Microbicides/Spermicides:
Opportunities for Industrial Collaboration
Summary of an International Conference

Section III. The Need for Vaginal Microbicides

The worldwide epidemic of STDs -- particularly HIV/AIDS -- continues unabated, demanding new approaches to the prevention of these infections. Approximately 333 million new cases of the five most common curable STDs occurred globally in 1995 in women and men of reproductive age. Meanwhile, as of 1998, nearly 30 million adults and children worldwide were believed to be living with the incurable HIV/AIDS. Heterosexual transmission accounts for about 75 percent of all HIV-1 infection, which causes the vast majority of AIDS cases worldwide.

Safe, effective, acceptable and affordable vaginal microbicides to reduce the risk of STD transmission, particularly HIV, are urgently needed as an alternative or adjunct to condom use. While the male condom, when used correctly and consistently, provides substantial protection against both bacterial and viral STDs, women do not control this method and may find it difficult to negotiate its use. The female condom, a female-initiated method, has not yet been shown in clinical studies to protect against STDs other than recurrent vaginal trichomoniasis. It also is relatively expensive, unavailable in many parts of the developing world, and may require partner consent.

Access to a safe and effective microbicide would benefit both women and men. However, women's need for a protective method that they can control is particularly great.

Biologically, women are more vulnerable to STDs than are men. Once infected with an STD, women are often asymptomatic. Because of this, their disease may go untreated, increasing their susceptibility to HIV infection. The consequences of STDs in women also tend to be more serious than in men. Untreated STDs in women can cause pelvic inflammatory disease (PID), which can lead to infertility or life-threatening ectopic pregnancy. Some STDs can harm a pregnancy. For social and economic reasons, women also are more vulnerable to STDs than men. Less education, income and power may limit their ability to refuse unsafe sex or negotiate safer sex. To survive economically, some women enter the sex industry, where they are more likely to acquire an STD.

Given this situation, one thing is clear: Millions of women are at risk of acquiring an STD, yet lack ways to protect themselves. The potential market for a vaginal microbicide is quite large.

Market Research

Reliable estimates of the size of a "commercially-realizable" vaginal microbicide market are lacking. These estimates are needed by private industry to evaluate the potential for product development.

Some estimates of the microbicide market have been made based on the spermicide market, which is rather small due to the availability of a number of alternative, popular contraceptive choices. Such a relatively small market is perceived as unattractive by large pharmaceutical companies, which have research and development projects of far greater commercial potential in their portfolios. However, the market for vaginal microbicides likely would be much larger than that for spermicides. This is because condoms, which are somewhat unpopular, are the only alternative to microbicides for prevention of STDs. In addition, interest in microbicides would likely be especially keen if they directly reduced the risk of HIV infection.

Results of a survey presented at the conference, of 1,000 American women of reproductive age, suggested that 12.6 million women in the United States are worried about getting HIV or an STD and are interested in using microbicides. Even if a microbicidal product were not 100 percent effective and cost as much as $2, an estimated 7.7 million women still would be interested in using it.

Industrial collaborators' interest in market potential might understandably focus on the developed world, where profits would be more likely. However, there also is a substantial potential for profitable sales of vaginal microbicides in the developing world, where large sales volumes could make narrow profit margins attractive. An estimated 150 million people in India, for example, are economically able to buy such a product. Substantial markets would be expected to exist in countries with large free-market economies, such as Brazil.

Sales of the product might be increased by identifying and promoting various uses for it. In addition to being used as a back-up to male and female condoms or an alternative when condoms are not used, variations of the formulations of a vaginal microbicide might be used to prevent perinatal transmission of infection, as a mouth rinse for oral sex, or as a postcoital means of STD protection.

The microbicide market could also be enlarged through educational efforts. Many women, for example, lack interest in STD prevention because they believe their partner is faithful. In fact, many partners in "monogamous" relationships are not faithful, putting their partners at risk. Educating women and men to this reality, besides being an important public health activity, would likely lead to increased interest in vaginal microbicides.

Finally, the marketability of a microbicidal product may depend upon whether or not it could be formulated both with and without contraceptive qualities. Some women living in cultures that strongly encourage them to bear children may reject a product if it prevents pregnancy.

Microbicides under Study

The ideal microbicide would be active against a range of STD-causing pathogens; not irritate mucosal surfaces; be available in spermicidal and nonspermicidal formulations; be acceptable, easy to use and affordable; coat and stick to mucosal surfaces; not be absorbed systemically; have long duration; be effective immediately; be stable at high temperatures; and maintain or even enhance normal vaginal ecology.

Products that are less than ideal are worthy of consideration if they can be made widely available sooner. In terms of preventing HIV/AIDS transmission, an imperfect method made available sooner may save more lives than an ideal method made available later. In addition, a microbicide with relatively low effectiveness, if used consistently, may offer equal or better protection than a more effective product, used inconsistently, like a condom.

To date, the agent that has been most extensively studied for possible use as a vaginal microbicide is the spermicidal surfactant nonoxynol-9 (N-9). A review of data from randomized, controlled Phase III trials of N-9 in a variety of settings suggests that this agent reduces the incidence of both gonorrhea and chlamydial infection by 15 percent to 25 percent. However, in a recently completed, randomized, controlled study by FHI in Cameroon, a 70 mg N-9 film showed no protective effect against HIV, gonorrhea or chlamydia infection in a group of approximately 1,300 sex workers who used condoms and received treatment for STDs.

Other Phase III trials of N-9 in different formulations and doses should further define N-9's potential as a microbicide. The Cameroon Ministry of Health and FHI have begun a Phase III trial in Cameroon of the effectiveness of Conceptrol gel (100 mg N-9) against gonorrhea and chlamydia. A second Phase III study of Conceptrol is to be conducted in Malawi (by the College of Medicine, University of Malawi, in collaboration with Johns Hopkins University and the University of North Carolina at Chapel Hill) and in Zimbabwe (by the University of Zimbabwe in collaboration with the University of California at San Francisco) under the auspices of the HIV Network for Prevention Trials (HIVNET). This study will look at HIV transmission. Finally, the Joint United Nations Programme on HIV/AIDS (UNAIDS) has initiated a Phase III study, coordinated by the Antwerp Institute for Tropical Medicine, in South Africa, Thailand and Côte d'Ivoire to determine the effectiveness of a low-dose gel (52.5 mg N-9) against HIV, gonorrhea and chlamydia.

Meanwhile, other new and exciting leads are emerging. At least another 30 products are being pursued for evidence of microbicidal activity, although some experts believe a combination of agents will be necessary to create an ideal microbicide.

Basic categories of promising topical microbicides include:

• Broad spectrum microbicides -- These include such surfactants as BCT-100 and novasome cream (Novovax); C31G (Biosyn); N-9 cream formulation that becomes a gel on contact with moisture (Biotek); a long-acting, sustained-release spermicide (Advanced Care Products/CICCR); and a different N-9 suppository (Digenis). They also include natural lactobacilli and acid buffering products, such as Buffergel (Reprotect LLC) and ACIDFORM (Topical Prevention of Conception and Disease [TOPCAD]), which are in Phase I clinical trials. Buffergel's mechanism of action is thought to be through its pH buffering effect in the presence of semen and perhaps as a physical barrier. It has protected mice from vaginal and rectal HSV-2 infection. ACIDFORM contains mucoadhesive polymers and N-9, and has a much higher buffering capacity than Buffergel.
• Inhibitors of viral entry and cell fusion -- These include sulfated polysaccharides, such as PC503, sponsored by the Population Council. This product, about to go into Phase II trials, has been shown to inhibit viral entry and cell fusion for HIV, HSV and chlamydia in vitro, and provide some protection against vaginal SIV transmission in monkeys. Another product in this category is the sulfonated polymer PRO2000 (Procept) that has been shown to inhibit HIV, HSV and chlamydia in vitro, protect mice against genital HSV-2 infection, cause little or no irritation to the rabbit vagina, and be non-mutagenic. In Phase I clinical trials, PRO2000 was shown to be safe in sexually abstinent women and was nontoxic and non-mutagenic to vaginal lactobacilli. Dextrin-2-sulphate (Emmelle), another product that prevents viral entry and cell fusion, has also been shown in Phase I trials to be safe and is now in Phase II trials. Two other polymers of high molecular weight, PSS and CS, look promising in vitro and are soon to go into Phase I trials.
• Inhibitors of HIV replication -- These include post-binding fusion inhibitors, such as bicyclams; nucleoside/nucleotide RT inhibitors such as PMPA, which is in Phase II trials as a therapeutic agent for HIV-infected persons; and AZT/ddI.

Research Challenges

Unlike existing spermicides such as N-9, new products require preclinical studies that present significant research challenges. Among those challenges are the lack of a well-established correlation between efficacy in vitro, in animal models and in clinical testing; insufficient knowledge about vaginal transmission of HIV and other STD pathogens; lack of information about optimal formulations; insufficient knowledge of cervico-vaginal and intercourse physiology; technical problems involving amount, solubility, purity, biological variability and dose; lack of good animal models; and a shortage of macaque monkeys, which are used for studies of efficacy against immunodeficiency viruses.

Also critical to the ultimate success of a topical microbicide is a better understanding of cultural sex norms and the product's potential acceptability -- factors to consider as microbicides enter human clinical trials. This is because acceptability ultimately determines use-effectiveness.

Various studies of microbicides or sperm-icides have suggested that several factors affect a topical microbicide's acceptability. Women tended to dislike formulations that were wet or messy, with some individuals decreasing the "dose" to reduce messiness. Women also stressed their preference for formulations that increased sexual pleasure. However, women's personal preferences varied greatly, suggesting that microbicidal use would increase if a variety of formulations were available.

To prevent women from using too little of a product to reduce messiness, some products might have to be reformulated. Dissatisfaction with the messiness of the Population Council's PC503, reported during Phase I testing, led researchers to reformulate the product into a smaller volume before proceeding to Phase II testing.

Developing a microbicide that could be used without a partner's knowledge may be important for women in coercive or commercial sexual relationships. However, recent studies indicate that the ability to hide microbicide use from a partner may be a less important determinant of acceptability than once thought.

The Regulatory Process

United States -- One industry concern in regard to vaginal microbicidal development is the prospect of facing a lengthy and difficult regulatory process. However, the FDA is committed to a priority review of marketing applications for products that would prevent serious and life-threatening diseases. Thus, the agency is making a concerted effort to facilitate its review of candidate topical microbicides for HIV prevention.

The FDA encourages sponsors of topical microbicides to seek input early in the drug development process. A sponsor of a topical microbicide to prevent HIV infection is currently eligible for a pre-investigational new drug (IND) consultation program in which the sponsor may submit concept documents and other supporting preclinical and clinical data or documents for review and comment by the FDA. In addition, a sponsor may request a meeting with FDA officials early in the process to clarify preclinical requirements needed to support clinical studies, and to seek advice about the overall regulatory process.

As part of this pre-IND consultation, the FDA has created a multidisciplinary microbicide review team to provide guidance to microbicide sponsors prior to Phase I trials. All INDs for topical microbicides that do not have contraceptive properties are reviewed by this team within 30 days. (Combination products -- such as those that are both microbicidal and contraceptive -- are assigned to the FDA group concerned with the primary indication.) The multidisciplinary review includes such issues as chemistry, manufacturing and controls, toxicology, microbiology/immunology, clinical factors, and biopharmacology (where indicated). Information on the pre-IND consultation can be obtained from the FDA.

Written guidance about the FDA regulatory process is also available. IND guidance documents include "Guidance for Industry: Content and Format of INDs for Phase I Studies of Drugs, Including Well-Characterized, Therapeutic Biotechnology-Derived Products" and "MAPP 6030.1-IND Process and Review Procedures." Nonclinical toxicology recommendations and requirements for testing are described in "ICH Nonclinical Toxicology Guidelines and Points to Consider" documents. All of these guidelines may also be found on the FDA's Web site.

At the clinical trial level, the FDA regulatory process time for the development of drugs for HIV prevention is compressed. This means that a product can go directly from Phase I/II trials to Phase II/III trials.

The objectives of Phase I/II trials of a topical microbicide are to assess safety, tolerability, and pharmacokinetics. Endpoints include histopathologic/microbiologic measures; assessment of genital epithelial disruption and inflammation of genital mucosa; and determination of the impact on vaginal pH and microflora. In order to assess the status of the genital mucosa, the FDA recommends colposcopy, including colpophotography, and may request that biopsies of abnormal sites/lesions be performed. Although the value of colposcopy was debated during the conference, the FDA suggests that it be used as a research tool. The FDA considers colposcopy to be noninvasive, objective and of possible use in diagnosing asymptomatic women with STDs and in identifying epithelial disruption that may be dose related.

Issues other than study design and trial population that are important in planning Phase I/II clinical trials are the formulation, dose, schedule, volume, distribution, and retention of the product; condom/other barrier integrity studies to ensure that the properties of the barriers are maintained when used with a topical microbicide; drug interaction studies to ensure that the safety and efficacy of a topical microbicide is unchanged in the presence of another topical product; and whether the product will be reviewed as an over-the-counter (OTC) drug. Sponsors of OTC drugs should discuss this with the FDA early in the review process, since additional research may be required.

The ideal study design for Phase II/III clinical trials is randomized and placebo-controlled (condom and placebo versus condom and active product). However, the FDA will consider other trial designs to expedite the process of developing a topical microbicide. Of importance is that trials be internally consistent in terms of rates of pregnancy, STDs, condom use, study drug use and adverse events. For example, if condoms in a clinical trial are reported to be used at a certain rate, pregnancy and STD rates should be consistent with the level of reported condom use.

The FDA will also accept foreign data as long as it deems investigators to be qualified, can validate raw data, and the data are applicable to the U.S. population and U.S. medical practice. It is suggested that a U.S. study site be included in a foreign clinical trial to obtain experience with the topical microbicide in the U.S. population. Sample size would be determined by incidence rates of disease in the countries where the drug is studied and how effective the product is: the more effective the product, the smaller the sample can be. In addition, the FDA may consider the following sufficient to establish product effectiveness: statistically persuasive data from one large, multicenter, well-controlled, internally consistent Phase III trial that is supplemented by confirmatory evidence, such as data from earlier clinical trials.

Clinical trials comparing placebo and an active microbicidal product in the absence of condom use could be expected to produce rapid and definitive results about the effectiveness of the product; however, such trials pose serious ethical concerns, given the lack of proven efficacy of any available product against life-threatening HIV/AIDS. Currently, consensus on this ethical issue mandates that trial participants be educated about risk factors for HIV infection and encouraged to use condoms during intercourse.

Clinical trials should be conducted under an IND. An approved new drug application (NDA) is required for already marketed products seeking a new indication, such as HIV prevention by N-9.

European Union -- Each of the 15 EU member states has individual requirements for the content of applications for permission to perform clinical trials with unlicensed medicinal substances. However, the regulatory processes for approval of new products are common to all EU countries.

In the EU, a license for a medicinal product that is a new chemical entity can be obtained either through a centralized or decentralized procedure. The centralized procedure is probably the best option for smaller companies because only one application, to the European Medicines Evaluation Agency (EMEA), is required. The application is assessed by the Committee on Proprietary Medicinal Products (CPMP), which delivers an opinion within 210 days. An opinion in favor of the product results in a license that is identical in all EU member states. The centralized procedure also allows for the possibility of an expedited review process at the CPMP's discretion.

A company opting for the decentralized procedure would make its application to one or more of the member states. The first member state to issue a license becomes the "reference" member state; the company could then request any or all other EU member states to "mutually recognize" the license within 90 days.

If a product is not a new substance, a sponsor seeking approval for a different indication and/or a different formulation can make an "abridged" application. The nature of this application depends on whether the active substance was originally approved through the centralized, decentralized or (before 1998) a national procedure. For example, a company could apply for an already marketed spermicidal foam to be approved as a gel, adding the microbicidal claim to the same application, provided that appropriate supporting data were included.

Although the routes to licensure are now consistent throughout the EU, how the product gets to the patient (for example, modes of sale, supply and dispensing) remains entirely at the discretion of each member state.

Written guidance about the EU regulatory process is available. The United Kingdom Regulatory Authority (Medicines Control Agency [MCA]) sells copies of regulatory guidelines via order form to subscribers. All documents are catalogued on the MCA Web site. The service's telephone is 44-171-273-0352 or 44-171-273-0228.

Other Private Sector Concerns

Cost -- Besides concerns about market size and regulatory processes, factors that could discourage industry from investing in the development of a vaginal microbicide include the cost of development.

Representatives from pharmaceutical companies attending the conference said that they would like to make a contribution to public health. Public service also can be a smart business decision because it can enhance a company's image. However, companies also must do well financially. Given that developing a vaginal microbicide is difficult and no microbicide has yet been demonstrated in clinical trials to significantly reduce risk of HIV acquisition, a large amount of costly research still needs to be done.

Pharmaceutical company representatives agreed that a partnership between public and private sectors is of mutual interest, since multilateral agreements would lower costs and risks for each party. But representatives emphasized that the right balance had to be struck. Three primary strategies emerged from conference discussions:

• The public sector could collaborate with pharmaceutical companies located in developing countries where a vaginal microbicidal product is most needed.
• Companies could make multilateral collaborative agreements, in order to lower development costs for each company.
• A small company (or "virtual" team) with energy, focus and expertise in preclinical investigations and product formulation, as well as an interest in a relatively small profit, could begin the process with financial support from funding agencies. Once a promising microbicidal product emerges, it could be transferred to a larger company for development, to include clinical trials, production and packaging.

Regardless of initial strategy, the public sector could assist in the development of an overseas market via social marketing and bulk commodity purchases. Policy-makers could facilitate access to foreign markets, help gain protection of intellectual property rights, and provide education necessary to maximize the market.

Liability -- Industry is concerned with the potential risk that users of a microbicidal product would bring a lawsuit if the product failed to protect them from an STD, or if it was alleged to have caused damage, for example, to a fetus or user.

Three ways to reduce the risk of litigation were discussed: good labeling, consumer education and counseling, and post-marketing surveillance.

Good labeling entails communicating an appropriate level of information about the product, as well as the potential risks of product use. Decisions against companies in product liability lawsuits usually occur if the likelihood and degree of risk are not adequately communicated. For example, labeling for a microbicidal product would be expected to state that the product "reduces risk" and is a "condom adjunct," so as not to imply that it always protects completely against sexually transmitted pathogens. (A microbicide alone may conceivably protect fully against STDs; however, solid evidence of this effectiveness would be difficult to obtain since, on ethical grounds, it is vitally important to promote condom use in clinical trials.)

All information about the product should be made available, even if certain risks are low. Side effects, often termed "nuisance" effects, should also be included in labeling. Considering the need for a vaginal microbicide to reduce STD risk, women are likely to accept nuisance effects. To understand better women's expectations and improve labeling and counseling, however, representatives of women's groups and potential users should be involved throughout the research and development process. If a microbicide were made readily available as a nonprescription OTC product, special efforts to identify means to counsel women about risks and benefits would be particularly important.

In the European community, the only basis for a lawsuit is harm caused by a defect in the product, not by the product itself. If the product were licensed and its labeling included fair and accurate information, a court ruling against the manufacturer would be unlikely, a conference speaker said.

Post-marketing surveillance would entail monitoring a microbicidal product once it is widely used in the general population. One example of post-marketing surveillance is pregnancy registries. Such registries collect prospective data on prenatal drug exposures, and can identify serious adverse events potentially related to drug use.

If these measures were utilized, the risk of liability for a microbicide product would actually be low, speakers said.