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Designing and conducting active-controlled trials of HIV pre-exposure prophylaxis (PrEP) therapeutics are becoming challenging due to inconsistency of adherence across trials and the need for increasingly larger trials to assess efficacy. In the United States (US), trials evaluating oral contraceptives (OC) use the Pearl Index to assess efficacy in single-arm trials. This article explores the possibility of using an index ("HIV Incidence Index") analogous to the Pearl Index to assess preventive efficacy in active-controlled HIV prevention trials in sexually-acquired HIV. One proposal for constructing an HIV Incidence Index is to use the incidence of sexually transmitted infections (STIs) during a trial to serve as a marker for HIV risk behavior and to estimate what the HIV seroconversion rate would have been had the participants not been on efficacious PrEP. In addition, a consensus of expert opinion will be needed to define clinically acceptable HIV seroconversion rates for populations at risk of HIV-infection receiving active PrEP. [ABSTRACT FROM AUTHOR]

Decreased efficacy of antibiotics due to resistant pathogens has created a need for the development of more effective medical interventions. Despite the increasing prevalence of pathogens resistant to one or more drugs, identifying and enrolling participants into clinical trials that evaluate new interventions for the treatment of some diseases can be challenging given the low prevalence of disease in which there are no effective treatments. Thus researchers might be tempted to consider externally-controlled trials that may allow for a reduction of the necessary number of prospectively-identified trial participants, thus easing recruitment burden and resulting in more timely trial completion relative to randomized controlled trials. We discuss advantages and disadvantages in externally controlled trials and review requirements for a valid externally-controlled trial. As ECTs are subject to the bias of observational studies, the criteria for a valid ECT should be carefully evaluated before these designs are implemented. Given considerable variation in study results in the resistant pathogen setting, the lack of information on important patient characteristics that may confound estimates of treatment effects, as well as the improvements in medical practice and evolving antibiotic resistance, the use of ECTs in the resistant pathogen setting, is not recommended. ECTs should be should be limited to specific situations where superiority of the effect of the new intervention is dramatic, the usual course of the disease highly predictable, the endpoints are objective (e. g., all-cause mortality) and the impact of baseline and treatment variables on outcomes is well characterized. Given that the resistant pathogen setting does not satisfy these criteria, we conclude that that randomized clinical trials are needed to evaluate new treatments for resistant pathogens. Innovative approaches to trial design that may ease recruitment burden while evaluating the benefits and harms of new treatments are being developed and utilized. [ABSTRACT FROM AUTHOR]