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How Cambodian Sex Workers Helped Change the Rules for Community Engagement


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How Cambodian Sex Workers Helped Change the Rules for Community Engagement

  1. 1. 41 Engaging the local community is a given when researchers design and execute clinical trials in HIV, but the process has grown increasingly systematic over the last 10 years, thanks in part to a group of tenacious female sex workers in Phnom Penh, Cambodia. Members of the Women Network for Unity (the WNU, established in 2000 “by a group of sex workers for sex workers”) were part of the intended participant pool in 2004 for a clinical trial to evaluate oral tenofovir for pre- exposure prophylaxis (PREP). The phase 3 trial was to enroll 960 uninfected female sex workers who would be randomized to receive either 300 mg of tenofovir or a placebo daily for one year. Three research entities were collaborating – the University of California, San Francisco (UCSF), Australia’s University of New South Wales (UNSW), and the Ministry of Health of Cambodia (NCHADS) – and funding came from the US National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation. Tenofovir was already in wide use to treat HIV infection in combination with other antiretrovirals. Could the drug help prevent infection, too? The HIV community looked on with hope. Researchers hadn’t yet begun recruiting for the trial in mid- August 2004 when Cambodian Prime Minister Hun Sen ordered Meg Egan Auderset a writer and editor of 20 years who has worked in a variety of set- tings in both the US and Western Eu- rope. Currently a Medical/Reg- ulatory Writer for Thomson Reuters, her primary as- signments in- clude reporting on FDA advi- sory committee meetings and drug approv- als for IDRAC’s AdComm Bul- letin. HowCambodianSexWorkers HelpedChangetheRulesfor CommunityEngagement
  2. 2. VOL5ISSUE2 42 gfgf The research team appeared to have done a thorough job when preparing for the trial. They had already begun meeting with stakeholders by early 2003, including NGOs like the Cambodian Womyn’s Agenda for Change, the organization that provided technical support to the WNU. An institutional review board (IRB) at UCSF approved the trial protocol in February 2003; an IRB at UNSW approved it in October. In July 2003, researchers signed a formal memorandum of understanding with the Cambodian Ministry of Health; that same month they held their first community information session about the trial. By September, researchers were holding focus groups and interviewing community members, including sex workers. Researchers formed a 13-member community advisory group (CAG), which met in March and May of 2004. The NCHADS formed an external advisory board in January 2004, including representatives from government, from UNAIDS, and from the World Health Organization (WHO); they met in January and June of 2004. But while researchers convened meetings with all the right people where they described their plans, extolled the potential benefits of tenofovir, and requested feedback, sex workers alleged partial truths and exploitation. The WNU organized their first- ever press conference on March 29, 2004, issuing a press release stating their opposition to “the use of sex workers in [a] poor country like Cambodia for experimentation especially when the drug has only been tested on healthy monkeys – never on healthy humans.” (In preclinical trials Cambodia had backed the trial The Cambodian government previously had signed off on the trial. The Cambodian Ethical Review Board received a preliminary trial protocol in March 2003 and approved it in July. According to the protocol, researchers would evaluate participants for rates of HIV infection, for adherence to the drug regimen, and for behavioral changes, and they would monitor for tenofovir side effects and toxicity. Trial participants would also receive: • Monthly compensation of $3 USD for 12 months. • Free condoms, free screening and treatment for sexually- transmitted infections, and counseling about risky behaviors. • HIV screenings. The trial would enroll only HIV-negative women. Women testing positive for HIV at the initial screening would be referred to the Cambodian Ministry of Health HIV clinic, where they would be treated in accordance with national guidelines. Enrolled participants who became HIV-positive during the trial would receive free, preferential access to comprehensive care and treatment at the Ministry of Health clinic. • Treatment for side effects experienced during the trial. Participants would not receive treatment for side effects or illnesses developed following the trial’s conclusion. preparations to be shut down. While the prime minister never offered a public explanation, words he spoke about HIV research at a Phnom Penh hospital opening 10 days before suggested he had taken the sex workers’ protests seriously. “If a trial is needed, please do it on animals, and don’t use Cambodians,” he said, according to international press reports. The prime minister’s decision to terminate trial preparations caught the HIV research community off-guard, sparking scores of meetings, years of soul-searching, and interruptions to other tenofovir PrEP trials. “It became very clear that the issues were not unique to tenofovir and pre-exposure prophylaxis. At their heart they related to the conduct of very complex HIV prevention studies in both low-resource communities as well as high-HIV-incident communities,” says Mitchell Warren, executive director of AVAC, an international non-profit devoted to HIV prevention. Warren represented AVAC at several meetings convened by the Joint United Nations Programme on HIV/AIDS (UNAIDS), the Gates Foundation, and other players influential in HIV research. “We realized that while the controversies at that moment related to the PrEP studies, they really could have been about any prevention trial.” GLOBAL FORUM | INFORM
  3. 3. 43 UNAIDS and AVAC approached the task collaboratively. In September 2006, an international working group developed the first draft of what would become the Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials. The agencies published the first edition of the GPP guidelines a year later. “I often say that, as challenging as those days were … as bad as some of the things were that happened, the one positive outgrowth was the development of the Good Participatory Practice Guidelines,” AVAC’s Warren says. While the 2007 edition was “far from perfect,” UNAIDS and AVAC agreed they should present the guidelines to the research world for a test drive, he says. “This sounds perhaps somewhat obvious and maybe simplistic, but if we were going to do guidelines for participation, they needed to be developed in a very participatory fashion,” Warren says. AVAC issued a series of small grants in June 2008 to 12 “GPP partners”: Community groups, trial sites, and nonprofits engaged in HIV prevention. In May 2009, AVAC and the 12 partners met in South Africa to exchange reactions and recommendations. A revision process followed; AVAC and UNAIDS published the second edition of the GPP guidelines in 2011. chanting and carrying signs that read “Sex Workers Infected by Gilead,” “Gilead Prefers Us HIV+,” and “$3 Can’t Buy Sex Workers’ Lives.” They spilled fake blood on Gilead displays and draped the company’s booth with a large black banner reading, “Closed Due to Death.” The drama attracted international media attention. One month later, Cambodian Prime Minister Hun Sen ordered trial preparations closed down. Good Participatory Practice (GPP): A systematic approach to community engagement The events in Cambodia shocked HIV researchers and mobilized protesters. In February 2005, the Cameroonian government suspended a tenofovir PrEP trial in that country; once again, ethical violations were alleged. HIV advocates worldwide met to discuss events, evaluate the damage, and plan the way forward. The International AIDS Society (IAS) convened a 2-day meeting at the request of the Gates Foundation, the US Centers for Disease Control and Prevention (CDC), and NIH. An international meeting on “creating effective partnerships,” convened in June by UNAIDS, was preceded by several regional consultations. As ethicists, researchers, and advocates unraveled and reviewed events, one gap surfaced again and again: The need for systematic guidelines for engaging external stakeholders at every step of the clinical research process. tenofovir had reduced the risk of simian immunodeficiency virus infection in newborn macaques.) The women demanded 30-plus years of insurance to protect against potential side effects – and they questioned why they hadn’t already been promised such insurance if tenofovir was as safe as researchers said. “If our members agree to take the risk, which may one day benefit people in richer countries and the drug company, then we deserve adequate protection for our future lives and our families,” the release read. Trial preparations continued, including focus groups and meetings attended by WNU representatives. The CAG held its second meeting in May 2004, and the second external review board meeting took place in June. On June 15, the WNU held a second press conference. They accused researchers of “unethical recruiting practices,” such as withholding the name of the drug and asserting that tenofovir use carried no side effects. “WNU wants recruitment processes to be better and more honest, with sex workers not pressured or given wrong information about the drug,” the accompanying WNU press release read. In July 2004, sex workers from the WNU travelled to Bangkok, Thailand, for the fifteenth International AIDS Conference. There they met up with members of Act Up-Paris and the Asia Pacific Network of Sex Workers (APNSW). Together, the 3 organizations staged a protest of the tenofovir trials that focused on tenofovir manufacturer, Gilead. Protesters interrupted a symposium on antiretrovirals,
  4. 4. VOL5ISSUE2 44 gfgf The trial will take place at sites in South Africa, Peru, Thailand, and at 4 sites in the US. Researchers plan to begin enrollment this spring, but community engagement began early on. “This is a complicated trial,” says Jim Pickett, chair of International Rectal Microbicide Advocates (IRMA) and a member of the MTN- 017 protocol team. “You do not want to launch something on a community that has not been fully engaged and given its opinions, its input, asked questions … You can’t just come in to foist something on them without letting them know what’s coming. They may be completely fine with it, but if you haven’t talked to them before you’re going to create an aura of distrust.” Stakeholder input altered the MTN-017 trial protocol significantly. During planning discussions in Pittsburgh, researchers questioned the wisdom of extending the proposed trial population – men who have sex with men – to include transgender women as well. Transgender women have different needs, researchers reasoned; they have different sexual identities. In addition, many take hormonal treatments that could interact with the trial medications. Sitting around a table in Pittsburgh, researchers concluded that enrolling transgender women would overcomplicate an already- complicated trial. Stakeholder meetings in Thailand convinced them otherwise. “When we were in Thailand, the community folks there were saying well, essentially, that doesn’t make sense because there’s not a hard line in our culture, in Groups outside of AVAC have touted the GPP guidelines as well. In a 2010 article published in the New England Journal of Medicine, researchers from the iPrEX study of Truvada (emtricitabine/tenofovir) for PrEP specifically mention use of the GPP guidelines when developing their study protocol. In 2011, when the Presidential Commission for the Study of Bioethical Issues published 14 recommendations for federally sponsored research involving human volunteers, one of the 14 advocated applying GPP beyond the HIV arena. And in 2012, the Critical Path to TB Drug Regimens initiative adapted the GPP guidelines for tuberculosis drug trials, publishing Good Participatory Practice Guidelines for TB Drug Trials. Development of the first phase 2b trial of a rectal microbicide to prevent HIV infection, MTN-017, has included extensive community engagement, according to Ross Cranston, MD, FRCP, protocol chair for the trial and director of the Anal Dysplasia Clinic and Research Program in the Division of Infectious Diseases at the University of Pittsburgh Medical Center. Researchers expect to enroll 186 participants and randomize each to 1 of 6 groups. Each group will experience the same 3 treatment periods, but in different orders: Daily oral Truvada; daily tenofovir reduced glycerin 1% gel, applied rectally; and tenofovir reduced glycerin 1% gel, applied rectally before and after receptive anal intercourse. Each treatment period will last 8 weeks; participants will meet with trial personnel every 4 weeks. The GPP guidelines answer the need for “normative guidance” for the community-engagement aspect of clinical research development, says AVAC Senior Program Manager Stacey Hannah. GPP espouses “respect, mutual understanding, integrity, transparency, accountability, and community stakeholder autonomy” as “guiding principles.” The document systematically identifies “stakeholder engagement activities” for each step of the clinical trial process: from “formative research activities” through to “post-trial access to trial products or procedures.” AVAC refers to the GPP guidelines as a “living document” that will change over time. “It’s an ongoing process,” Hannah says. “And, you know, the hard thing about GPP is that every trial is different. Every community is different. Every trial is going to have different considerations and different issues that might come up. GPP is really just a guideline for ‘how do we make sure that we’re thinking about all of this?’” Putting GPP into action Unlike good clinical practice (GCP) and good laboratory practice (GLP) standards, no regulatory body enforces GPP. Even so, funders increasingly are requiring researchers to follow them, according to Warren and Hannah, who say that researchers and trial sites regularly contact AVAC for assistance. GLOBAL FORUM | INFORM
  5. 5. 45 of unused pills and gel at study visits, researchers estimated an overall adherence rate of 90%. Blood tests of study participants told them otherwise: On average, tenofovir was present in the blood of just 23% of participants randomized to 1% tenofovir gel, 28% of participants randomized to oral tenofovir, and 29% of those randomized to oral Truvada. The rate of new HIV infections among VOICE participants were shocking. Overall, 5.7 of participants contracted HIV during the trial, with no statistically significant difference in the rate of new infections between participants taking the study drugs and those taking placebo. As the clinical research field broadens its focus to include anal microbicides and, potentially, an HIV cure, challenges associated with participant recruitment, enrollment, and participation are changing as well. There is a question about how “generalizable” the GPP guidelines are, Warren says. GPP continues to evolve, and AVAC is focused on developing tools to help research teams and trial sites adapt them to their own needs. “If we for one minute think this is simple, that any one thing is the answer, that’s when we lose,” Warren says. “There is no ‘one’ in AIDS. There is no ‘one’ cure. There is no ‘one’ prevention. There is no ‘one’ treatment. When we begin to think that there is one magical shiny new thing that’s going to magically end the epidemic, then we have just given the virus a gift.” References available upon request. our communities, between gay men and transgender women,” Pickett recalls. “It’s more fluid. Gender identity is not this bound thing.” Similarly, after community meetings in Pittsburgh, the research team decided against enrolling partners as trial participants. It was stakeholders who pointed out that the exchange of body fluids could alter PK measurements. “[Stakeholder meetings] took up an awful lot of time, and they were absolutely essential to moving this [protocol] forward,” Cranston says. In each of the communities “they were engaged. They were vocal. They were absolutely invested in this study. It was very affirming.” Even the most thorough engagement process can’t guarantee the desired clinical trial outcome, however, as researchers for the phase 2b VOICE (“Vaginal and Oral Interventions to Control the Epidemic”) trial learned recently. The VOICE team followed the GPP protocol closely, Warren says, but even with all the vetting and conversations, informed consent forms and face-to-face meetings, researchers could not ensure that participants would actually take their assigned drugs. VOICE enrolled more than 5,000 women in South Africa, Uganda, and Zimbabwe, randomizing them to one of five trial arms. The study intended to evaluate the safety and effectiveness of daily oral tenofovir, daily oral Truvada, and daily 1% vaginal tenofovir gel, versus placebo, to determine whether the treatments offered protection against HIV infection. Based on participant self-reports and the collection