CLINICAL Ethics TRIALS

Clinical Trials 2015, Vol. 12(4) 394–402 Ó The Author(s) 2015 Testing the waters: Ethical Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1740774515579165 considerations for including PrEP in a ctj.sagepub.com phase IIb HIV vaccine efficacy trial

Liza Dawson1, Sam Garner2, Chuka Anude3,PaulNdebele4,Shelly Karuna5, Renee Holt6,GailBroder5, Jessica Handibode7, Scott M Hammer8, Magdalena E Sobieszczyk8 for the NIAID HIV Vaccine Trials Network

Abstract Background: The field of HIV prevention research has recently experienced some mixed results in efficacy trials of pre-exposure prophylaxis, vaginal microbicides, and HIV vaccines. While there have been positive trial results in some studies, in the near term, no single method will be sufficient to quell the epidemic. Improved HIV prevention methods, choices among methods, and coverage for all at-risk populations will be needed. The emergence of partially effective prevention methods that are not uniformly available raises complex ethical and scientific questions regarding the design of ongoing prevention trials. Methods: We present here an ethical analysis regarding inclusion of pre-exposure prophylaxis in an ongoing phase IIb vaccine efficacy trial, HVTN 505. This is the first large vaccine efficacy trial to address the issue of pre-exposure prophy- laxis, and the decisions made by the protocol team were informed by extensive stakeholder consultations. The key ethi- cal concerns are analyzed here, and the process of stakeholder engagement and decision-making described. Discussion: This discussion and analysis will be useful as current and future research teams grapple with ethical and sci- entific study design questions emerging with the rapidly expanding evidence base for HIV prevention.

Keywords HIV vaccine trials, ethics, standard of prevention, HIV prevention, design

Background the decisions made by the protocol team were informed by extensive stakeholder consultations. The key ethical The field of HIV prevention research has recently expe- concerns are analyzed here, and the process of stake- rienced some mixed results. Several biomedical inter- 1 holder engagement and decision-making described. ventions, including pre-exposure prophylaxis (PrEP), This discussion and analysis will be useful as current treatment as prevention,2 vaccines,3 and vaginal micro- 4 and future research teams grapple with the rapidly bicides, have shown some success in clinical trials; expanding evidence base for HIV prevention. however, negative trial results have complicated the pic- ture. In the near term, no single method will be suffi- 1Division of AIDS, NIH/NIAID, Bethesda, MD, USA cient to quell the epidemic. Improved HIV prevention 2Henry M. Jackson Foundation, Bethesda, MD, USA methods, choices among methods, and coverage for all 3AstraZeneca, Gaithersburg, MD, USA 4 at-risk populations will be needed. As biomedical inter- Medical Research Council of Zimbabwe, Harare, Zimbabwe 5Fred Hutchinson Cancer Research Center, , WA, USA ventions are tested and approved by regulatory bodies, 6Program for Appropriate Technology in Health (PATH), Seattle, WA, questions arise as to whether they should be incorpo- USA rated into ongoing prevention trials, raising complex 7AVAC: Global Advocacy for HIV Prevention, New York, NY, USA scientific and ethical questions. We present here an ethi- 8Department of Medicine, Columbia University, New York, NY, USA cal analysis regarding inclusion of PrEP in an ongoing Corresponding author: vaccine efficacy trial, HVTN 505. This is the first large Liza Dawson, Division of AIDS, NIH/NIAID, Bethesda, MD 20892, USA. vaccine efficacy trial to address the issue of PrEP, and Email: [email protected]

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 Dawson et al. 395

Prevention package in HIV clinical trials general reason is the ethical requirement of beneficence: Clinical trials of biomedical HIV prevention methods a person who is able to help another person in need, without unreasonable sacrifice of her own interests, have always included a prevention package designed to should do so. This Good Samaritan argument places a help reduce HIV acquisition. This practice developed responsibility on researchers and sponsors to help from stakeholders’ consensus during the 1990s that research participants as long as this does not consist of investigators have an ethical obligation to provide unreasonable personal sacrifice.15 However, general behavioral risk reduction counseling to participants in arguments for beneficence do not help determine what HIV prevention trials.5 The prevention package typi- level of benefit is sufficient. cally also includes counseling about post-exposure pro- In spite of the many arguments in favor of providing phylaxis (PEP), free male and female condoms, prevention benefits, questions have been raised about lubricant, and diagnosis and treatment of (or referrals providing a package of prevention services above and for) sexually transmitted diseases (STDs). The intent is beyond what is locally available.5,16 Concerns expressed to provide benefit to participants by helping them include high costs, potentially privileging the study pop- reduce HIV risk. At the same time, any reduced risk ulation relative to the broader community, and creating from the prevention package will also lead to increased undue inducement to participate in research. clinical trial size, since it will reduce the overall rate of While a consensus has developed over the last decade HIV incidence in the trial. The same issues arise in that a standard package of prevention benefits is ethi- principle in HIV prevention trials involving people who cally important, the interventions provided in the pack- inject drugs (PWID), for whom both sexual and par- age have been determined pragmatically. Affordable enteral HIV transmission are relevant. Different risk and feasible interventions such as counseling, condoms, reduction methods for drug injection, such as provision and STD treatments can be provided in diverse settings of clean syringes, have also been advocated as part of a 6 and do not usually interact with biomedical products or prevention package in trials involving PWID. Our dis- typically affect the original research questions. cussion in this case centers around prevention of sexual Counseling about PEP, used optimally as an emergency transmission of HIV, as that is the main focus of intervention following unprotected, high-risk exposure, HVTN 505. is also incorporated into risk reduction counseling con- Initial concerns about the need for risk reduction ducted in prevention studies. Uptake of this strategy counseling arose in early HIV vaccine trials, as has been limited in many settings, however, due to fac- researchers became aware that many study participants tors such as cost and challenges with medication adher- falsely assumed (or hoped) that they would be pro- ence.17–22 tected from infection by as-yet unproven products, and As new biomedical methods become validated, the 7 may have been tempted to engage in riskier behavior. prevention package question becomes more compli- The concern about risk disinhibition is further fueled cated. The use of new methods may affect trial design, by the observed phenomenon that many trial partici- increase clinical trial costs, or threaten scientific validity pants do not fully accept that they may receive a pla- of the study, and yet failure to address use of new inter- 8 cebo, even when randomization is emphasized during ventions would lead to concern about neglect of partici- the informed consent process. The provision of a pre- pant welfare. Inclusion of the new methods is a way of vention package is part of the obligation to minimize accommodating the new realities in the field while there risks in clinical trials, namely, the risk of behavioral is ongoing debate about when and how new methods disinhibition. Failure to provide the package might be should be used at the population level, and how gov- viewed as intentionally allowing or even increasing the ernments and donors should balance their financing of risk of HIV negative individuals being exposed to different prevention and treatment options. In an 9,10 HIV. In addition, the emergence of increased risk of uncertain environment, it may be difficult to predict HIV acquisition in a previous , the STEP whether introducing new interventions into a trial trial (HVTN 502),11,12 was a reminder that all research would increase or decrease relevance of the trial results involves uncertainty about product safety as well as for health policy decision-making. efficacy, and this risk of unintended adverse effects pro- These issues touch on two fundamental ethical com- vides further rationale for concern for protection of mitments: ensuring the social value of clinical research, study participants. and the protection of study participants. When the pre- There are additional reasons for providing addi- vention interventions have the potential to interfere tional benefits to trial participants. Participation in with the scientific objectives of the trial, a tension research can be viewed as a contribution to society that emerges between protection of participant welfare, on deserves reciprocity, and a prevention package is a way the one hand, and the need to reliably and efficiently of giving back to the participants.13 Others have answer the primary study questions on the other. In emphasized the researcher/participant relationship as a spite of the existence of international ethical guide- key factor in creating ethical obligations.14 A more lines23,24 and specific guidance documents on

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 396 Clinical Trials 12(4) biomedical HIV prevention trials,6,25 to date, no com- (FDA) approved Gilead’s submission for the use of prehensive ethical framework has been developed which Truvada for HIV prevention in certain populations. can directly adjudicate this ethical tension. We describe These events have stimulated vigorous debate about here the decision-making about inclusion of PrEP in a the appropriate role of PrEP in HIV prevention pro- major HIV vaccine trial, HVTN 505, providing an early grams. Many believe that more information is needed look at the issues clinical trial stakeholders will face in about clinical implementation of PrEP, costs, and future HIV prevention research. prioritization for at-risk groups. These developments have also raised the question of whether, when, or how PrEP should be offered to trial participants in HIV pre- Methods vention clinical trials. There is currently no standard of HVTN 505 practice in the field on use of PrEP in programs or research. Decision-making is complicated by the con- HVTN 505 is a phase 2b HIV vaccine trial evaluating 26 tinuing need for adequate antiretroviral (ARV) treat- two vaccine candidates, designed to elicit both anti- ment for those who are already infected. body and T-cell responses, consisting of three injections At the moment, PrEP with Truvada is not widely used of DNA prime vaccine encoding proteins (clade B gag, in any country, and at the time of the HVTN 505 discus- pol, nef, and env proteins from clades A, B, and C) sions, the inclusion of PrEP in a clinical trial would go derived from HIV followed by a single boost of a recom- beyond available clinical care in most settings. Also at binant adenovirus-5 (rAd5) vector vaccine encoding five that time, Centers for Disease Control and Prevention proteins (clade B gag-pol fusion protein and clades A, (CDC) had released preliminary guidance on PrEP, * B, and C env) derived from HIV. Primary study objec- although more recent guidance has come out from CDC tives include assessment of (a) protection against HIV and World Health Organization (WHO).30,31 acquisition through sexual exposure, (b) viral load set- point for those individuals who are infected despite receipt of the vaccine, and (c) safety of the vaccine regi- Communication, HVTN 505 participant surveys, and men. The study enrolled 2504 healthy, HIV-uninfected, community consultation Ad5 neutralizing antibody (nAb) negative, circumcised The first communication step was to discuss the results US men who have sex with men (MSM) and male-to- of the iPrEx study with study participants and commu- female (MTF) transgender persons who have sex with nities, which was done via a letter to participants men, aged 18–50 years, at high risk of HIV-1 infection shortly after the release of the results to inform partici- through sexual exposure at 21 US study sites. pants about the study, in addition to written educa- In April 2013, vaccinations in the HVTN 505 study tional materials about PrEP, individual education were halted after a prescheduled Data and Safety sessions with participants at study visits, meetings with Monitoring Board review indicated that vaccination Community Advisory Boards at every site, as well as failed either to decrease acquisition of infection or community forums. The timeline for these activities lower HIV viral load for those who became infected relative to events surrounding the use of Truvada for after vaccination. There were 71 incident HIV-1 infec- PrEP is shown in Figure 1. The dialogue was framed tions (41 in vaccine and 30 in placebo recipients), 48 of around informing people about PrEP and the results of which occurred at least 4 weeks after completing the the iPrEx study, and informing them that the HVTN vaccination regimen. There were 27 in the vaccine 505 team is considering what the results mean to 505 group and 21 in the placebo group, a difference that and obtaining their feedback about what the results of was not statistically significant. The conditional prob- iPrEx mean to the relevant communities and to preven- ability of observing a different outcome with addi- tion research. This process took place from November tional vaccinations was too low to support continuing 2010, after the release of iPrEx results, through the vaccinations. HVTN 505 has been modified to summer of 2011.32 The HVTN 505 team also imple- become an observational study with close attention to mented an online survey33 from January to March lost-to-follow-up rates and monitoring of HIV infec- 2011 to educate enrolled study participants about PrEP 27 tions in both study arms. and collect data on their views of PrEP acceptability, affordability, plans to seek access to PrEP, and any Background on Truvada for PrEP concerns regarding use of PrEP by the respondents. In 2010 and 2011, results from three major interna- tional trials showed that daily oral TruvadaÒ is effica- Decision on PrEP for HVTN 505 participants cious in reducing risk of acquisition of HIV in MSM Subsequently, the team took up the question of PrEP and transgender women,1 heterosexual discordant cou- use in the context of study participation. The team ples,28 and in heterosexual men and women.29 In determined that it would not be feasible to redesign the August 2012, US Food and Drug Administration study to reliably measure the combined effectiveness of

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 Dawson et al. 397

Figure 1. Timeline of events related to community consultation.

PrEP plus vaccine, so the main question was whether or obligations to study participants and communities, how PrEP might be provided as option for study parti- effects on study design, health policy considerations, cipants. While the efficacy of Truvada in MSM and and stakeholders’ opinions. transgender women populations in clinical trials is solidly established, and the risks of side effects are rea- sonably low, PrEP has not yet been widely implemented Researchers’ obligations to study participants and in any country since its recent approval by the FDA. communities The question arose as to whether participants in HVTN Generally, obligations of beneficence require that 505 should be offered PrEP, and if so, whether it should researchers provide research-related health care com- be paid for by the study or some other mechanism. mensurate with the relevant standard of care. In this Three options were considered: (a) provision of case, PrEP had not become ‘‘standard’’ in the sense of information about PrEP to study participants but no widespread use and general availability. Pivotal clinical further action, (b) provision of information about PrEP trials had been completed, but additional studies of and referral of participants to sources of PrEP outside implementation, adherence, and longer term safety had the study, and (c) provision of both information as well not yet been done. Also, policies regarding insurance as PrEP to those participants who were interested, as coverage and clinical practice were still in flux, suggest- part of the study itself. The HVTN 505 protocol team ing that PrEP was not an established standard of care. leadership undertook extensive community consulta- Given this picture, it is unclear what obligations tions through HVTN-wide meetings, teleconferences, researchers would have regarding Truvada provision. and meetings with advocacy groups when considering Also, some of the HVTN 505 trial sites are not direct how to handle the PrEP decision. Ultimately, the gen- care providers, making direct provision of Truvada eral consensus was to provide information and educa- through those sites more complicated, since use of tional materials about PrEP, developed specifically for Truvada requires medical monitoring. Some argued vaccine trial participants, as well as referrals to provi- that sites should not provide an intervention they are ders willing to prescribe PrEP for trial participants not well equipped to deliver and monitor. wanting access. The protocol team approached Gilead Since PrEP was not widely available, providing it to and secured a donation of the product for HVTN 505 HVTN 505 trial participants could be seen as unfairly study participants. The coordinating center for the privileging these participants over others in the commu- HVTN also established a contractual relationship with nity. However, it also could be argued that study parti- an independent mail-order pharmacy that could distri- cipants could be given more benefits due to their bute the drug to individual participants. contribution to medical research and assumption of risks and burdens of study participation. In fact, the Joint United Nations Programme on HIV/AIDS’ Ethical considerations regarding inclusion of PrEP (UNAIDS) Ethical Considerations in Biomedical HIV In reviewing the ethical considerations associated with Prevention Trials states that investigators should pro- this decision, we considered four key areas: researchers’ vide all ‘‘state of the art’’ risk reduction methods to

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 398 Clinical Trials 12(4) participants in clinical trials when they are scientifically If PrEP is provided at no cost in the research trial, validated or are approved by regulatory authorities.6 does this put unreasonable pressure on a trial partici- The document also states that plans for inclusion of pant to continue in the study simply to maintain access? new methods should be outlined in the protocol: Participation in the trial during the follow-up period involved only blood draws and HIV testing and did not Mechanisms for negotiation among all research stake- pose a high risk for participants—meaning that conti- holders, including the community, about the standards for nuation in the study did not involve unreasonable risk enhancement of the risk reduction package during the trial or burden. If the study were unreasonably risky, this as new biomedical HIV prevention modalities are scientifi- calculation might be different. But as some commenta- cally validated or are approved by national authorities tors have noted,34 unreasonably risky studies should be need to be set in the study protocol. Negotiations should stopped by Institutional Review Boards (IRBs) in any take into consideration feasibility, expected impact, and the ability to isolate the efficacy of the biomedical HIV case, making most arguments about undue inducement modality being tested, as other prevention activities untenable. And as noted above, one of the arguments improve. in favor of offering additional benefits to study partici- pants is precisely because of their contribution to sci- ence through study participation—in other words, While the guidance is helpful in outlining key issues for promoting reciprocity in trial benefits. consideration, interpretation of the requirement for After analyzing direct effects of provision of PrEP ‘‘state of the art’’ risk reduction methods may be chal- with Truvada to study participants along with potential lenging when some modalities have been scientifically effects on communities, it seems reasonable, but not validated but not fully implemented in host countries. ethically required, to offer free access to participants, Another speculation was that use of Truvada would even when this access is not available to the broader encourage riskier behavior. There was no evidence of community. This approach is consistent with the spirit this in previous clinical trials (nor is this concern unique of the UNAIDS guidelines in that the process of con- to Truvada). However, a critical difference in the post- sultation identified potential benefits to participants approval period for Truvada was that the product was and views in favor of PrEP provision, in spite of the then known to work and had FDA approval for use in fact that PrEP has not been widely implemented in the HIV prevention. The concern about risk disinhibition United States or in any country at present with PrEP is speculative, as no systematic data exist on this point. Effects on study design and health policy Another further theoretical possibility was diversion of Truvada during the trial. HVTN 505 participants considerations could access Truvada through the study and sell it to The ethical conduct of clinical research depends on car- others via a ‘‘black market,’’ resulting in unmonitored rying out scientifically sound, useful studies. use of the product. This could create negative conse- Introducing new prevention methods into a clinical quences for individuals using the product, and greater trial may affect study efficiency, potential for answering potential for generating drug-resistant virus. With ade- the primary research question(s), or usefulness for fur- quate measures, however, the risk of black market ther decision-making in regulatory, policy, or research activity could be mitigated. To address this challenge, domains. Therefore, ethical assessment must include the study team developed plans to intensify counseling evaluation of the impact of including PrEP in HVTN on use of Truvada to emphasize that PrEP requires 505 on the study’s scientific viability and usefulness. monitoring by qualified clinicians. If a large number of HVTN 505 participants used There may be added burden to research participants PrEP, this would likely reduce HIV incidence in the using Truvada who subsequently drop out of the trial: trial, leading to the need for a larger sample size. Prior difficulty accessing the frequent HIV testing required to FDA approval of PrEP but after publication of the for monitoring. HIV vaccine trial participants who iPrEx trial results, a previous HVTN 505 study proto- received a study vaccine may require nucleic acid test- col amendment had already included an allowance for ing (NAT) for HIV to distinguish between true HIV larger study size to accommodate an estimate that 20% infection and vaccine-induced sero-positivity (VISP). of the HVTN 505 participants might be using PrEP, or While former HVTN trial participants who exhibit might use PEP repeatedly. Therefore, the study team VISP are offered ongoing NAT testing through the was not concerned that PrEP use would lead to an HVTN, this may be less convenient than standard test- underpowered trial in this case. ing. Therefore, counseling on longer term implications It is important to consider the overall usefulness of of VISP and use of PrEP was provided to HVTN 505 the trial’s primary results for future decision-making in participants seeking PrEP. research and policy decisions. In this case, allowing use

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 Dawson et al. 399 of PrEP in the trial neither significantly enhances nor respectful treatment of stakeholders and participants in detracts from the usefulness of the primary results, research enterprise, regardless of specific outcomes. since the study was not powered to measure the com- In anticipation of the FDA decision regarding use of bined effect of the vaccine regimen and PrEP, and there Truvada as PrEP, the HVTN 505 protocol team held a would be no combination strategy developed on the series of consultations with site investigators, leadership basis of this trial. The usefulness of the primary objec- at the National Institute of Allergy and Infectious tives, vaccine efficacy and lowering viral load set-point, Diseases (NIAID), IRBs, advocacy group members, will not be significantly altered. If the study’s scientific including the NIAID Be The Generation Bridge integrity had been significantly reduced by provision of Partners, and community stakeholders. During the PrEP, scientific goals could conflict with the goal of consultations, it was evident that majority favored providing more benefits to trial participants, creating a PrEP provision and education about PrEP in the trial, stark dilemma. Fortunately, these circumstances did and only minority opposed provision of PrEP. Key not lead to such an ethical impasse. considerations in favor of providing PrEP were as fol- One theoretical possibility is biological interaction lows: (a) some considered it unethical not to provide an between PrEP and vaccine products, which could affect option that was proven effective and (b) providing either safety or efficacy in the study. Due to the sepa- PrEP broadens the choice of HIV prevention options rate and unrelated mechanisms of action of the two for participants. products, it is unlikely that significant interactions Key considerations mentioned against provision of would occur. A more plausible possibility would be PrEP were as follows: (a) concerns about side effects, synergistic action in reducing HIV acquisition or viral (b) challenges with adherence, (c) the risk of generating load set-point, making it difficult to identify indepen- HIV-1 resistance to Truvada, and (d) the potential for dent vaccine-specific effects. The HVTN 505 protocol behavioral disinhibition. The HVTN 505 protocol team is collecting self-report of Truvada use and is monitor- also conducted a survey of 400 study participants ask- ing blood levels of Truvada in a sample of participants ing about their views on PrEP. Results showed that to approximate the true uptake of PrEP during the about 30% of participants were moderately or very trial, which may be helpful for future analysis of the interested in using PrEP, although a majority (68%) interaction of the two products, although this protocol expressed that they were unlikely to take it at their own is not powered to measure interaction statistically. expense.33 Also, the additional data to be collected about safety At the end of the consultations, there was agreement and reported adherence to PrEP are informative for the that the preferred option was to reintensify education prevention field, the pharmaceutical sponsor, and and counseling about PrEP and develop a referral sys- future implementation decisions, as well as informing tem rather than to provide the drug directly at trial future study design decisions. sites as part of the study. This option was viewed by all In sum, the study integrity or ability to detect an stakeholders as empowering the participants to make effect of the HIV vaccine regimen would not be signifi- informed decisions about PrEP independent of their cantly diminished by the addition of PrEP. While there study participation, creating a flexible system that are cases in which additional prevention modalities would be compatible with variety of infrastructures at have significant impacts on a study’s ability to generate trial sites, and feasible given diverse levels of expertise endpoints or draw conclusions about the intervention and experience with PrEP at the sites. Most impor- of interest, in this case, the addition of PrEP was not tantly, the referral plan ensures that participants have a deemed a threat to the study’s design. It is important to relationship with a primary care provider who can pre- note that in general, the integrity of the study and the scribe PrEP and monitor its use after the conclusion of ability to answer the research questions must always be HVTN 505. considered when adding or changing prevention modal- If Truvada had been purchased through HVTN 505 ities in any HIV prevention trial. study funds, this would have increased study costs sig- nificantly. The possibility of free access to PrEP through a HVTN-supported mail-order pharmacy Opinions/views of key stakeholders mechanism and donation from Gilead alleviates this The views of stakeholders are pragmatically and ethi- burden on the sponsor and the team. However, the cally important. First, it may be simply impossible to most important consideration for the study participants conduct the study if key stakeholders do not agree on is the ability to make a choice about whether or not to basic arrangements. Second, even if it is possible to use PrEP. carry out the study over the objections of some parties, The decision by the research team to include PrEP these kinds of actions can create lasting damage to in HVTN 505 can affect longer term relationships important relationships and foster distrust among key among stakeholders such as community members and stakeholders. Third, there is inherent value in the researchers. On the one hand, provision of PrEP may

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 400 Clinical Trials 12(4) positively affect community members’ views of the prevention packages. The relationship of the prevention research. On the other hand, offering the options of package to the local or national standard of care will accessing PrEP may set a precedent for future vaccine also be a subject of discussion and will impact the over- trials. Provision of PrEP in HVTN 505 depended on all utility of each prevention trial in informing policy the manufacturer’s willingness to provide the product, decisions. Frequently, local and national standards of which may not always be available in future trials. care differ among different countries that may be Therefore, issues regarding costs and procurement may involved in a multisite trial, complicating this analysis. become more complex in future cases. There is frequently no easy formula for balancing com- peting ethical priorities in providing participant benefits and advancing scientific inquiry. Further conceptual Discussion analysis will be required to fully explicate ethical responsibilities of researchers and funders in these The discussions about PrEP in HVTN 505 offer useful scenarios. lessons. First, regarding the process, the team’s exten- sive consultations with community representatives and other parties facilitated full consideration of stake- Conclusion holder views and transparent communication. These steps will be essential in all HIV vaccine and prevention The question of how to design and conduct future HIV efficacy trials. The tradition of robust community prevention trials will become increasingly complex as engagement in HIV vaccine research has provided a more partially effective prevention methods are devel- 35 good foundation for discussions of complex new issues oped. Ethical and scientific challenges may intensify involving emerging prevention methods, and the design as new interventions become widely distributed. The and conduct of clinical trials. That said, diverse opi- key domains considered in the case of PrEP introduc- nions may be expressed, and there will not always be tion during the HVTN 505 efficacy trial will be essential consensus on the best way to move forward in a trial as aspects to consider in future cases. The approach taken stakeholders grapple with new evidence and policy by the HVTN 505 leadership team highlights the impor- changes in the field. In this case, consensus was reached tance of thorough consultations with all stakeholders. on how to move forward. As the HIV prevention standard of care evolves and Second, the most contentious ethical dilemmas did clinical trial design becomes increasingly challenging, not arise in full force in this case, since (a) PrEP could both ethically and scientifically, communication and be offered in the trial without unduly disrupting the sci- transparency with all stakeholders will continue to be entific integrity of the study; (b) a supply of PrEP was essential. made freely available by Gilead, obviating any con- cerns about barriers to access; and (c) the stakeholders Acknowledgements consulted approved of the plan. Also, this trial was The authors and the HVTN 505 team gratefully acknowledge conducted exclusively in the United States, thus not the input of study participants, site staff, investigators, raising further complexities about different standards Community Advisory Board Members, community stake- of care in limited-resource settings and countries and holders, and advocates who participated in the consultations. different regulatory standards and approvals. Future The HVTN 505 team also gratefully acknowledges support trials will likely encounter these knotty ethical chal- from Gilead Sciences for the TruvadaÒ used in the Referral lenges. In the near future, more difficult trial design Program and for the commitment to the development and decisions will emerge as clinical trial teams face an implementation of the Referral Program. array of partially effective biomedical prevention meth- ods. The feasibility and desirability of incorporating Declaration of conflicting interests different prevention interventions into clinical trials will The views expressed in this article are those of the authors have to be explored with attention to stakeholder views and do not necessarily represent the official views of the and interests, scientific soundness of the trial, utility of National Institutes of Health (NIH). the trial for decision-making, local standards of care, and ethical acceptability. In the most difficult cases, Funding participant benefit conflicts directly with scientific goals of the study. No specific funding was provided for the preparation of this article. The HVTN 505 clinical trial was supported by grants Our analysis should be helpful for these future sce- from the National Institute of Allergy and Infectious Diseases narios in that we have identified key domains for dis- of the NIH (UM1AI68614, UM1AI068618, UM1AI68635, cussion and debate. At a minimum, scientific integrity UM1AI069496, UM1AI69452, UM1AI069412, UM1AI0 must be protected for a trial to go forward, and stake- 69470, UM1AI069481, UM1AI069439, UM1AI069534, UM1 holder consultation should identify key areas of consen- AI069511, UM1AI069554, UM1AI069418, UM1Al069532, sus or disagreement in considering different elements of UM1AI069424, UM1AI069501, and UM1AI036219 and

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 Dawson et al. 401 contract HHSN272200800014C), Columbia University’s 10. Ramjee G, Coumi N, Dladla-Qwabe N, et al. Experiences Clinical and Translational Science Award from the National in conducting multiple community-based HIV prevention Center for Advancing Translational Sciences, NIH trials among women in KwaZulu-Natal, South Africa. (UL1TR000040), the NIH Intramural Research Program, AIDS Res Ther 2010; 7: 10. Emory Center for AIDS Research (P30AI50409), the 11. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy Harvard Center for AIDS Research (P30AI06354), the assessment of a cell-mediated immunity HIV-1 vaccine Baylor–University of Texas Center for AIDS (the Step Study): a double-blind, randomised, placebo- Research (UM1AI036211), the Colorado Clinical controlled, test-of-concept trial. Lancet 2008; 372: Translational Science Institute (TR00 0154), and the National 1881–1893. Center for Advancing Translational Science, NIH 12. Gray GE, Allen M, Moodie Z, et al. Safety and efficacy (UL1TR000451). of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, rando- mised, placebo-controlled test-of-concept phase 2b study. Note Lancet Infect Dis 2011; 11: 507–515. * Full title of HVTN 505: Phase 2b, randomized, placebo- 13. National Bioethics Advisory Commission (NBAC). Ethi- controlled test-of concept trial to evaluate the safety and effi- cal and policy issues in international research: clinical trials cacy of a multiclade HIV-1 DNA plasmid vaccine followed in developing countries. Rockville, MD: NBAC, 2001. by a multiclade HIV-1 recombinant adenoviral vector vac- 14. Stobie M and Slack C. Treatment needs in HIV preven- cine in HIV-uninfected, adenovirus type 5 neutralizing anti- tion trials: using beneficence to clarify sponsor-investigator body negative, circumcised men and male-to-female (MTF) responsibilities. Dev World Bioeth 2010; 10: 150–157. transgender persons, who have sex with men. The study was 15. Lie RK, Emanuel EJ and Grady C. Circumcision and reviewed by appropriate Institutional Review Boards (IRBs) HIV prevention research: an ethical analysis. Lancet at participating institutions and informed consent was 2006; 368: 522–525. obtained from all trial participants. 16. Philpott S, Heise L, McGrory E, et al. The challenge of defining standards of prevention in HIV prevention trials. J Med Ethics 2011; 37: 244–248. References 17. Mayer KH, Mimiaga MJ, Cohen D, et al. Tenofovir DF 1. Grant RM, Lama JR, Anderson PL, et al. Preexposure plus lamivudine or emtricitabine for nonoccupational chemoprophylaxis for HIV prevention in men who have postexposure prophylaxis (NPEP) in a commu- sex with men. NEnglJMed2010; 363: 2587–2599. nity health center. J Acquir Immune Defic Syndr 2008; 47: 2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of 494–499. HIV-1 infection with early antiretroviral therapy. N Engl 18. Pinkerton SD, Martin JN, Roland ME, et al. Cost-effec- J Med 2011; 365: 493–505. tiveness of postexposure prophylaxis after sexual or 3. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. injection-drug exposure to human immunodeficiency Vaccination with Alvac and Aidsvax to prevent HIV-1 virus. Arch Intern Med 2004; 164: 46–54. infection in Thailand. N Engl J Med 2009; 361: 19. Laporte A, Jourdan N, Bouvet E, et al. Post-exposure 2209–2220. prophylaxis after non-occupational HIV exposure: 4. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. impact of recommendations on physicians’ experiences Effectiveness and safety of tenofovir gel, an antiretroviral and attitudes. AIDS 2002; 16: 397–405. microbicide, for the prevention of HIV infection in 20. Scheid DC, Hamm RM and Stevens KW. Cost effective- women. Science 2010; 329: 1168–1174. ness of human immunodeficiency virus postexposure pro- 5. Global Campaign for Microbicides. Rethinking the ethical phylaxis for healthcare workers. Pharmacoeconomics roadmap for clinical testing of microbicides: report on an 2000; 18: 355–368. international consultation. Washington, DC: Global Cam- 21. Beymer MR, Bolan RK, Flynn RP, et al. Uptake and paign for Microbicides, 2005. repeat use of postexposure prophylaxis in a community- 6. The Joint United Nations Programme on HIV/AIDS based clinic in , California. AIDS Res Hum (UNAIDS) and World Health Organization (WHO). Retroviruses 2014; 30: 848–855. Ethical considerations in biomedical HIV prevention trials. 22. Landovitz RJ, Combs KB and Currier JS. Availability of Geneva: UNAIDS, 2012. HIV postexposure prophylaxis services in Los Angeles 7. Chesney MA, Chambers DB and Kahn JO. Risk beha- County. Clin Infect Dis 2009; 48: 1624–1627. vior for HIV infection in participants in preventive HIV 23. World Medical Association (WMA). Declaration of Hel- vaccine trials: a cautionary note. J Acquir Immune Defic sinki: ethical principles for medical research Involving Syndr Hum Retrovirol 1997; 16: 266–271. human subjects. Ferney-Voltaire: WMA, 2013. 8. Ndebele PM, Wassenaar D, Munalula E, et al. Improv- 24. Council for International Organizations of Medical ing understanding of clinical trial procedures among low Sciences (CIOMS). International ethical guidelines for bio- literacy populations: an intervention within a microbicide medical research involving human subjects. Geneva: trial in Malawi. BMC Med Ethics 2012; 13: 29. CIOMS, 2002. 9. Thapinta D, Jenkins RA, Celentano DD, et al. Evalua- 25. UNAIDS and AVAC. Good participatory practice: guide- tion of behavioral and social issues among Thai HIV vac- lines for biomedical HIV prevention trials. Geneva: cine trial volunteers. J Acquir Immune Defic Syndr Hum UNAIDS, 2011. Retrovirol 1999; 20: 308–314. 26. NCT00865566, www.clinicaltrials.gov

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015 402 Clinical Trials 12(4)

27. Hammer SM, Sobieszczyk ME, Janes H, et al. Efficacy high risk of HIV: recommendations for use in the context trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J of demonstration projects. Geneva: WHO Press, 2012. Med 2013; 369: 2083–2092. 32. Broder GB, Maynard JP, Karuna ST, et al. Implement- 28. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral ing good participatory practice (GPP) in HVTN 505-the prophylaxis for HIV prevention in heterosexual men and HIV Vaccine Trials Network (HVTN) experience. AIDS women. N Engl J Med 2012; 367: 399–410. Res Hum Retroviruses 2014; 30: A105–A106. 29. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antire- 33. Fuchs JD, Sobieszczyk ME, Madenwald T, et al. Inten- troviral preexposure prophylaxis for heterosexual HIV trans- tions to use preexposure prophylaxis among current missioninBotswana.NEnglJMed2012; 367: 423–434. phase 2B preventive HIV-1 vaccine efficacy trial partici- 30. Centers for Disease Control and Prevention (CDC). Pre- pants. J Acquir Immune Defic Syndr 2013; 63: 259–262. exposure prophylaxis for the prevention of HIV infection 34. Emanuel EJ. Undue inducement: nonsense on stilts? Am in the United States: a clinical practice guideline. , J Bioeth 2005; 5: 9–13. GA: CDC, 2014. 35. Janes H, Gilbert P, Buchbinder S, et al. In pursuit of an 31. World Health Organization (WHO). Guidance on oral HIV vaccine: designing efficacy trials in the context of pre-exposure prophylaxis (PrEP) for serodiscordant cou- partially effective nonvaccine prevention modalities. ples, men and transgender women who have sex with men at AIDS Res Hum Retroviruses 2013; 29: 1513–1523.

Downloaded from ctj.sagepub.com at Fred Hutchinson Cancer Research Center - Arnold Library on August 27, 2015