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Accessible Unlicensed Requires Authentication Published by De Gruyter July 18, 2019

Designing & Conducting Trials to Reliably Evaluate HIV Prevention Interventions

Thomas R. Fleming, Victor DeGruttola and Deborah Donnell

Abstract

While much has been achieved, much remains to be accomplished in the science of preventing the spread of HIV infection. Clinical trials that are properly designed, conducted and analyzed are of integral importance in the pursuit of reliable insights about HIV prevention. As we build on previous scientific breakthroughs, there will be an increasing need for clinical trials to be designed to efficiently achieve insights without compromising their reliability and generalizability. Key design features should continue to include: (1) the use of randomization and evidence-based controls, (2) specifying the use of intention-to-treat analyses to preserve the integrity of randomization and to increase interpretability of results, (3) obtaining direct assessments of effects on clinical endpoints such as the risk of HIV infection, (4) using either superiority designs or non-inferiority designs with rigorous non-inferiority margins, and (5) enhancing generalizability through the choice of a relative risk rather than risk difference metric. When interventions have complementary and potentially synergistic effects, factorial designs should be considered to increase efficiency as well as to obtain clinically important insights about interaction and the contribution of component interventions to the efficacy and safety of combination regimens. Key trial conduct issues include timely enrollment of participants at high HIV risk recruited from populations with high viral burden, obtaining ‘best real-world achievable’ levels of adherence to the interventions being assessed and ensuring high levels of retention. High quality of trial conduct occurs through active rather than passive monitoring, using pre-specified targeted levels of performance with defined methods to achieve those targets. During trial conduct, active monitoring of the performance standards not only holds the trial leaders accountable but also can assist in the development and implementation of creative alternative approaches to increase the quality of trial conduct. Designing, conducting and analyzing HIV prevention trials with the quality needed to obtain reliable insights is an ethical as well as scientific imperative.

Acknowledgements

The authors are appreciative of the outstanding leadership by Holly Janes in organizing and chairing the symposium, ‘HIV Prevention Efficacy Trial Designs of the Future’ held in Seattle in November 2018, that provided substantive inspiration regarding the future of HIV prevention research. This research was partially supported by funding provided by a National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant titled ‘‘Statistical Issues in AIDS Research’’ (R37 AI 29168), and by a National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant titled ‘‘Methods to advance the HIV Prevention Research Agenda’’ (R37 51164).

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Received: 2019-02-20
Revised: 2019-05-22
Accepted: 2019-05-29
Published Online: 2019-07-18

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