[en] Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. Objective: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. Methods: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. Results: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are 'responder' (or 'failure'). The definition of a 'failure' patient would be someone with progression of JSN>0.5 mm over a period of 2-3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. Conclusion: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion. (C) 2004 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Disciplines :
Orthopedics, rehabilitation & sports medicine Rheumatology
Author, co-author :
Abadie, Eric ; Université de Liège - ULiège > Epidémiologie et santé publique
Ethgen, Dominique ; Université de Liège - ULiège > Epidémiologie et santé publique
Avouac, Bernard ; Université de Liège - ULiège > Unité d'exploration du métabolisme osseux
Bouvenot, Gilles
Branco, Jaime
Bruyère, Olivier ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
Calvo, Gisèle ; Centre Hospitalier Universitaire de Liège - CHU > Imagerie médicale
Devogelaer, Jean-Pierre
Dreiser, Renee L
Herrero-Beaumont, Gabriel
Kahan, Andre
Kreutz, Godfried
Laslop, Andrea
Lemmel, Ernst M
Nuki, George
Van de Putte, Leo
Vanhaelst, Luc
Reginster, Jean-Yves ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
Reginster JY. The prevalence and burden of osteoarthritis. Rheumatology 2002;41:3-6.
Prevalence of self-reported arthritis or chronic joint symptoms among adults. MMWR 2002;51:948-950.
Guidance for the industry. Clinical development programs for drugs, devices and biologicals products intended for the treatment of osteoarthritis. US Department of Health and human Services. Food and Drug Administration, Center for Drug Evaluation and Research. July 1999. Available from: Ttp://www.fda. gov/cder/guidance/2199dft.htm
Points to consider on clinical investigation of medicinal products used in the treatment of osteoarthritis. European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products. July 1998. Available from: Http://www. emea.eu.int/pdfs/human/ewp/078497en.pdf
Group for the Respect of Ethics and Excellence in Sciences (GREES). Recommendations for the registration of drugs used in the treatment of osteoarthritis. Ann Rheum Dis 1996;55:552-7.
Peterfy CG. Imaging the disease process. Curr Opin Rheumatol 2002;14:590-6.
Garnero P. Osteoarthritis: Biological markers for the future. Joint Bone Spine 2002;69:525-30.
Reginster JY, Bruyere O, Henrottin Y. New perspectives in the management of ostearthritis structure modification: Facts or fantasy? J Rheumatol 2003;30: 14-20.
Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir MA, Choquette D, et al. and the Diacerein Study Group. Efficacy and safety of diacerein in osteoarthritis of the knee. Arthritis Rheum 2000;43:2339-48.
Dougados M, Nguyen M, Berdah L, Mazieres B, Vignon E, Lequesne M. for the ECHODIAH Investigator Study Group. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis. Arthritis Rheum 2001;4:2539-47.
Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term effect of glucosamine sulfate on osteoarthritis progresion: A randomized placebo-controlled clinical trial. Lancet 2001;27: 251-65.
Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulphate delays progression of knee osteoarthritis: A 3-year, randomized placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113-23.
Richy F, Bruyere O, Ethgen O, Cucherat M, Henrottin Y, Reginster JY. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis. A comprehensive meta-analysis. Arch Intern Med. 2003;163:1514-22.
Brandt KD, Mazucca SA, Conrozier T, Dacre JE, Peterfy CG, Provvedini D, et al. What is the best radiographic protocol for a clinical trial of a structure modifying drug in patients with osteoarthritis. J Rheumatol 2002;29:1308-20.
Mazucca SA, Brandt KD, Buckwalter KA. Detection of radiographic joint space narrowing in subjects with knee ostearthritis. Arthritis Rheum 2003;48:385-90.
Gale DR, Chaisson CE, Totterman SM, Schwartz RK, Gale ME, Felson D. Meniscal subluxation: Association with osteoarthritis and joint space narrowing. Osteoarthritis and Cart 1999;7:526-32.
Conrozier T, Lequesne M, Favret H, Taccoen A, Mazieres B, Dougados M, et al. Measurement of the radiological hip joint space width. An evaluation of various methods of measurement. Osteoarthritis and Cart 2001;9:281-6.
Gordon C, Wu C, Petrefy CG, Li J, Duryea J, Klifa C, Genant HK. Automated measurement of radiographic hip joint space width. Med Phys 2001;28: 267-77.
Biswal S, Hastie T, Andriacchi TP, Bergman GA, Dillingham MF, Lang P. Risk factor for progressive cartilage loss in the knee. Arthritis Rheum 2002; 46:2884-92.
Cicuttini FM, Wluka AE, Forbes A, Wolfe R. Comparison of tibial cartilage volume and radiologic grade of the tibiofemoral joint. Arthritis Rheum 2003;48:682-8.
Pessis E, Drape JL, Ravaud P, Chevrot A, Dougados M, Ayral X. Assessment of progression in knee osteoarthritis: Results of a 1 year study comparing arthroscopy and MRI. Osteoarthritis Cart 2003;11: 361-9.
Raynaud JP, Kauffman C, Beaudoins G, Berthaumie MJ, de Guise JA, Bloch DA, et al. Reliability of quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. Osteoarthritis and Cart 2003;11:351-60.
Gandy SJ, Dieppe PA, Keen MC, Maciewic RA, Watt I, Waterton JC. No loss of cartilage volume over three years in patients with knee osteoarthritis as assessed by MRI. Osteoarthritis and Cart 2002;10:929-37.
Link TM, Steinbach LS, Ghosh P, Ries M, Lu Y, Majumdar S. Osteoarthritis: MRI imaging findings in different stages of disease and correlation with clinical findings. Radiology 2003;226:373-81.
Mosher TJ, Dardzinski BJ, Smith MB. Human articular cartilage: Influence of aging and early symptomatic degeneration on the spatial variation of T2 Radiology 2000;214:259-66.
Liess C, Lussert S, Karger N, Heller M, Gluer CC. Detection of changes in cartilage water content using MRI T2 mapping in vivo. Osteoarthritis and Cart 2002;10:907-13.
Nieminen MT, Rieppo J, Toyras J, Hakumaki M, Silvennoinen J, Hyttinen MM, et al. T2 relaxation reveals spatial collagen architecture in articular cartilage: A comparative quantitative MRI and polarized light microscopic study. Magn Reson Med 2001; 46:487-93.
Bashir A, Gray ML, Harke J, Burstein D. Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI. Magn Reson Med 1999;41: 857-65.
Tiderius CJ, Olson LE, Leander P, Ekberg O, Dahlberg L. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) in early knee osteoarthritis. Magn Reson Med 2003;49:488-92.
Regatte RR, Akella SV, Borthakur R, Reddy R. Proton spin-lock ratio imaging for quantification of glycosaminoglycans in articular cartilage. J Magn Reson Imaging 2003;17:114-21.
Young-Min SA, Cawston TE. Markers of joint destruction: principles, problems and potential. Ann Rheum Dis 2001;60:545-8.
Poole R. Can serum biomarkers assays measure the progression of cartilagedegeneration in osteoarthritis. Arthritis Rheum 2002;46:2549-52.
Garnero P, Ayral X, Rousseau JC, Christgau S, Sandell LJ, Dougados M, et al. Uncoupling type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis. Arthritis Rheum 2002;46:2613-24.
Bruyere O, Collette J, Ethgen O, Rovati LC, Giacovelli G, Henrottin Y, et al. Biochemical markers of bone and cartilage remodeling in prediction of long term progression of knee osteoarthritis, J Rheumatol 2003;30:1043-50.
Pham T, Van Der Heidje D, Lasserre M, Altman RD, Anderson JJ, Bellamy N, et al. Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol 2003;30:1648-54.