title: Study design considerations for evaluating efficacy of systemic preexposure prophylaxis interventions.
abstract: BACKGROUND
  The development of interventions for systemic pre-exposure prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration's approval of emtricitabine/tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention.
  
  
  METHODS
  Possible designs for a PrEP phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules.
  
  
  RESULTS
  Noninferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the 3 PrEP trials demonstrating efficacy of FTC/TDF. However, these HIV endpoint trials may require extremely large number of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on previous placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (ie, women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting.
  
  
  CONCLUSIONS
  Following Food and Drug Administration's approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. deborah@fhcrc.org
authors.forename: Deborah
authors.initials: D
authors.lastname: Donnell
authors.forename: James P
authors.initials: JP
authors.lastname: Hughes
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Ying Q
authors.initials: YQ
authors.lastname: Chen
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Fleming
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004338:Drug Combinations; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D055118:Medication Adherence; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D018401:Sample Size; D000068698:Tenofovir; D016896:Treatment Outcome; D014481:United States
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine