The concept of a woman-controlled HIV prevention technology that could be applied vaginally to block the virus began to take hold in the early 1990s. The idea of a “topical microbicide” was (and still is) particularly appealing because the majority of the currently used prevention strategies (condoms, monogamy, etc.) rely predominantly on the male partner: if he is unwilling to adopt these strategies, economically and politically vulnerable women throughout the world often have no choice but to remain at risk for HIV infection. More than 50 substances have been considered as possible microbicides. After more than a decade of hard work, only a handful of these are nearing large-scale clinical trials to determine their effectiveness (see pages 11-12). Research and development have been slowed by a number of factors including the absence of involvement by large pharmaceutical companies and the under-investment from the public sector. Increasingly, support has come from private foundations, including the Rockefeller Foundation. The Rockefeller Foundation Microbicide Initiative The Rockefeller Foundation Microbicide Initiative was created in late 2000, when the foundation invited key players1 to work together to find ways to speed development of a safe, effective, and accessible microbicide. Charged with identifying novel approaches and the key elements of successful development of microbicides, working groups were formed in five key areas: public health benefits, science, pharmaco-economics, access, and advocacy. The reports from these five working groups are summarized in the following sections.2 Public health benefits Averting new infections and saving lives are the main reasons for developing microbicides. It is quite likely that the first generation of microbicides (as well as vaccines) will be only partially protective. But even a partially effective product could have an important impact on public health. Using dynamic epidemiologic models, researchers at the London School of Hygiene and Tropical Medicine have estimated that if only 20 percent of women in 73 low-income countries used a 60-percent efficacious microbicide for half of all otherwise unprotected sex acts, 2.5 million HIV infections would be averted over three years in women, men, and infants. Accelerating microbicide science Better understanding of the early events in HIV infection via mucosal surfaces has led to new approaches to both prevention and treatment. A number of microbicides are being developed that target critical HIV-binding molecules found on target cells in the genital mucosa. As these research leads increase in number, it is becoming apparent that the microbicide field will need to employ rational selection criteria for the use of scarce product development resources. A significant challenge is the lack of validated preclinical in vitro and animal safety and efficacy models. Unlike HIV therapeutics, no microbicides have been shown to prevent HIV transmission in large-scale clinical trials. As a result, the predictive value of different in vitro and in vivo models cannot be measured. It is clear that efforts to compare preclinical data across the current products as they move toward clinical studies will become increasingly important, as will strategic approaches to the design of cost-effective and clinically appropriate development. In the absence of investment by large pharmaceutical companies, most of the work on microbicides is carried out by small companies and nonprofit research organizations that lack the individual capacity for formulating, manufacturing, and packaging. Opportunities exist to coordinate efforts in these areas, capitalizing on potential cost- sharing as well as providing scientific benefits to the field as a whole. Many compounds in the microbicide pipeline are ready for clinical testing for safety and effectiveness. Additional strategies to accelerate microbicide research and development must focus on this most resource-intensive component of the development pathway. Achieving proof-of-concept for microbicides is critical for public health and for furthering investment in the development of new microbicide concepts and combinations. The economics of microbicide development Based on an assumption that a product will be used by less then 10 percent of sexually active women, modeling exercises suggest that the market size for a microbicide would be $0.9 billion by 2011 and twice that by 2020. Depending upon the characteristics of the microbicide, these numbers could vary considerably, ranging from $5 billion for a product that meets needs for daily hygiene, vaginal health, and general protection against sexually transmitted infections (STIs) to only $0.1 billion for a product that was considered unacceptable by women. The high costs of drug development in general, and microbicides specifically, will result in a net negative return on investment for a first- generation product. On the other hand, second- and third-generation products may offer the potential for significant returns. As a result, it is unlikely that pharmaceutical and biotechnology companies will play a major role in the development of a first-generation microbicide. The public and nonprofit private sectors have been driving microbicide development; however, there is a considerable gap between currently available support and the resources needed to ensure that one of the products now in the pipeline makes it to market. Preparing for microbicide access and use The success of microbicides will be measured not only through scientific research and product development but by how widely accessible they will be in a timely fashion to the people who need them the most. The majority of the effort to date has been focused on product research and development, but access efforts must occur in parallel with those of research and development. Ideally, they should inform each other. Successful access to microbicides will involve careful attention to a variety of issues including: A product’s appeal and ease of application. Marketing strategies to ensure destigmatization of use and realistic expectations of effectiveness. Distribution channels that offer the greatest potential for making microbicides widely accessible. Strategies to reduce product and distribution costs so that microbicides are affordable to everyone. Understanding of the regulatory processes and requirements for approval of new products in different countries throughout the world. Attention to these issues cannot wait until a product has passed through all stages of research and development. The dire need for an HIV prevention technology cannot be met by waiting for an effective microbicide to appear in the hands of individuals at risk. Global advocacy for microbicides Global advocacy for microbicides is essential for creating the political will to ensure sufficient investments by governments and private foundations. In a field where initial returns on investments are unlikely and proof-of-concept has not yet been obtained, advocacy efforts have helped drive the scientific enterprise forward. To generate further political commitment and mobilization of resources, it will be critical to increase the visibility of microbicides in the international arena. Because microbicides are a user-controlled technology, all aspects of microbicide research and development can be informed by user perspectives—from input into the types of product formulations to the design of clinical trials. However, advocacy extends well beyond research and development into traditional access areas such as product pricing and distribution. Importantly, advocacy must also address critical issues of stigma, gender bias, and women’s empowerment—all of which will play a role in the ultimate accessibility of microbicides. The International Partnership for Microbicides (Family Health International) To accelerate the discovery, development, and accessibility of microbicides, a new public-private partnership, the International Partnership for Microbicides (IPM), was formally launched in Antwerp, Belgium, during Microbicides 2002 in May (see pages 5-9).With support from the Rockefeller Foundation and several government donors, the IPM’s work will be based on partnerships with currently under-resourced microbicide developers and others engaged in microbicide research, helping them to address critical gaps and obstacles and promote rapid product development. The IPM, housed at Family Health International, aims to increase the efficiency of the development and delivery of a microbicide by: Expanding the breadth and level of public and private sector funding. Identifying critical gaps in research and development, access, and advocacy. Leveraging partnerships with both new and existing public and private players. Rockefeller Foundation Microbicide Initiative The IPM will help speed the progress of highpotential products through the pipeline by facilitating review of products across the field. In addition, the IPM will try to address areas of common need for the field including research on formulations, testing of animal models, submission of regulatory documents, manufacturing and packaging, and capacity of clinical trial sites. The IPM will take an active role in catalyzing, initiating, and managing programs in the access arena and will dedicate resources to developing a strategic agenda and a program of work in access that will focus on five major factors: user perspectives; country preparedness; manufacturing and distribution; financing; and regulatory approval and licensing. The access effort will employ the same approach as research and development, namely, mapping existing efforts, identifying gaps, and selecting appropriate partners to work with to address those gaps. Unlike other areas of science, where profit motives are sufficient to propel innovation, microbicides will become a reality only if partnerships are forged among the like- minded and underresourced organizations that have brought the field so very close to producing a safe and effective product. The IPM has been established for that very reason—to take us to the next step. Zeda Rosenberg, ScD, is the interim executive director of the International Partnership for Microbicides (Family Health International). She served as the scientific director for the HIV Prevention Trials Network (HPTN) at FHI, where she oversaw the scientific and operational coordination for clinical trials in the areas of prevention of mother-to-child, sexual, and intravenous drug use transmission of HIV both domestically and internationally. Dr. Rosenberg continues to serve as the chair of the HPTN Microbicide Science Working Group. _______________________ 1 From academia, nonprofit research organizations, the pharmaceutical industry, governmental agencies, United Nations organizations, advocacy groups, and donors. 2 Rockefeller Foundation. Mobilization for Microbicides: The Decisive Decade. Contents | Note to the Reader | Microbicides:What They Are and Why We Need Them | Special Report: Microbicides 2002 | The Female Condom Experience: Lessons for Microbicides | A New Public-Private Partnership for Microbicides | Challenges in Microbicides Advocacy | Public Information | Resources