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  • Review Article
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Creative trial design in RA: optimizing patient outcomes

Nature Reviews Rheumatology volume 9, pages 183–194 (2013)Cite this article

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Abstract

The rheumatology community has witnessed remarkable advances in the management of rheumatoid arthritis (RA) made possible by the development of highly effective biologic DMARDs. Robust randomized controlled trials of clinical efficacy, equipped with validated outcome measures, ensured these therapies could enter the clinical arena and thus substantially improve patient outcomes. Current management principles, which follow a 'treat-to-target' paradigm, advocate tight control of disease activity with the aim of achieving clinical remission. However, efficacy trials are not yet aligned with this approach, hampering patient recruitment. This impediment and the usual approach of inclusion of previously failed treatment arms (to protect methodological concerns) is prompting reappraisal of RA trial design and the consideration of more pragmatic studies that reflect real-life practice. In addition, the aspirations of the rheumatology community to strive for personalized medicine means innovative approaches to trial design are needed to complement the efficacy trial. This Review appraises the current trial landscape and provides insights and key concepts from other fields such as oncology as to the potential utility (as well as the limitations) of pragmatic trial designs such as adaptive trials and biomarker-driven trials.

Key Points

  • Clinical efficacy trials have been instrumental in ensuring successful drug development and the introduction of many biologic DMARDs since the 1990s

  • The evidence base for and the success of the current management principles of treat-to-target is forcing consideration of more pragmatic trials to reflect real-life practice

  • Unanswered questions remain about the optimal use of both biologic and nonbiologic DMARDs, as well as how to achieve personalized medicine, which could be answered using novel pragmatic trial designs

  • Adaptive trials (including biomarker-driven trials) offer the opportunity of realising more targeted management in exploratory, early phase (I and II) trials and in phase III (confirmatory) pragmatic trials

  • Methodological and statistical challenges, including the risk of type I errors, means caution is needed in the conduct of adaptive trial designs

  • The rheumatology community needs to focus on putting itself in a position to deliver alternatives to the 'classic' efficacy trial design

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Figure 1: Current approach to the management of RA: treat-to-target.
Figure 2: Implications of the treat-to-target approach for RA trial design.
Figure 3: Broad comparison of efficacy and pragmatic trial designs for the three main treatment populations in RA.
Figure 4: Flow diagram of biomarker-driven enrichment and stratification trial designs.
Figure 5: Possible scenarios and designs for future RA studies.

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Acknowledgements

The authors are grateful to J. Wright for undertaking the literature search that informed this Review. The work of M. H. Buch is funded by a National Institute of Health Research Clinician Scientist Award.

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Authors and Affiliations

  1. Division of Rheumatic & Musculoskeletal Disease, NIHR Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK

    Maya H. Buch & Paul Emery

  2. Leeds Institute of Health Sciences, Charles Thackrah Building, University of Leeds, 101 Clarendon Road, Leeds, LS2 9LJ, UK

    Sue Pavitt

  3. MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK

    Mahesh Parmar

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M. H. Buch and S. Pavitt researched data for the article, M. H. Buch, S. Pavitt and P. Emery provided substantial contributions to discussions of content, M. H. Buch and S. Pavitt wrote the article with contribution from M. Parmar, and all authors reviewed/edited the manuscript before submission.

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Correspondence to Maya H. Buch.

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Competing interests

M. H. Buch has acted as a consultant and speaker for Abbott, Bristol-Myers Squibb, Pfizer and Roche-Chugai. P. Emery has acted as a consultant and speaker for Abbott, Bristol-Myers Squibb, Merck Sharpe Dohme, Pfizer, Roche-Chugai and UCB. S. Pavitt and M. Parmar declare no competing interests.

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Buch, M., Pavitt, S., Parmar, M. et al. Creative trial design in RA: optimizing patient outcomes. Nat Rev Rheumatol 9, 183–194 (2013). https://doi.org/10.1038/nrrheum.2013.5

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