title: Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency.
abstract: BACKGROUND
  Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures.
  
  
  METHODS
  We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the proposed design and its context in the drug development program, as well as the responses of the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAWP), were extracted and categorized. For 41 more recent procedures (1 January 2009 to 8 May 2012), additional details of the trial design and the CHMP/SAWP responses were assessed. In addition, case studies are presented as examples.
  
  
  RESULTS
  Over a range of 5½ years, 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials. Almost all were proposed as confirmatory phase III or phase II/III studies. The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment. While 12 (20%) of the 59 proposals for an adaptive clinical trial were not accepted, the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%). In the more recent 41 procedures, the most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias.
  
  
  CONCLUSIONS
  For the majority of proposed adaptive clinical trials, an overall positive opinion was given albeit with critical comments. Type I error rate control, bias and the justification of the design are common issues raised by the CHMP/SAWP.
authors.forename: Amelie
authors.initials: A
authors.lastname: Elsäßer
authors.forename: Jan
authors.initials: J
authors.lastname: Regnstrom
authors.forename: Thorsten
authors.initials: T
authors.lastname: Vetter
authors.forename: Franz
authors.initials: F
authors.lastname: Koenig
authors.forename: Robert James
authors.initials: RJ
authors.lastname: Hemmings
authors.forename: Martina
authors.initials: M
authors.lastname: Greco
authors.forename: Marisa
authors.initials: M
authors.lastname: Papaluca-Amati
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria. Martin.Posch@meduniwien.ac.at.
authors.forename: Martin
authors.initials: M
authors.lastname: Posch
mesh_terms: D026683:Advisory Committees / Q000592:standards; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000592:standards; D017326:Clinical Trials, Phase III as Topic / Q000379:methods* / Q000592:standards; D015709:Correspondence as Topic; D005060:Europe; D006801:Humans; D008389:Marketing of Health Services; D017410:Practice Guidelines as Topic; D012107:Research Design / Q000592:standards; D018401:Sample Size