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Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency.
- Source :
-
Trials [Trials] 2014 Oct 02; Vol. 15, pp. 383. Date of Electronic Publication: 2014 Oct 02. - Publication Year :
- 2014
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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.<br />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.<br />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.<br />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.
- Subjects :
- Clinical Trials, Phase II as Topic standards
Clinical Trials, Phase III as Topic standards
Europe
Humans
Practice Guidelines as Topic
Sample Size
Advisory Committees standards
Clinical Trials, Phase II as Topic methods
Clinical Trials, Phase III as Topic methods
Correspondence as Topic
Marketing of Health Services
Research Design standards
Subjects
Details
- Language :
- English
- ISSN :
- 1745-6215
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- Trials
- Publication Type :
- Academic Journal
- Accession number :
- 25278265
- Full Text :
- https://doi.org/10.1186/1745-6215-15-383