Clinical Trial Design for HIV Prevention Research: Determining Standards of Prevention

Abstract

This paper seeks to advance ethical dialogue on choosing standards of prevention in clinical trials testing improved biomedical prevention methods for HIV. The stakes in this area of research are high, given the continued high rates of infection in many countries and the budget limitations that have constrained efforts to expand treatment for all who are currently HIV-infected. New prevention methods are still needed; at the same time, some existing prevention and treatment interventions have been proven effective but are not yet widely available in the countries where they most urgently needed. The ethical tensions in this field of clinical research are well known and have been the subject of extensive debate. There is no single clinical trial design that can optimize all the ethically important goals and commitments involved in research. Several recent papers have described the current ethical difficulties in designing HIV prevention trials, especially in resource limited settings; however, there is no consensus on how to handle clinical trial design decisions, and existing international ethical guidelines offer conflicting advice. This paper acknowledges these deep ethical dilemmas and moves beyond a simple descriptive approach, to advance an organized method for considering what clinical trial designs will be ethically acceptable for HIV prevention trials, balancing the relevant criteria and providing justification for specific design decisions.

“We Need to Deploy Them Very Thoughtfully and Carefully”: Perceptions of Analytical Treatment Interruptions in HIV Cure Research in the United States—A Qualitative Inquiry

“…16,48 Biomedical scientists should also pay attention to participant's motivations for enrolling in ATI studies, 73 use the word ''cure'' cautiously, if at all, 74 and demonstrate attention to and specificity in risk descriptions. 63 Other underexplored topics in our study were the interplay between standards of care, 17,61 and prevention standards 75 in the context of ATIs, particularly given that one of the most prevalent concerns expressed by respondents around ATIs was the risk of transmitting HIV to others. Secondary HIV transmission events have been known to occur in the context of therapeutic HIV vaccine trials involving ATIs.…”

Ethical considerations regarding oral preexposure prophylaxis in HIV prevention trials

“…[15] While this framework outlines some necessary considerations for determining whether OPTF should be included in a trial, based on the observations above it is arguably insufficient. At minimum, this framework will need to be supplemented by 1) concern for the autonomous preferences of individuals regarding the acceptability of particular methods of prevention; 2) procedural justice to capture fair processes for decision making [16]; and 3) social justice [17].…”

Taking stock of the present and looking ahead: envisioning challenges in the design of future HIV prevention efficacy trials

“…13 While many ethicists have reflected on these guidelines and highlighted differences between them, no clear consensus has been reached, reflecting underlying tensions between obligations to study participants and the necessity to conduct research to discover more effective and user-friendly HIV prevention tools. 10,11,[14][15][16][17][18] Some have called for the development of processes around determining the standard of prevention, 14,16 recognizing the difficulties of achieving sufficient stakeholder education and input into this decision for individual trials in development. 10,16,19 One point of consensus that has emerged is that ongoing and future trials are ethically compelled to include the provision of oral PrEP in the standard prevention package, unless justified by trial investigators on ethical and scientific grounds.…”

“…24,25 and general medical ethical guidance documents 26,27 as well as HIV-specific guidance from UNAIDS 12 address the issue, although there continues to be lack of consensus within the HIV prevention field around criteria for the choice of placebo vs. active control. 10,11,[13][14][15] Some ethical guidance hinges on an imprecise concept of "similarity" of the experimental intervention relative to a proven intervention 10,18 If a new intervention is "similar" or in the same prevention "class" as a proven intervention, it is generally agreed that ethics would mandate comparing the new intervention to the existing intervention, i.e. to use an active control.…”