The changing face of multiple sclerosis clinical trial populations

Abstract

Background:

Since the commercial introduction of disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS), there have been numerous randomized placebo-controlled and head-to-head clinical trials assessing the efficacy and safety of these agents in relapsing–remitting MS (RRMS).

Scope:

Recent trials in the past 10 years demonstrate that the characteristics and behavior of clinical trial populations in RRMS have changed. Here we review evidence from key published clinical trials of DMDs in RRMS that highlights the general shift in trial populations, and examine the implications of this shift for future trial design.

Findings:

Populations in recent studies are characterized by lower clinical disease activity. This difference is apparent with regards to baseline patient characteristics and on-study behavior in terms of outcomes (e.g., relapse rates). The reasons for this shift are probably multifactorial and include study design, current treatment options, patient selection, and a possible change in the natural history of MS.

Conclusions:

The variation among study designs makes it difficult to draw more extensive conclusions about changes in clinical trial populations. However, these recent changes undoubtedly will affect interpretation of recent study results, some of which based clinical and statistical assumptions on earlier trials. Furthermore, the shift in populations has major implications for the design of future studies: (1) assumptions regarding effect size and statistical powering must be based on comparable patient populations; (2) larger trials of longer duration may be needed, possibly with stopping criteria based on the number of actual events rather than a preset, fixed time point for the end of study; (3) the use of biomarkers to facilitate identification of subpopulations may be considered; and (4) enhanced measures of disease activity (e.g., composite outcomes) may help to identify effects in multiple relevant MS outcomes. Furthermore, trial design may need to be modified to study the effects of a medication in patients who are representative of the anticipated patient population. To ensure that the clinical trial experience of a drug is reflected in its eventual clinical use, ‘real-life’ observation study programmers should be conducted to continuously monitor its effects in relevant populations and in comparison with available therapies.

Keywords::

• Clinical trial populations
• Clinical trial outcomes
• Disease activity
• Disease-modifying drug
• Multiple sclerosis
• Relapse rates

Transparency

Declaration of funding

Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, provided financial support for medical writing and editing.

Declaration of financial/other relationships

B.M.J.U. has received honoraria for consultancy from Novartis, Merck Serono, Synthon and Danone Research, and from Ariez Medical Publishing for serving as a journal editor. The MS Center of the VU University Medical Center has received financial support for research activities from Biogen Idec, Bayer Schering Pharma, GlaxoSmithKline, Merck Serono, Novartis, and Teva. F.B. has received compensation for serving as consultant from Bayer Schering Pharma, BioMS, Medicinova, Merck Serono, Novartis, sanofi-aventis, and UCB. P.K.C. has received compensation from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Pfizer, sanofi-aventis, and Teva; and research funding from Bayer Schering Pharma, Merck Serono, Novartis, Pfizer, sanofi-aventis, and Teva. J.D.G. was an employee of Merck Serono S.A. – Geneva, Switzerland, at the time of manuscript writing. D.R.J. has received personal compensation from Bayer, EMD Serono, GlaxoSmithKline, Pfizer, and Teva Neuroscience, as well as research funding from Bayer, Merck Serono, and Teva Neuroscience. D.D.M. is an employee of EMD Serono Inc. but at the time of manuscript development was employed at the University of Michigan Medical Center, Ann Arbor, MI, USA.

Acknowledgments

The authors thank Jane Davies and Matthew Evans of Caudex Medical, Oxford, UK (supported by Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany), for assistance in preparing the initial draft of the manuscript, collating the comments of authors and other named contributors, assembling tables and figures and coordinating submission requirements. The authors also acknowledge Dr Steven R. Schwid (deceased), a friend and colleague who made significant contributions to early discussions on the concepts presented here.

Notes

* Rebif is a registered trade name of Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.

† Betaferon is a registered trade name of Bayer Schering Pharma AG, Berlin, Germany.

‡ Betaseron is a registered trade name of Bayer HealthCare Pharmaceuticals, Montville, NJ, USA.

§ Avonex is a registered trade name of Biogen Idec Inc., Weston, Massachusetts, USA.

¶ Copaxone is a registered trade name of Teva Neuroscience, Petach Tikva, Israel.

# Novantrone is a registered trade name of EMD Serono, Rockland, MA, USA.

** Tysabri is a registered trade name of Elan Pharmaceuticals (Dublin, Ireland)/Biogen Idec Inc. (Weston, MA, USA).

†† Gilenya is a registered trade name of Novartis AG, Stein, Switzerland.

‡‡ Movectro is a registered trade name of Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.