A day later than promised, let’s kick off our discussion of “Research Rashomon: Lessons from the Cameroon Pre-exposure Prophylaxis Trial Site” (PDF). The case study concerns a clinical trial of whether tenofovir, an antiretroviral drug, could prevent HIV infection. Before it was halted in the face of concerns raised by activists and the media, the particular clinical trial discussed in this case was conducted in Cameroon. Indeed, one of the big questions the activists raised about the trial was whether it was ethical to site it in Cameroon.

From the case study:

Tenofovir was first approved by the US Food and Drug Administration (FDA) as an AIDS treatment drug in October 2001. Almost immediately, researchers started contemplating the use of tenofovir as a potential drug for HIV prevention. Family Health International (FHI), a US-based international nonprofit public health agency, submitted a proposal to the Bill & Melinda Gates Foundation to evaluate the use of tenofovir as an oral prophylaxis to prevent HIV acquisition among high-risk populations. The proposed study was a randomised, double-blinded, placebo-controlled trial in uninfected women at risk for acquiring HIV in West Africa.

At about the same time, Dr. John Kaldor from the University of New South Wales (UNSW) in Australia was also developing a protocol to test oral tenofovir for PrEP. Dr. Kimberly Page Shafer, a researcher at the University of California at San Francisco (UCSF), had sent a similar proposal to the US National Institutes of Health (NIH) to test oral tenofovir as an HIV prevention among sex workers in Cambodia.

For its part, Gilead Sciences, the company that developed tenofovir, was initially somewhat reluctant to become involved with the prevention trials; it was already working to address registration, pricing, and access issues for treatment, and did not see the potential market for prevention being especially profitable. Gilead, however, has generally been supportive of PrEP research and has cooperated with the PrEP research field. (pp. 11-12)

One of the issues that became very controversial about the Cameroon PrEP trial was the location of the clinical trial in Cameroon (as opposed to someplace else, like the US). When involved in research with human subjects, researchers have obligation that go beyond conducting scientifically sound research. They also have obligations to protect the welfare of research subjects, to respect their autonomy, and to ensure that the risks and benefits of the research are distributed justly.

The Gates Foundation called in ethics experts for a one-day consultation on the proposed studies. Among other things, the ethics consultation raised some concerns about the siting of the trials:

Participants raised a number of concerns regarding the proposed location of the trial (Cameroon) and the trial population (women with multiple sex partners, including but not limited to sex workers). They questioned whether it was appropriate to conduct the trial with a vulnerable population of women in a developing country if it could potentially be done in a less vulnerable US or European population; this was felt to be a particular problem if the product were found to be effective and the United States would be a main market. (p. 13)

After this ethics consultation, FHI tried to tackle four questions:

1. Are the trials addressing a significant health risk that is a priority for the country that will be hosting the research?
2. Will the host-country populations benefit from the research results?
3. Can appropriate steps be taken to minimize all medical, social, and psychological risks associated with the research?
4. Is the research unnecessarily burdening vulnerable populations?

To address these issues, FHI proposed to:

• Make country site selection contingent on ensuring that national ministries of health would support the use of tenofovir for prevention should it prove effective and that the trial would not detract from the conduct of other important research or public health activities.
• Negotiate prior agreements between the host country and the Gates Foundation, Gilead, and any other potential sources of support, for implementation of an HIV chemoprophylaxis programme, if efficacy were demonstrated.
• Conduct formative research at all sites to identify effective strategies for an appropriate and effective informed consent process; risk reduction conselling; referrals for care for those identified as HIV infected; supporting sustainable improvements in local access to care; preventing inappropriate use of the study drug outside of the trial; and minimising the potential for stigmatisation of trial participants.
• Address safety issues by phasing the study with initial slow enrollment followed by appropriate medical monitoring throughout the trial and clear procedures for handling adverse medical events.

In terms of placing the burden on vulnerable populations, FHI noted that it would be impossible to conduct useful HIV prevention research with populations that were not vulnerable in some way, whether in the United States or elsewhere. They reasoned that, if the research were valuable and the potential benefits could be assured, the primary ethical issue was to minimize harm. They proposed to minimize harm by making every effort to identify populations that had strengths as well as vulnerabilities and to implement the research in ways that potentially enhanced strengths; by engaging in a process of community consultation through the formative research, with the goals outlined in the previous paragraph; and by making every effort to ensure that the trial would result in data of sufficiently high quality to guide public health decisions in the host countries and generate funding to support those decisions. (p. 14)

What do you think about FHI’s approach here? Did these considerations do enough up front to address researchers’ ethical obligations to the human subjects of their research? Was there more they should have done?

In particular, should the research protocols for clinical trials like this involve a positive justification for the choice of a particular site (“Here are the reasons why conducting the research in Cameroon is better than any of the available alternative …”)? Or is an explanation of the steps that will be taken to conduct a trial ethically in a particular location justification enough?

How important in justifying the site of a clinical trial are issues that bear on what will lead to useful data, meaningful results? (These might include what would be an appropriate population in terms of exposure to the virus that the PrEP is hoped to protect against; the ability to control the study and collect good data; the availability of local researchers with experience conducting this sort of clinical trial and infrastructure for the research, including providing medical treatment for human subjects in the trial; and governmental agencies amenable to this sort of research.)

How important in justifying the site of a clinical trial are primarily ethical considerations? (These might include whether the human subjects are drawn from a vulnerable population; whether they can they be properly informed about the risks and benefits of participation in the research and protected from harms; the extent to which access to participation in this clinical trials is itself a good to be distributed justly; and the likelihood that the knowledge generated will be accessible to the population from whom the human subjects were drawn.)

For those of you who have done the reading, feel free to talk about the specific issues the activists raised about locating the trial in Cameroon. Were the activists off-base, or were their concerns reasonable? What do you think about how researchers responded (or didn’t) to these concerns?