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LETTER |
The author is an associate editor of the Journal and an independent consultant.
Correspondence: Requests for reprints should be sent to Michael Gross, PhD, 315 West 3rd St, No. 712, Long Beach, CA 90802 (email: m144{at}earthlink.net).
The viewpoint of an expert as renowned as Stone—he received a lifetime achievement award at the international Microbicides 2004 conference for his leadership in the field—deserves careful consideration. As in his letter here, last spring Stone expressed a sense of urgency about proceeding forthwith to implement planned large-scale trials, irrespective of their impact on testing of new microbicide concepts: "Every day we’re not doing something, people are getting infected and dying . . . we’ve just got to get these products out there."1
Indeed we must, provided they do more good than harm. Stone knows that the notable outcome to date from microbicide efficacy trials of previous nonoxynol-9–based products was an excess of HIV infections among women who received the experimental products compared with women who received a placebo.2 He recognizes that preclinical and early clinical safety studies used to qualify products for entry into large-scale trials failed to detect problems that imperiled women volunteers and that the techniques have not improved since then.
Stone believes that "optimal trial design in terms of having the highest chance of giving reliable answers to the questions we are asking must be tempered by other considerations, especially the need to minimize harms—physical, social, emotional—to trial participants and others involved."3 The best way to minimize harm is to expose the fewest volunteers to experimental products, because experience tells us that danger may not be detected until a disproportionate number of women assigned to the experimental product become infected. The best way to do that is to conduct either a single, robust trial of the strongest candidate, based on available preclinical assays, or a hypothesis-driven comparative trial, if there is a scientific justification for testing more than one.
Robin Shattock—who has been applying his pioneering laboratory models for screening candidate microbicides both to the current generation of products and to newer candidates, some of which represent novel concepts of protection—drew the opposite conclusion from that of Stone. Shattock estimated that 5 million new infections might result from proceeding with all impending trials, instead of ensuring capacity for rapid entry of new candidates or combination products into large-scale trials.4 The precedent set by trials of all candidates in a class, instead of screening for best-in-class, will only exacerbate congestion at the critical stage of efficacy testing. Even if one or more of the current products displays efficacy, there is no reason to expect that we would learn of a correlate of protection relevant to future candidates based on other modes of action.
In addition to chairing one of the groups he cited as endorsing current plans, the International Working Group on Microbicides, Stone has been working with a media consultant to "develop [his] contacts with UK journalists and position [him] as an independent scientific resource that they can utilize."5 How independent is Stone? He serves on the Management Board of the Medical Research Council (MRC)/Department for International Development Microbicides Development Programme, sponsor and donor for 1 of the 6 current trials. This trial tests a product that requires 10 times more active agent than the best-performing product to achieve equal potency against the predominant HIV subtype associated with sexual transmission. In preclinical efficacy studies, Emmelle (ML Laboratories, St. Albans, England) protected only 2 of 4 monkeys; in comparison, the best-performing product protected 7 of 7.4 While Stone continued to defend Emmelle, a product he championed when he directed MRC’s microbicides program, the MRC was deciding to discontinue support for this candidate.6 The second product in the proposed MRC trial is the better-performing one, but, in the inexplicable matrix of trials and products contemplated by current plans, this candidate is being investigated in at least one other large-scale trial.
I share Stone’s recognition that achieving multistakeholder consensus on a rational trial design strategy would be arduous and protracted. His letter sheds light on why it would be so difficult.
References
1. Brown H. Marvellous microbicides. Intravaginal gels could save millions of lives, but first someone has to prove that they work. Lancet. 2004;363: 1042–1043.[Medline]
2. Stone A. Microbicides: a new approach to preventing HIV and other sexually transmitted infections. Nat Rev Drug Discov. 2002;1:977–985. Available at: http://www.ifh.org.uk/pdf/Nature%20Review%20text%20for%20Websites%2010%201%2003.doc. Accessed July 27, 2004.[ISI][Medline]
3. Stone A. Phase III microbicide trials: confronting the scientific, regulatory, and ethical challenges. Presented at: Microbicides 2004; March 28–31, 2004; London, United Kingdom. Abstract 02449. Available at: http://www.microbicides2004.org.uk/abstract/posters/c_02449.html. Accessed July 27, 2004.
4. Shattock R. How close are we to an effective microbicide? Presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8–11, 2004; San Francisco, Calif. Available at: http://www.retroconference.org/2004/pages/webcast.htm. Accessed July 26, 2004.
5. International Family Health, Microbicides Advocacy & Networking Project. February–March 2004 update. Available at: http://www.ifh.org.uk/pdf/Microbicides%20Advocacy%20Update%20April%2004.doc. Accessed July 27, 2004.
6. Global Campaign for Microbicides. Global Campaign News, issue 41. Available at: http://www.global-campaign.org/gcnews.htm#uk. Accessed September 23, 2004.
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