(CHMP)临床试验设计非劣效界值选择

STATISTICS IN MEDICINE

Statist.Med.2006;25:1628–1638

Published online in Wiley InterScience().DOI:10.1002/sim.2584

London,27July2005

Doc.Ref.EMEA/CHMP/EWP/5872/03Corr Committee for Medicinal Products for Human Use(CHMP) Guideline on the Choice of the Non-Inferiority Margin Draft Agreed by the E cacy Working Party December1999–January2004 Adoption by Committee for Release for Consultation February2004

End of Consultation(Deadline for Comments)May2004

Agreed by Working Party June2004

Adoption by Committee July2005

Date for Coming into E ect January2006

INTRODUCTION

Many clinical trials comparing a test product with an active comparator are designed as non-inferiority trials.The term‘non-inferiority’is now well established,but if taken literally could be misleading.The objective of a non-inferiority trial is sometimes stated as being to demonstrate that the test product is not inferior to the comparator.However,only a superiority trial can demonstrate this.In fact a non-inferiority trial aims to demonstrate that the test product is not worse than the comparator by more than a pre-speciÿed,small amount.This amount is known as the non-inferiority margin,or delta( ).

There are many situations where a non-inferiority trial might be performed as opposed to, or in addition to,a superiority trial over placebo.These include:

•Applications based upon essential similarity in areas where bioequivalence studies are not possible,e.g.modiÿed release products or topical preparations;

•Products with a potential safety advantage over the standard might require an e cacy comparison to the standard to allow a risk-beneÿt assessment to be made;

•Cases where a direct comparison against the active comparator is needed to help assess risk-beneÿt;

•Cases where no important loss of e cacy compared to the active comparator would be acceptable;

•Disease areas where the use of a placebo arm is not possible and an active control trial is used to demonstrate the e cacy of the test product.

In theÿnal4situations above a non-inferiority trial would not be necessary if superiority could be shown over the reference product.

In order to demonstrate non-inferiority,the recommended approach is to pre-specify a mar-gin of non-inferiority in the protocol.After study completion,a two-sided95%conÿdence ?EMEA2005

Reproduction and/or distribution of this document is authorised for Received16March2006 non commercial purposes only provided the EMEA is acknowledged Accepted16March2006