Choice of Control in Clinical Trials—Issues and Implications of ICH-E10


The International Conference on Harmonization guideline entitled “Choice of Control Group in Clinical Trials” (ICH-E10) was a long awaited document. The concept paper gave reason to hope that the guideline would provide clear and harmonized guidance in an area that has been very much disputed, including the burning issue of the role of placebo control. In the main, the final guideline was disappointing in spite of the long preparation time. In many respects it did not succeed in providing harmonized guidance across regions and it is not specific enough on a number of issues, leaving drug development stakeholders uncertain about what needs to be done. Examples of such issues are: 1. The focus on individual studies rather than on a drug’s whole clinical development program; 2. The choice of active control and the noninferiority margin (8) in a noninferiority trial; 3. The interpretation of “assay sensitivity”; 4. The bias in favor of placebo-control; and 5. The failure of proposed alternative designs to resolve the unethical use of placebo.

The guideline does not acknowledge the gradual change of the clinical trial environment, which is making placebo-controlled trials more and more difficult to conduct. This change is driven by the existence of effective treatments in most therapeutic areas in combination with the new version of the Declaration of Helsinki. Sooner or later, efficacy for a new drug will need to be demonstrated using active-controlled noninferiority or superiority studies for most indication areas. In order to meet this inevitable evolution, efforts must be made to further develop the methodology for noninferiority trials, and to ensure that published meta-analyses provide the necessary information to allow the design of high-quality noninferiority studies in the future.

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Correspondence to Bernhard Huitfeldt PhD.

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On Behalf of the European Federation of Statisticians in the Pharmaceutical Industry

The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) is a federation of 10 national organizations of medical statistics in which pharmaceutical statistics is a major area of interest. The following countries are represented in EFSPI: Belgium, Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom. This paper was endorsed by the Council of EFSPI.

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Huitfeldt, B., Danielson, L., Ebbutt, A. et al. Choice of Control in Clinical Trials—Issues and Implications of ICH-E10. Ther Innov Regul Sci 35, 1147–1156 (2001).

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Key Words

  • ICH-E10
  • Control group
  • Placebo-controlled trials
  • Noninferiority trials
  • Clinical trial environment
  • Declaration of Helsinki