Pneumonia workshop raises more questions than answers At a meeting on April 1–2, the US Food and Drug Administration (FDA) AntiInfective Advisory Committee is due to present its conclusions on changing guidelines for the design of clinical trials of treatment for community-acquired pneumonia (CAP). This meeting was preceded by a joint FDA/Infectious Diseases Society of America (IDSA) workshop (Silver Spring, MD, USA) on Jan 17–18. At the January meeting the FDA presented its views on appropriate design of trials of antibiotics to treat CAP, and received feedback from interested parties. For approval to treat CAP, the FDA currently requires two randomised, controlled, multicentre studies showing that the new drug is non-inferior to an established agent. Additionally, the FDA’s view is that a new antibiotic must be approved to treat CAP before it is likely to be licensed for other community respiratory-tract infections. However, the pharmaceutical industry and IDSA are critical of the FDA for failing to provide guidance on the noninferiority margin by which to prove
the required lack of diﬀerence. John Rex (AstraZeneca, UK) commented that it is currently not feasible to clear the regulatory hurdles required by the FDA. Experts reviewed the aetiology, epidemiology, treatment, and management of CAP to provide the data that the FDA needs to set standards for measuring the beneﬁt of antibiotics. Unless the expected beneﬁt of treatment can be estimated numerically, it is not possible to design a study to show that a new drug is no better, or no worse, than an existing agent. However, discussions were further complicated by FDA representatives stating the need for placebo-controlled studies in mild CAP, a study design that has not been used before in CAP treatment trials. This idea was rejected by many meeting delegates. Tom File (SUMMA Healthcare, Akron, OH, USA) referred to data from the 1930s showing the substantial mortality associated with pneumonia, and the subsequent impact that serum therapy, sulpha drugs, and penicillin had on mortality reduction as well as quicker response. Dan Musher
(VA Medical Center, Houston, TX, USA) and Helen Boucher (New England Medical Center, Boston, MA) both stated that placebo-controlled studies in CAP were not ethical and would not be approved by research ethics committees. The FDA sees a need for endpoints in CAP trials other than clinical cure as determined by the physician. David Gilbert (IDSA) reviewed alternative clinical endpoints—for example, time to apyrexia and patient-recorded outcomes. However, critics of the FDA consider the latter endpoint to be unvalidated. Barry Eisenstein (Cubist, Lexington, MA, USA) and others raised the issue of the ethics of trials using comparator drugs to which resistance among pneumococci is expected and thus a high failure rate is likely. Amidst the controversy, it is clear that without new clinical trials guidelines, development of new community antibiotics will be badly aﬀected.
See Leading Edge page 209 For more information on the FDA workshop on CAP see http://www.fda.gov/cder/ meeting/CAP.htm For more information on FDA guidance for industry on antibacterial drug products see http://www.fda.gov/cder/ guidance/7884dft.pdf
Glenn Tillotson Glenn Tillotson is an employee of Replidyne
Microbicide researchers have reacted with dismay to the results of the Carraguard trial, which has found that the seaweed-based vaginal gel is safe but does not block HIV transmission. The study, funded by the US-based Population Council and the Bill & Melinda Gates Foundation, included 6202 women at three sites in South Africa: Cape Town, Durban, and Pretoria. The results are a blow to HIV prevention eﬀorts. High hopes had been pinned on Carraguard because it was the only microbicide candidate to have completed a phase III trial. Council spokesman in South Africa Sumentheran Govender says work has already begun on a new candidate microbicide that will use Carraguard as a base for an antiretroviral drug called http://infection.thelancet.com Vol 8 April 2008
MIV150. Khatija Ahmed, the council’s principal investigator at the test site near Pretoria, said that although the results were “disappointing” they were not a setback for HIV microbicide research, adding: “The safety ﬁnding of Carraguard is important because it is using ingredients in the next generation of products that are being developed”. Salim Abdool Karim, director of the Centre for Aids Programme of Research in South Africa, which is recruiting women for a tenofovirbased microbicide, said the results indicated the need to redouble eﬀorts with new generation antiretrovirals, formulated as topical microbicide gels. The failure of the Carraguard trial follows a string of recent upsets in microbicide research. In 2007, two large
studies were stopped after it was found that women who received the active product UsherCell, a cellulose sulphate, were more likely to become infected with HIV. The higher strength version of PRO2000, a microbicide being tested in Zambia, Tanzania, South Africa, and Uganda, has also been found to be ineﬀective and was removed from trials. However, the ﬁeld of microbicide research has also had some good news with an announcement that a vaginal microbicide gel containing the antiretroviral drug tenofovir is safe and acceptable for sexually active HIV-negative women. The HPTN059 phase II tenofovir trial involved 200 women in the USA and India.
Oscar Burriel/Science Photo Library
Disappointment at failure of microbicide candidate
For more information on the Carraguard trial see http://www. popcouncil.org/mediacenter/ newsreleases/Carraguard_ Findings.html For more information on the Centre for Aids Programme of Research in South Africa trial see World Report Lancet 2007; 370: 17–18 For more information on microbicide research see Newsdesk Lancet Infect Dis 2006; 6: 325–26