Modified April 24, 2016
First Tuskegee, then Guatemala, and now VRC01
In April, 2016 NIH initiated a study of the HIV broadly neutralizing monoclonal antibody (bNAb) VRC01. The study mimics two infamous studies, Tuskegee and Guatemala, universally declared unethical for withholding effective treatment from sexually transmitted infections in
disadvantaged populations. (1-3) As if the memory of unethical studies has faded, or worse, is no longer of concern, the NIH sponsored placebo controlled VRC01 study will enroll over 4,000 vulnerable subjects in three continents supported by an avalanche of influence and money.(4,5) Research subjects in income poor countries with inadequate protection from HIV infection will be exploited; research subjects will be told that even though there is no benefit to them for their participation, “mankind” will benefit; medical journals will reject any outside criticism of clinical research emanating from academic centers; the determination of what is and what is not ethical will reside within the domain of a handful of ethicists many of whom are from the same institutions sponsoring the research and some of whom have called for dismissing traditional clinical research ethical guidelines. Under these circumstances stopping the VRC01 study seems impossible.
The Tuskegee study was performed between 1932 and 1972 and the Guatemala study conducted between 1946 and 1948. Neither of the studies was declared unethical when they were conducted and in the case of the Guatemala studies, the unethical nature was not revealed until 2010, more than 60 years after its completion, when Susan Reverby uncovered the study as she was conducting research on the Tuskegee experiments. The combined research subjects in the Tuskegee Guatemala studies was less than 2,500—the VRC01 NIH study proposes to enroll greater than 4,000 individuals. Most will be HIV uninfected men who have sex with HIV infected men. 1,500 research subjects will be HIV uninfected sub-Saharan African women repeatedly exposed sexually to HIV infection. Some will be infants born to HIV infected mothers at high risk of transmitting HIV who will be asked to sign a 14 page informed consent while they are in labor. One third of the research subjects will receive a placebo during the time they are exposed to HIV. The remainder will receive an experimental monoclonal antibody that has, by the researchers own admission, no benefit or proven efficacy in preventing HIV infection in humans , will unlikely be a treatment available to individuals in resource poor countries, and even if remotely successful, in the investigators own words, would only be an “incentive to develop the next generation mAb.”(4,5)
The VRC01 study is problematic from many perspectives. Fundamental scientific and ethical principles are in question. Exposure of thousands of individuals to ineffective treatment or placebo while waiting for a statistically significant end point of HIV infection is tantamount to using the research subjects as chattel. Not requiring or providing universally recommend preexposure (PrEP) or postexposure prophylaxis (PEP) for prevention while evaluating a product of no proven benefit to the population under study is disingenuous. Evidence is already available that viral resistance to VRC01 occurs quickly and that there are more potent bNAb that could be used in combination to prevent it. There is agreement among scientists that, just as with antiretroviral drugs, a combination of bNAb will be necessary for success making the VRC01 study superfluous until more data becomes available from US studies.(6) Additionally, safety studies are incomplete.
In order to for the VRC01 study to be successful, HIV infection must occur in the placebo group. This is perhaps why there is no signed agreement or requirement for the research subjects to be on preexposure prophylaxis(PrEP) during the study or for the HIV infected partner to use condoms. While the researchers acknowledge that PrEP is the standard of care for discordant couple they do not provide it for the research study subjects. Instead, they vaguely state that the research subject should obtain PrEP from a “local program” while acknowledging that it might not even be available. If PrEP were not available the individual would still be enrolled in the study. Further, if an individual in the study knew that they had been exposed to HIV the standard of care for postexposure prophylaxis (PEP) would not be provided and again vaguely, the individual would be referred to a “local program.” (PEP requires administration within 72 hours of exposure in order to be effective.) The protocol is also strangely silent about requiring that the HIV infected sexual partner be on antiretroviral treatment and the HIV infection well controlled during the entire study period to reduce the risk of HIV transmission. It appears that the VCR01 study is not about doing what is best for the research subjects but about what is best for the research study.
Economic questions relating to the cost of the VRC01 clinical research trial are intertwined with ethical issues. The estimated cost of the entire the VRC01 phase 2 clinical trial, assuming that the more than 4,000 research subjects will be enrolled and followed for three or more years is $250 million. Add in the production of the monoclonal antibody and it is likely to exceed $300 million. The size of the study is 8 times greater than that of other phase 2 studies approved by the FDA and the cost a staggering 18 times greater. (7,8) The unprecedented size and cost for the VRC01 phase 2 research study suggests that the motive for conducting a study of this magnitude may have more to do with funding and resources that will accrue to the investigators and their institutions than to ending the HIV epidemic.
The cost of the VRC01 study is disproportionately excessive considering that the 2010 budget for all clinical research trials within NIH was $3.1 billion. The fact that this study, acknowledged by the research investigators themselves, will not result in a useful therapeutic product to prevent HIV transmission or a therapy that would benefit individuals in resource poor countries, raises significant economic and ethical questions of how accountability is determined within and outside of NIH. These are reasons why the study should be stopped and the funds shifted to other urgent public health threats such as the Zika virus epidemic.
Finally, there are issues of who reviewed and approved the VRC01 clinical study and how its various components were evaluated for scientific, ethical, economic, and legal components to avoid conflict of interests. With a total cost of a single clinical research study approximating $250 million, an amount that is equivalent to 25% of the one year NIH budget for HIV, what message is conveyed to the public on what NIH considers to be greatest public health needs.
An editorial in the medical journal Lancet stated that the report card for institutional commitments to global health points out inadequacies in commitment and that “… a clear set of ‘stretch’ goals should be identified to increase access to research that could help save millions of lives. (9) With so many resources in the hands of a small group it is time for these institutions to extend their reach to where it’s needed most.” Perhaps, as with the 1996 Levine Panel Report on NIH priorities it is time to once again evaluate the priorities of NIH funded research both within NIH and within universities.
1- How Tuskegee Changed Research Practices. http://www.cdc.gov/tuskegee/after.htm
2- Reverby, S. M. 2013. “Will the STI studies in Guatemala be remembered, and for what?” Sex Transm Infect 89 (4):301-2.
3- Frieden, T. R., and F. S. Collins. 2010. “Intentional infection of vulnerable populations in 1946-1948: another tragic history lesson.” Jama 304 (18):2063
4- NIH Launches Large Clinical Trials of Antibody-Based HIV Prevention https://www.niaid.nih.gov/news/newsreleases/2016/Pages/AMP-studies-launch.aspx
5- VRC01 in Children and Adults http://www.hptn.org/web%20documents/annualmtg15/Presentations/Joint_Plenary/HPTN_IMPAACT_VRC01.pdf
6- Stephenson, K. E., and D. H. Barouch. 2016. “Broadly Neutralizing Antibodies for HIV Eradication.” Curr HIV/AIDS Rep 13 (1):31-7. doi: 10.1007/s11904-016-0299-7;
7- FDA. Drug Development
8- Examination of Clinical Trial Costs. Hui-Hsing Wong et. al.
9- 2013. “Measuring universities’ commitments to global health.” Lancet 381 (9874):1248. doi: 10.1016/s0140-6736(13)60823-5.