not be made to bear the burdens and risks of research designed to be solely of benefit to another community and that is not relevant to their own situation.

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3. Thus, research should be relevant in the context in which it is conducted, and it is an obligation to make some returns to the communities hosting the research. All main stakeholders in a given research initiative should be able to regard the activities involving themselves as meaningful and relevant from their own particular view. 4. Many of the people and population groups that are invited to participating in research in developing countries have an experience of being excluded from the common good. Researchers therefore need to approach lay subjects with a humble attitude, and the expectation of having a good case for the relevance of the research project. 5. Research participants should be remunerated for their time and contribution. This could take the form of a mix between compensation for actual expenses and lost income and a more substantial contribution to the community or group hosting the given project. 6. If general health benefits seem to ensure hosting and facilitating research, it is important to ensure that the contribution is reasonably sustainable or at least does not disturb already existing facilities or coping mechanisms. 7. It should be a general requirement that research results be returned to the community hosting research, both in recognition of the entitlement of the participants to the benefits from the results, but also as a preventive mechanism against gross misrepresentations. 8. In all collaborative research efforts involving scientists from countries with a weak research infrastructure and scientists from countries with a strong infrastructure resources should be allocated to local capacity building and social development.

39.6.3. Sharing of Burden and Benefits between Research Scientists In setting up collaborative research projects the partners should identify major issues about design and implementation. The responsibility of each partner should be defined and agreements should specify how rewards will be shared. The partners should also make arrangements for future negotiations and some mechanism for arbitration.

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39.6.4. Sharing of Burden and Benefits between Sponsors and Scientists Scientists should strive to conduct the research as specified in the agreement with the sponsor and the scientists. In order to empower African scientists national governments should provide adequate resources to ensure that local scientists are not too dependent on external funding. International or foreign donors should always recognize the need and obligation not only to support the research work proposed, but also ascertain that reasonable resources are allocated to enhance local research capacity. The basic salaries for researchers in developing countries are often completely inadequate. Donors should therefore be prepared to negotiate remuneration of scientists. 39.7. Conclusions and Recommendations 1. Health research must be undertaken in partnership between investigators, research, subjects, host communities, and sponsors. 2. There must be a binding partnership memorandum ensuring that: “ The research agenda is set together by the partners; “ There is mutual, transparent, and equitable sharing of responsibilities and benefits, including property and intellectual rights; and “ There is capacity building of host scientists and institutions. 3. The memorandum must be explicit on the issues of: “ Ownership, access, and use of generated data, human secretions, tissues, and genome; “ Obtaining permission from host community for new use of the above; “ Access and use of the above by others outside the partnership and or profession; and “ How these will be disposed at the end of the study. 4. There should be provisions for dissemination and promotion of utilization of research findings by operational staff, study subjects, host communities and institutions, policy and decision makers, relevant non-governmental organizations (NGO), and entrepreneurs.

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5. The confirmed safe and effective intervention should also be administered at an appropriate stage of the study to subjects previously treated by a placebo or any other ineffective intervention.

40. Final Plenary Recommendations 1. Most of the issues raised at the Seminar on Health Research Ethics in Africa, were to a large extent covered by the International Ethical Guidelines for Biomedical Research Involving Human Subjects, developed by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). The latest edition of these guidelines published 1993, was noted to have taken into account most of the currently known ethics issues and needs of developing communities found in Africa, elsewhere in other developing regions, and to some extent in developed countries. It was further noted that these guidelines would be regularly reviewed to take into account new scientific and other developments. The guidelines were therefore acceptable for adoption as a minimum standard for African countries. 2. However, there was dissatisfaction with the CIOMS WHO Guidelines’ definition of ‘under-developed’ communities. The definition being basic to the principles of the ethics issues in the reference communities should go beyond economic values to encompass socio-cultural and other dimensions. Furthermore, the expression should be rephrased to the conventional ‘developing’ communities, which was less offensive and acceptable. 3. Similarly, the International Conference on Harmonization/Good Clinical Practice (ICH/ GCP) Guidelines do not address community concerns. It was recommended that the next review of the guidelines should address these concerns. 4. It was noted that most African countries individually and collectively, unlike European, American, and some Asian countries, had neither national nor regional certification for drugs and vaccines. African countries were, therefore, urged to establish and develop certification of drugs and vaccines at national, or better still, at the African regional level.

5. The certification institution should also be empowered to undertake public inquiry into cases suspected of violations and penalize those found guilty. The certification institution should be strengthened and mandated to promote exchange of experiences between researchers, manufacturers, and institutions within and outside Africa; and to undertake harmonization and supervision of the certification standards. 6. Having agreed that there was a need for a bioethics forum to look after and safeguard African interests in that field, African countries were urged to form as a matter of urgency a Pan African Bioethics Initiative. The forum should be empowered to promote, set standards, undertake harmonization, supervision, and co-ordination of related activities between researchers, institutions, within and between African countries, and at regional and international levels. It was recommended that the African Malaria Vaccine Testing Network, which already has an appropriate secretariat and database, should take up the necessary action towards the establishment of the Initiative. 6. It was regrettably noted that some African countries although undertook health research, had either inadequately developed institutional and or national ethics review committees, or none at all. These countries were urged to establish and develop these committees, preferably at both national and institutional levels. Although the ethics review committees should be independent at all levels, the national committees should undertake the responsibilities of supervision, co-ordination, setting standards, and harmonization. The committees should promote good and stop bad research respectively, through policing of all proposed and ongoing research. The ethics review committees should be empowered to raise their own funds to meet their operational costs, but without jeopardizing their autonomy in so doing. The funds could be raised through charging administrative overheads on research and other development projects, in the same way as similar institutions do in developed countries. 7. It was agreed that ethics clearances given by partner non-African institutions including international organizations for research to be undertaken in African countries were by themselves

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insufficient. For such research, ethics clearance must be obtained also from the host partner African institutions. 8. Since research based on bad science is unethical, the countries have the prerogative of either having the ethics review committees combine the roles of ethics and scientific reviewing of research proposals or having separate committees for these roles. When the two roles are combined by one committee, the reviewing process may be expedited, especially if the reviewers are carefully selected to take into account underlying scientific and ethics issues. 9. The quorum of the ethics review committees should be based on representative memberships, and not merely on numbers of members. The membership composition should have a broad base of disciplines, should certainly include lay members, and be balanced for the two sexes. The committees should have options for co-opting temporary members for their special expertise or interests in the subjects under review. However, such members should not have voting rights, and conflicts of interests must be avoided. 10. In order to ensure standardization and avoid errors of omission and commission, the reviewing process of proposals should use a checklist ensuring among other things: “ Capacity building of local researchers and institutions; “ Community awareness and participation in the proposed research; “ Sensitivity to local cultures and children’s welfare; “ Protection of populations vulnerable to abuse by health research; “ Targeted dissemination and promotion of utilization of the results, particularly by the beneficiary populations; “ Agreement on ownership, use, and access to the research outputs by those in and outside the research partnership and medical profession; “ Procedures for obtaining and documenting informed consent; and “ Compliance to the CIOMS WHO Guidelines and good clinical practices (GCP).

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11. Community consent must always be obtained because it is an effective safeguard against abuse of vulnerable populations within developing communities. Furthermore, it is symbolic of respect and recognition of the local socio-cultural arrangements. Community consent should be obtained directly from the community itself and or indirectly from its political leadership, and or relevant institutions such as non-governmental organizations (NGOs), schools, and public health service departments. However, individual consent must always be obtained and preside over community consent. 12. It was noted that good health research invariably involves collaboration between investigators themselves; investigators and donors; investigators, communities, and donors; various local and external institutions; and or all the above. In order to ensure transparency, avoid conflicts, and facilitate equitable sharing of research burdens and benefits, such research must have a collaborative memorandum of understanding. The memorandum should among other things specify: “ Ownership of data and specimens; “ Intended original use of the data and specimens; “ Requirement for host permission for any other use of the data and specimens; “ Conditions for getting access to data and archived specimens; “ End of study disposal of the above research outputs and spin-offs; and “ Arrangements for authorship consonant with the inputs from the investigators. 13. Research proposals as well as memorandums of understanding should show that research hosts, institutions, and sponsors have: “ Collaborated in setting the research agenda and priorities; “ Commitment to mutual trust, transparency, development of sustainable research capacity for local researchers, host institutions, health services, community welfare, and equitable sharing of benefits resulting from intellectual property rights; and “ Budgetary allocations for topping up remuneration of local researchers, as a motivation as

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well as a preventive measure against brain drain; Binding agreement providing access to test products with proven efficacy being made available to participating individuals and communities;

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Recognition of inputs made by host communities and according them the right of being the first to receive and discuss the research findings, specifically thanked for their participation, and small presents given to children if warranted by their participation.