title: An adaptive design to bridge the gap between Phase 2b/3 microbicide effectiveness trials and evidence required for licensure.
abstract: BACKGROUND
  Vaginally and rectally applied microbicides are being developed to help prevent sexual acquisition of HIV. Due to the lack of surrogate outcomes, the path toward licensure typically moves directly from expanded safety studies to expensive Phase 2b/3 trials with rare incident infection outcomes. The need to confirm an initial trial's significant finding can lead to serious delays in implementing essential programs to reduce the spread of HIV.
  
  
  OBJECTIVE
  To propose an adaptive design where a Phase 2b/3 study powered to detect a clinically meaningful effect with evidence of one trial (observing one-sided p < 0.025) is allowed to expand by a prespecified, feasible amount if interim data suggest the chance of further achieving a more robust evidence threshold (p < 0.001, potentially sufficient for licensure from a single trial) is promising.
  
  
  METHODS
  As an example, prespecified conditional power criteria are used to determine whether a 90-event trial with 90% power to detect a 50% reduction in risk should be expanded to 130 events. Asymptotic results and simulations are used to assess false-positive error rates and other operating characteristics of the design.
  
  
  RESULTS
  False-positive error rates can be controlled at the desired 0.025 and 0.001 levels with appropriate choice of critical values or expansion criteria. The chance of achieving robust evidence can approach that of a 130-event trial with traditional stopping boundaries (controlling a = 0.001) but with substantially lower expected size for plausible effectiveness levels.
  
  
  CONCLUSIONS
  Conditional power calculations assume the interim estimate of effect is an unbiased estimate for the remainder of the trial, an assumption which may not hold if product adherence varies over time. Observing a measure of effect with p < 0.001 may not be sufficient for licensure. A decision to expand the trial would be informative to investigators regarding the interim effect size.
  
  
  CONCLUSIONS
  A moderate increase in trial size can make the difference between a study with good power to detect a clinically meaningful effect and one which may reasonably obtain the robust evidence required for regulatory bodies and public health programs to consider making a new microbicide available to persons at risk of HIV infection. The proposed design allows for this possibility while not requiring investigators to make an up-front commitment to a prohibitively large trial.
authors.affiliation: Family Health International (FHI 360), Durham, NC 27713, USA. dtaylor@fhi360.org
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Taylor
authors.forename: Anneke
authors.initials: A
authors.lastname: Grobler
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
mesh_terms: D000891:Anti-Infective Agents, Local / Q000627:therapeutic use*; D015982:Bias; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003627:Data Interpretation, Statistical; D017277:Drug Approval; D005189:False Positive Reactions; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D008004:Licensure; D012107:Research Design; D018401:Sample Size; D016896:Treatment Outcome
chemical_list: D000891:Anti-Infective Agents, Local