The time has come to limit the placebo period in rheumatoid arthritis trials to 3 months: A systematic comparison of 3- and 6-month response rates in trials of biologic agents.

Maarten Boers ^1*

¹ VUmc, Netherlands

^* To whom correspondence should be addressed. E-mail: m.boers{at}vumc.nl.

Accepted 3 September 2009

Abstract

Background: Most registration trials in rheumatoid arthritis (RA) include a placebo arm in the setting of an incomplete response to disease-modifying antirheumatic treatment (DMARD-IR). A minimum duration of 6 months is required despite serious methodological and ethical shortcomings.

Purpose: To study whether a 3-month placebo period is sufficient to prove efficacy.

Methods: Meta-analysis of placebo- or active control trials of biologic agents in DMARD-IR RA, comparing the contrast in ACR response between experimental and control groups at 3 and 6 months.

Results: Twenty trials yielded 15 placebo and 18 active control contrasts (> 10.000 patients). At 3 months active treatment showed a highly significant contrast with placebo for ACR20 and -50 in every instance. As all groups improved further the mean contrast at 6 months was unchanged. For ACR70 the contrast was clearly greater at 6 months due to further improvement only in the experimental groups. In active control trials contrasts were smaller, and for ACR50 and-70 these decreased somewhat due to 'catch-up' responses in the control groups.

Conclusion: The placebo phase of registration trials for RA can be limited to 3 months. An accompanying viewpoint proposes to then switch placebo patients to standard of care, allowing a more valid and comprehensive assessment including safety.