Clinical testing of microbicides: a global research priority
Karim, Salim S. Abdool
From the HIV Prevention and Vaccine Research Unit, Medical Research Council, Durban, South Africa.
Correspondence to: Dr Salim S. Abdool Karim, HIV Prevention and Vaccine Research Unit, Medical Research Council, P.O. Box 17120, Congella, 4013, Durban, South Africa. Tel: +27 31 2020777; fax: +27 31 2020950; e-mail: email@example.com
Received: 13 February 2001; accepted: 13 February 2001.
Microbicides are chemical products applied to the vagina or rectum with the aim of reducing the spread of sexually transmitted organisms, including HIV. The concept of a microbicide preventing HIV infection is based on evidence from animal models and an extrapolation of the biological action of these products, but it has not yet been proved in human trials. Currently, more than 40 products are in development, mainly as a result of the enthusiasm with which organizations traditionally interested in contraception have expanded their realms of interest to include microbicides. At least 10 of these products have entered human trials, but only one, nonoxynol 9, has been tested for its effectiveness in preventing HIV infection in phase III trials. The dearth of clinical trials on microbicides, in the midst of an abundance of clinical trials of drugs to treat HIV infection, is partly due to the lack of commitment to microbicides on the part of the major pharmaceutical companies.
Not one of the four phase III trials of nonoxynol 9 conducted to date in Kenya [1,2], Cameroon , South Africa, Benin, Cote D'Ivoire and Thailand  has been conducted or principally sponsored by the established pharmaceutical industry. Strong commitment to microbicide development has come from the public sector and small, under-resourced biotechnology companies, but not from the mainstream pharmaceutical industry.
Concerns about the economic viability of microbicides have been misplaced; a multi-country consumer survey  showed that microbicides have potential as profitable products with an international demand and willingness to pay for them. Similarly, concerns that women, the principal target group for these products, may not be able to create sufficient product demand, are unwarranted. Studies from several countries [6–8] have found high levels of microbicide acceptability among women. Acceptability studies have not been limited to women; men from the USA, Mexico and Zimbabwe also reported high levels of microbicide acceptability .
The conduct of micobicide trials in humans poses numerous challenges related to the measurement of product adherence, concomitant condom use that can obscure the microbicide effects, and ethical concerns . Some of these challenges are not unique to microbicide trials and most of them are certainly not insurmountable. The International Working Group on Microbicides (IWGM) guidelines deal with these issues and draw upon the available wealth of experience in microbicide trials to provide a carefully thought-out set of recommendations on the clinical development pathway for microbicides .
In the aftermath of the disappointing results, first from Cameroon , and then from the COL-1492 trial , it is important that we do not let the methodological, logistic and ethical complexities of conducting phase III microbicide trials become the enemy of scientific progress on microbicides. Vigilance is necessary to avoid the search for methodological purity becoming a reason for inaction. Indeed, more phase III trials are urgently needed to assess microbicides such as carraguard, buffergel, dextrin-2-sulphate and PRO2000, which have all been shown to be safe. In the absence of measures that correlate with protection from HIV infection, clinical endpoints such as HIV seroconversion measured in phase III trials remain the only yardstick to assess microbicides.
One of the important lessons from the COL-1492 trial, which became evident only when the phase III ended, was the importance of ongoing safety monitoring in phase III trials. Although the run-in phase II safety assessment for COL-1492 showed the product to be safe , the phase III trial had requisite statistical power to discover the adverse effects of COL-1492 .
The obligation to establish safety before tests for effectiveness can proceed is an imperative of the clinical testing pathway. With microbicides, however, phase II/III trials have to place equal importance on safety and effectiveness. In this respect, the IWGM guidelines’ proposal to assess longer-term (3–6 months) safety as a ‘run-in’ phase II component of a phase II/III trial, in which an interim assessment of safety is performed to determine whether enrolment can be expanded to a phase III trial of both safety and effectiveness, is an important recommendation to streamline and speed up the clinical testing pathway without compromising on safety.
Paradoxically, the disappointing COL-1492 results have created a greater sense of commitment and urgency to move the microbicide research agenda forward. To do this, we need more phase II/III safety and effectiveness trials. In this rapidly evolving field, the IWGM guidelines serve an important role of sharing the collective wisdom of past phase III trials to simplify the process of the clinical testing of microbicides and highlighting this as a global research priority.
1. Kreiss J, Ngugi E, Holmes K. et al. Efficacy of nonoxynol 9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. JAMA 1992, 268: 477 –482.
2. Martin HL, Richardson BA, Stevens CE, Lavreys L, Ngugi E, Mandalyia K, Kreiss J. Evaluation of a low dose nonoxynol 9 gel for the prevention of sexually transmitted diseases. 12th World AIDS Conference. Geneva, 1998 [Abstract 33610].
3. Roddy RE, Zekeng L, Ryan KA, Tamoufe U, Weir S, Wong EL. A controlled trial of nonnxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998, 339: 504 –510.
4. Van Damme L. Advances in topical microbicides. XIIIth International AIDS Conference. Durban, 2000 [Abstract WeOr62].
5. Hill R, Ryan J, Stone A, Fransen L. Vaginal microbicides for the prevention of HIV/AIDS: assessment of the potential market. Int J Pharm Med 2000, 14: 271 –278.
6. Hammett TM, Mason TH, Joanis CL. et al. Acceptability of formulations and application methods for vaginal microbicides among drug-involved women: results of product trials in three cities. Sex Transm Dis 2000, 27: 119 –126.
7. Bentley M, Fullem A, Srirak N et al. Acceptability of a novel microbicide, buffergel, during phase I safety trial in four international sites. XIIIth International AIDS Conference. Durban, 2000 [Abstract TuPpC1170].
8. Ramjee G, Abdool Karim SS, Morar NS, Gwamanda Z, Xulu G, Ximba T, Gouws E. Acceptability of a vaginal microbicide among female sex workers. S Afr Med J 1999, 89: 673 –676.
9. Blanchard K, Coggins C. Men's attitudes toward a potential vaginal microbicide in Mexico, the US, and Zimbabwe. 12th World AIDS Conference. Geneva 1998 [Abstract 33141].
10. Ramjee G, Morar N, Alary M, et al. on behalf of the COL 1492 study group. Challenges in the conduct of vaginal microbicide effectiveness trials in the developing world. AIDS 2000, 14: 2553 –2557.
11. Mauck C, Rosenberg Z, Van Damme L, for the International Working Group on Microbicides. Recommendations for the clinical development of topical microbicides – an update. AIDS 2001, 15: 857 –868.
12. Van Damme L, Chandeying V, Ramjee G, Rees H, Sirivongrangson P, Laga M, Perriens J, on behalf of COL-1492 Phase II Study Group. Safety of multiple daily applications of COL- a nonoxynol-9 vaginal gel, among female sex workers. AIDS 2000, 1492, 14: 85 –88.
HIV; microbicides; safety and effectiveness; trials
© 2001 Lippincott Williams & Wilkins, Inc.