title: Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials.
abstract: BACKGROUND
  Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.
  
  
  OBJECTIVE
  To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual.
  
  
  METHODS
  We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual.
  
  
  RESULTS
  Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001).
  
  
  CONCLUSIONS
  A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging.
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Carlisle
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada jonathan.kimmelman@mcgill.ca.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kimmelman
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Tim
authors.initials: T
authors.lastname: Ramsay
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: MacKinnon
mesh_terms: D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data*; D057239:Early Termination of Clinical Trials / Q000706:statistics & numerical data*; D006805:Human Experimentation / Q000706:statistics & numerical data*; D006801:Humans; D018579:Patient Selection; D012107:Research Design / Q000706:statistics & numerical data; D018570:Risk Assessment; D014481:United States
keywords: Medical ethics; clinical trials; recruitment; research ethics; trial accrual