Study design approaches for future active-controlled HIV prevention trials

Author:

Donnell Deborah12ORCID,Kansiime Sheila34,Glidden David V.5,Luedtke Alex2,Gilbert Peter B.12,Gao Fei12,Janes Holly12

Affiliation:

1. Fred Hutchinson Cancer Center , Seattle , WA , USA

2. University of Washington , Seattle , WA , USA

3. Medical Research Council/Uganda Virus Research Council and London School of Hygiene and Tropical Medicine , Uganda Research Unit , Entebbe , Uganda

4. Medical Research Council International Statistics and Epidemiology Group , London School of Hygiene and Tropical Medicine , London , UK

5. University of California San Francisco , San Francisco , CA , USA

Abstract

Abstract Objectives Vigorous discussions are ongoing about future efficacy trial designs of candidate human immunodeficiency virus (HIV) prevention interventions. The study design challenges of HIV prevention interventions are considerable given rapid evolution of the prevention landscape and evidence of multiple modalities of highly effective products; future trials will likely be ‘active-controlled’, i.e., not include a placebo arm. Thus, novel design approaches are needed to accurately assess new interventions against these highly effective active controls. Methods To discuss active control design challenges and identify solutions, an initial virtual workshop series was hosted and supported by the International AIDS Enterprise (October 2020-March 2021). Subsequent symposia discussions continue to advance these efforts. As the non-inferiority design is an important conceptual reference design for guiding active control trials, we adopt several of its principles in our proposed design approaches. Results We discuss six potential study design approaches for formally evaluating absolute prevention efficacy given data from an active-controlled HIV prevention trial including using data from: 1) a registrational cohort, 2) recency assays, 3) an external trial placebo arm, 4) a biomarker of HIV incidence/exposure, 5) an anti-retroviral drug concentration as a mediator of prevention efficacy, and 6) immune biomarkers as a mediator of prevention efficacy. Conclusions Our understanding of these proposed novel approaches to future trial designs remains incomplete and there are many future statistical research needs. Yet, each of these approaches, within the context of an active-controlled trial, have the potential to yield reliable evidence of efficacy for future biomedical interventions.

Funder

National Institute of Allergy and Infectious Diseases

The Second European & Developing Countries Clinical Trials Partnership

Publisher

Walter de Gruyter GmbH

Subject

General Earth and Planetary Sciences,General Environmental Science

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