How to define responders in osteoarthritis

Abstract

Background:

Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures.

Scope:

Regulatory agencies require relevant clinical benefit on symptoms and structure modification for registration of a new therapy as a disease-modifying osteoarthritis drug (DMOAD). An international Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and International Osteoporosis Foundation was convened to explore the current burden of osteoarthritis, review current regulatory guidelines for the conduct of clinical trials, and examine the concept of responder analyses for improving drug evaluation in osteoarthritis.

Findings:

The ESCEO considers that the major challenges in DMOAD development are the absence of a precise definition of the disease, particularly in the early stages, and the lack of consensus on how to detect structural changes and link them to clinically meaningful endpoints. Responder criteria should help identify progression of disease and be clinically meaningful. The ideal criterion should be sensitive to change over time and should predict disease progression and outcomes such as joint replacement.

Conclusion:

The ESCEO considers that, for knee osteoarthritis, clinical trial data indicate that radiographic joint space narrowing >0.5 mm over 2 or 3 years might be a reliable surrogate measure for total joint replacement. On-going research using techniques such as magnetic resonance imaging and biochemical markers may allow the identification of these patients earlier in the disease process.

Keywords::

• Magnetic resonance imaging
• Osteoarthritis
• Pain
• Responder
• Structure-modifying drug
• X-ray

Transparency

Declaration of funding

This study was not funded.

Declaration of financial/other relationships

C.C. has disclosed receiving consulting fees and paid advisory boards for Alliance for Better Bone Health, Glaxo Smith Kline, Roche, Merck Sharp and Dohme, Lilly, Amgen, Wyeth, Novartis, Servier, and Nycomed. R.R. has disclosed receiving fees for advisory boards or lectures for Merck Sharp and Dohme, Eli Lilly, Amgen, Novartis, Servier, Nycomed, Nestlé, and Danone. J.A.K. has disclosed receiving consulting fees, paid advisory boards, lecture fees, and/or grant support from the majority of companies concerned with skeletal metabolism. J.D.A. has disclosed receiving consulting and/or speaker fees for Amgen, Eli Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi Aventis, and Warner Chilcott, as well as research funding (clinical trials) from Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi Aventis, and Warner Chilcott. T.B. has disclosed receiving consulting and/or speaker fees and paid advisory boards for Novartis, Ipsen, Menarini, Takeda, Ardea Bioscience, Savient, Biocryst, Mayoli-Spindler, Roche, and Pfizer. F.B. has disclosed receiving grants for research from Pierre Fabre, Expanscience; Speakers fees and paid advisory boards: Merck Sharp & Dohme, Novartis, Pfizer, Rottapharm, Servier, AstraZeneca, TransPharma, Sanofi Aventis, Genevrier, TRB Chemedica, Nicox, BioIberica, and UCB. B.F., H.J., S.R., and F.P. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. W.F.L. has disclosed receiving speakers fees and paid advisory boards from Pfizer, Servier, Merck, Amgen, Novartis, Will Pharma, Procter & Gamble, Abbott, Roche, and Lilly. J.-P.P. is owner of ArthroLab Inc., and discloses receiving consulting fees from AstraZeneca, Bioibérica, Boehringer Ingelheim, Elanco, Ferring, Merck, Pfizer, Rottapharm, Servier, TRB Chemedica, and Virbac. J.M.-P. is owner of ArthroLab Inc. and discloses receiving consulting fees from AstraZeneca, Bioibérica, Boehringer Ingelheim, Elanco, Ferring, Merck, Pfizer, Rottapharm, Servier, TRB Chemedica, and Virbac. J.-Y.R. has disclosed receiving consulting fees, paid advisory boards, lecture fees, and/or grant support from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB, Merck Sharp and Dohme, Rottapharm, IBSA, Genevrier, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Novo-Nordisk, and Bristol Myers Squibb. O.B. has disclosed receiving grants for research from GlaxoSmithKline, IBSA, Merck Sharp & Dohme, Theramex, Novartis, Pfizer, Rottapharm, Servier; consulting or lecture fees from IBSA, Rottapharm, Servier; and reimbursement for attending meetings: IBSA, Merck Sharp & Dohme, Novartis, Pfizer, Rottapharm, Theramex, Servier.

CMRO Peer Reviewers on this manuscript have received honoraria for their review work, but have no other relevant financial relationships to disclose.

Acknowledgements

This paper was derived from an international Working Group meeting on 22 September 2011 supported by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). We would like to thank W. Dere and B. Mitlak for their valuable input to this paper.