Money, Moralism and Microbicides: Barriers in Microbicides Development
Microbicides have been heralded as an "HIV prevention tool of the future,"1 and indeed, the last two decades have seen significant strides in their promotion. However, considerable challenges to microbicides research and development have emerged. One of the most consequential has been the lack of investment by the pharmaceutical industry and, to a lesser degree, by the U.S. government.2 Considering the exponential increase in seroprevalence rates for women who have sex with men, and men who have sex with other men, even a moderately effective microbicidal product could avert an estimated 2.5 million new cases of HIV in men, women, and infants over a three-year period.3
Microbicides are considered to be "public health goods" -- products which would be of enormous benefit to society with regard to health, quality of life, and productivity. Particularly for individuals who traditionally have diminished bargaining power to negotiate when, where, and how sex takes place -- women, gay men, and gender and sexual minorities -- microbicides could be a user-controlled product of tremendous benefit. Various factors, including gender violence, place women in particular at increased risk for HIV. For many women who engage in sex with men, including within the context of marriage, it can be extremely difficult if not outright dangerous to insist on condom use.4 Likewise, abstinence and mutual monogamy are seldom viable options. Additionally, from a biological standpoint women are 2.5 times more susceptible than men to heterosexually transmitted HIV infection.5
The State of Microbicides ResearchResearchers expect that a topical microbicide will likely come in the form of a cream, foam, gel, ring, or suppository delivery vehicle, which could be applied vaginally or rectally prior to sexual intercourse. In order to be considered effective the product must not cause irritation or activate a dangerous immune response for the majority of users.6 Most microbicides that are currently being researched are designed to do one or more of the following:
The process of bringing a microbicidal product to market has been long and arduous. The reality is that developing a safe and efficacious microbicide is much more difficult than originally anticipated. Currently, there are dozens of vaginal microbicides in various stages of laboratory testing. However, only ten are now in the clinical trials stage. Of these, three are in Phase III effectiveness trials, warranting guarded optimism about their viability as products marketable to the public within the next five to ten years. A cautionary approach is well placed, considering the fact that in the past year and half research difficulties have forced the closure of two Phase III trials.
In November of 2005, Family Health International (FHI), a nonprofit international public health organization, in cooperation with Cellegy Pharmaceuticals, announced the closure of the Phase III trial testing of a vaginal microbicide gel called Savvy. The Savvy trials were terminated after it was recognized that HIV incidence in the study population in Ghana was too low to conclusively demonstrate whether the Savvy microbicide was more effective in preventing the transmission of HIV than the placebo. A second Savvy trial, underway in Nigeria, was closed in September of 2006; HIV incidence in the trial community was also lower than initially expected. However, the decision to close this trial was primarily due to the lack of clear signals that the product was effective in reducing the risk of HIV transmission.
In addition to Savvy, FHI was testing a cellulose sulfate (CS) vaginal microbicide. CONRAD, a not-for-profit reproductive health research organization, was also conducting CS trials until early 2007, when it terminated clinical studies at the recommendation of its Data Safety and Monitoring Board. Preliminary results from Benin, India, South Africa, and Uganda revealed a higher HIV incidence among females using the active microbicidal product than among those in the placebo group. It has not yet been determined why there was an increased risk of HIV transmission. Although no evidence of increased risk was found in the CS trial being conducted in Nigeria by FHI, that study was also halted as a precautionary measure.
More promising news came in March of 2007, when it was announced that another vaginal microbicide gel, PRO2000, would continue in Phase III trials. The Independent Data Monitoring Committee (IDMC) for the Microbicide Development Programme (a partnership of various African and European research institutions and academic organizations) met to review the information available on the PRO2000 trials. Just two months earlier IDMC decided that an additional examination of the data was needed in light of recent trial closures. Following a thorough review, the IDMC then determined that the PRO2000 trials could still continue with the understanding that another evaluation of the data would again take place in July of 2007.
In late March of 2007 the field reached a major milestone when data collection was completed for the Phase III trial of Carraguard, a vaginal microbicide being studied by various South African research institutions and the Population Council, a non-profit organization conducting biomedical, public health, and social science research. This Phase III trial began in March 2004 and was conducted at three different sites in South Africa. Results from the Carraguard trials are expected by the end of 2007, and if all goes well, they will produce the first data on the effectiveness of vaginal microbicides as a tool to reduce the risk of HIV infection.
Formulating microbicides for rectal use has proved to be even more complex than developing ones for vaginal use. This is due to the fact that the cells on the rectum are one layer thick, compared to most vaginal cells, which are approximately 40 layers thick. As a result, rectal tissue is much more susceptible to infection, irritation, and tearing during sex. In addition, there are more immune cells with CD4 receptors and more CD4 receptors per cell on the rectal tissue, making the rectum acutely vulnerable to HIV infection. Finally, because the rectum is an open-ended cavity, larger amounts of more potent microbicides may be required to ensure adequate coverage and protection.
Efforts to move rectal microbicides research forward must also be understood against a backdrop of pervasive moral and social stigmas associated with homosexuality and with the practice of anal intercourse -- some of which have been enshrined in law. Even though data suggests that anal intercourse is commonly practiced by both homosexuals and heterosexuals (35% of heterosexual women report having had anal sex at some point in their lives), anal sex is still stigmatized as a deviant activity practiced exclusively by gay men.7 In response to initiatives to increase research and development funding for rectal microbicides, Bob Maginnis, former senior policy analyst for the Christian, right-wing Family Research Council and current Fox News analyst, declared, "We are facilitating, at taxpayer expense, an illegal and immoral activity that's abhorrent to most Americans... if we make homosexual sex safer, all we're going to do is promote promiscuity, which will lead to more STDs."8
Until the U.S. Supreme Court ruling in Lawrence v. Texas,9 anti-sodomy laws were still on the books in 13 states.10 Anal sex remains a criminal offense in many countries, often punishable by imprisonment; sometimes by death. Members of the U.S. military are still subject to criminal prosecution under the military's sodomy statute.11 The same sentiment that kept anti-sodomy laws on the books until the early 21st century continues to present obstacles to moving rectal microbicides research forward.
Funding ChallengesThe disinclination by drug companies to invest in microbicides is directly related to the profit driven-nature of the "disease business."12 Some theorists have even gone so far as to suggest that for drug companies, maintaining and even expanding diseases is a precondition of growth that assures the Pharmaceutical Research and Manufacturers of America (PhRMA) an indefinite and limitless stream of profit-making potential.13 While this is not to suggest that the pharmaceutical industry is the lone culprit in the slow pace of microbicides development, PhRMA's relative inattention towards accelerating the development of desperately needed HIV/AIDS prevention drugs merits further examination.
PhRMA's unwillingness to invest in microbicides and other needed drugs for poorer countries is usually couched in terms of investment risk analysis, whereby research costs are weighed against potential profit margin. The industry has articulated other reasons for not investing in microbicides. Among the most salient are their lack of technological expertise in developing products applied intravaginally; regulatory hurdles in testing potential microbicidal candidates in high-risk areas in developing nations; and an uncharted terrain when it comes to anticipating the risk-benefit formulary which must be met for FDA licensure. While a few major pharmaceutical companies (Bristol-Myers Squibb, Merck, Gilead, and Glaxo-SmithKline) have contributed compounds to the microbicides research field, most major drug companies have not participated in microbicides research. The reality is that for the average pharmaceutical company, a risky microbicidal product will never be as enticing an investment as popular top-sellers such as antidepressant, allergy, hypertension, and erectile dysfunction medications. Studies show that these aforementioned drugs are currently being developed and marketed to the virtual exclusion of most other desperately needed drugs for serious chronic and life-threatening conditions. As one Public Citizen study attests, "the drug industry is shifting the core of its business away from the unpredictable task of creating drugs and towards the steadier business of selling them."14
As for-profit institutions, pharmaceutical companies are largely focused on investment costs and returns. Additionally, the pharmaceutical industry continuously relies on a research and development "canard" which premises that pharmaceutical companies "need extraordinary profits...in order to conduct expensive and risky research into innovative new drugs."15 Certainly, microbicides research and development expenditures are not insignificant. Late stage Phase III clinical trials of microbicides generally range from US $30 million to US $50 million.16 Total costs for developing one microbicide, including all stages of research and registration of the product range from US $36-$65 million.17
Pharmaceutical companies also factor how product pricing will affect returns. If a product is to be accessible in lower-income countries the financial costs of developing the microbicide may outweigh the financial returns on the product. In fact it is often argued that pharmaceutical companies fear that the pressure to provide a microbicide free of charge in developing countries would further undermine the potential to yield profitable returns.18
The norms dictated by our global economic system lend justification to the pharmaceutical industry's lack of investment in microbicides research and development. However, with over US $550 billion in total global pharmaceutical sales per year19 and top executive pay packages that on average top tens of millions dollars, it is difficult to find a morally defensible argument for a continued lack of investment in such a critical public health good.
In the absence of a commitment by multinational pharmaceutical companies to sufficiently prioritize, participate in, and fund microbicides research and development, the onus has been placed on smaller-scale biotech firms and global health research NGOs to pick up the slack. Both the biotech firms and public sector non-profits conducting microbicides research and trials depend on competitive government and philanthropic grants or to a lesser degree on venture capital. The reliance on these institutions to conduct costly microbicides research has resulted in a slow pace of progress.
In 2004 global investment in microbicides research was approximately US $142 million, a figure nearly double that of microbicides investment in 2000.
Nevertheless need continues to outstrip existing funding levels. Experts calculate that in order to accelerate the development of microbicides and bring an effective microbicidal product to market within the next few years, global annual investment must be roughly doubled, to at least US $280 million.20 Advocates in the United States are trying to push policy makers to commit to increased public-sector funding and resources for microbicides research and development via the passage of the Microbicides Development Act (MDA). In an effort to move the microbicides agenda forward the legislation was re-introduced in early March 2007. Currently, the US Agency for International Development (USAID), the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health (NIH), are all working on microbicides research and development. At the NIH, several institutes are conducting microbicides research. As it now stands, there is no single line of administrative accountability and no specific funding coordination. The MDA would establish a dedicated unit for microbicides research and development within the NIH's National Institute of Allergy and Infectious Diseases, streamlining administrative accountability and funding coordination. It would also authorize funding increases as needed at the CDC, NIH and USAID for the development of microbicidal products.
With the MDA, Congress has an opportunity to offset government and health care industry reluctance to adequately prioritize microbicidal development. Until now, the troubling inference has lingered that those most at risk of contracting HIV -- the same likely consumer beneficiaries of microbicides -- are not valuable enough to warrant a life-saving investment on their behalf. A decision to advance microbicides research and development will send a different message and may well alter the fate of millions of women worldwide.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.