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  • Review Article
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Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales

Nature Reviews Rheumatology volume 9, pages 665–673 (2013)Cite this article

Subjects

Key Points

  • The market for biologic therapies for rheumatic diseases is large, with sales totalling over $200 billion to date; however, their popularity is not justified by the available evidence

  • The clinical trial evidence relating to biologic agents used to treat rheumatic diseases has several shortcomings that prevent optimal implementation of these agents in clinical practice and complicate regulatory decision making

  • A paucity of head-to-head comparisons, limited follow-up times, variations in outcome definitions and nomenclature, and non-publication of trials and outcomes limit our understanding of biologic agents

  • Most trials are pharmaceutical-industry-sponsored, and have short follow-up periods and small sample sizes, which restrict our interpretation of the clinical relevance of the findings with regard to long-term disease outcomes

  • The lack of long-term randomized trials of biologic agents has limited our understanding of the association of these drugs with adverse events, particularly the risk of malignancies and serious infections

  • Larger study populations, longer follow-up times, better reporting and head-to-head comparisons of biologic agents would increase knowledge of the benefits and risks associated with the different treatments available

Abstract

Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.

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Figure 1: Network of comparisons for RCTs in psoriasis, PsA, and AS.
Figure 2: Published meta-analyses of trials of biologic agents in psoriasis and RA.

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Author information

Authors and Affiliations

  1. Department of Health Research and Policy, Stanford Prevention Research Centre, Stanford University School of Medicine, 1265 Welch Road, Stanford, 94305, CA, USA

    John P. A. Ioannidis, Kristian Thorlund & Edward J. Mills

  2. Division of Rheumatology, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, 45110, Greece

    Fotini B. Karassa

  3. Faculty of Health Sciences, University of Ottawa, 75 Laurier Avenue East, Ottawa, K1N 6N5, ON, Canada

    Eric Druyts

Authors
  1. John P. A. Ioannidis
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  4. Kristian Thorlund
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Contributions

All authors made substantial contributions to all stages of the preparation of this manuscript.

Corresponding author

Correspondence to John P. A. Ioannidis.

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Competing interests

K. Thorlund and E. J. Mills declare that they have acted as consultants for GSK, Merck, Novartis, Nycomed and Pfizer. J. P. A. Ioannidis, F. B. Karassa and E. Druyts declare no competing interests.

Supplementary information

Supplementary Table 1

Eligible randomized controlled trials of anti-TNF agents in immune-mediated diseases (DOC 427 kb)

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Ioannidis, J., Karassa, F., Druyts, E. et al. Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nat Rev Rheumatol 9, 665–673 (2013). https://doi.org/10.1038/nrrheum.2013.134

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