Journal of the Formosan Medical Association
Volume 107, Issue 12, Supplement , Pages S14-S18, December 2008

Considerations in Adapting Clinical Trial Design

  • H.M. James Hung

      Affiliations

    • Corresponding Author InformationCorrespondence to: Dr H.M. James Hung, Division of Biometrics I, OB/OTS, CDER, US FDA, 10903 New Hampshire Avenue, WO21, Room 4616, Silver Spring, MD 20994-0002, USA

Division of Biometrics I, Office of Biostatistics and Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Maryland, USA

Received 20 August 2008; received in revised form 9 September 2008; accepted 22 September 2008.

Article Outline

The concept of adaptation of trial design during the course of a clinical trial has recently drawn much interest from the pharmaceutical industry. The interest arises partly because statistical decision trees employed to address multiple complex clinical hypotheses within a clinical trial are increasingly complex, and the statistical information generated from learning data prior to designing the trial is often insufficient to provide informative guidance for planning a pivotal trial. While the conventional fixed designs, which usually permit no modification influenced by the internal trial data of key design specifications, often cannot cover the range of complex statistical decision trees that must be prespecified in the study protocol, it seems natural to consider modifications of trial design at some point in the trial. In regulatory practice, some adjustments to study protocols are mostly made known to regulatory agencies in the form of so-called protocol amendments. However, such design modifications may demand careful consideration in dealing with any biases that may be caused by the adaptation, and may impede the interpretability of trial results.

Key Words:  adaptive design , alpha spending , fixed design , group sequential design , logistics , trial conduct

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References 

  1. Bauer P , Köhne K . Evaluations of experiments with adaptive interim analyses . Biometrics . 1994;50:1029–1041
  2. Hung HMJ , O'Neill R , Wang SJ , Lawrence J . A regulatory view on adaptive/flexible clinical trial design (with rejoinder) . Biomet J . 2006;48:565–573 613–5.
  3. Chow SC , Chang M . Adaptive Design Methods in Clinical Trials . New York: Chapman & Hall; 2006;
  4. Bauer P , König F . The reassessment of trial perspectives from interim data–a critical view . Stat Med . 2006;25:23–36
  5. The CAPRICORN Investigators  . Effect of carvedilol on outcome after myocardial infarction in patients with leftventricular dysfunction: the CAPRICORN randomized trial . Lancet . 2001;357:1385–1390
  6. Pocock SJ . Group sequential methods in the design and analysis of clinical trials . Biometrika . 1977;64:191–199
  7. O'Brien PC , Fleming TR . A multiple testing procedure for clinical trials . Biometrics . 1979;35:549–556
  8. Lan KKG , DeMets DL . Discrete sequential boundaries for clinical trials . Biometrika . 1983;70:659–663
  9. Hung HMJ , Wang SJ , O'Neill R . Statistical considerations for testing multiple endpoints in group sequential or adaptive clinical trials . J Biopharm Stat . 2007;17:1201–1210

PII: S0929-6646(09)60004-8

doi:10.1016/S0929-6646(09)60004-8

Journal of the Formosan Medical Association
Volume 107, Issue 12, Supplement , Pages S14-S18, December 2008

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