Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis
Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis
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DOI：
10.1016/j.joca.2004.01.006
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发表时间：
2004-04-01
影响因子：
7
通讯作者：
Reginster, JY
中科院分区：
文献类型：
--
作者：
Abadie, E;Ethgen, D;Reginster, JY
背景：药物发现环境中的最新创新产生了新的化学实体，有可能成为骨关节炎(DMOAD)的疾病修饰药物。监管机构承认，这些化合物可以被授予DMOAD适应症，前提是它们可以证明它们可以减缓疾病的进展；进展将由结构变化的替代物来校准，方法是在平片上测量关节间隙狭窄(JSN)，并警告这种延迟的JSN将转化为患者的临床益处。目的：尊重科学伦理和卓越科学组织(GREES)组织了一个工作组，以评估这些新技术是否可以替代普通X光来评估DMOAD。方法：GREES包括学术科学家、监管机构成员和制药行业的代表。在对国际文献进行广泛搜索之后，从1980年到2002年，组织了两次专家会议，以编写供监管当局参考的文件。结果：磁共振成像(MRI)现在被用来测量骨关节炎患者的软骨形态和完整性参数。虽然一些数据令人鼓舞，但MRI观察到的软骨结构的短期变化与长期的放射学或临床变化之间的相关性是必要的。因此，GREES建议MRI可以作为II期研究的结果，但在接受MRI作为III期临床试验的主要终点之前，还需要进一步的数据。正在测试骨和软骨重塑的生化标记物，以预测骨性关节炎和测量疾病进展。最近公布的数据是有希望的，但作为OA疾病进展的替代终点的验证需要更多的研究。GREES建议生化标记物仍然局限于“概念验证”研究，或者作为第二阶段和第三阶段临床试验的次要终点。然而，GREES强调了获取有关生化标记物的额外信息的重要性，以帮助更好地了解将用于OA的药物的作用模式。监管机构认为，临床结果改善的证据对于批准DMOAD至关重要。进行全关节置换术的时间可能是评估DMOAD疗效的最相关的临床终点。然而，目前，由于患者的手术意愿或经济因素等非疾病相关因素的偏差，手术时间不能用于临床试验。在这个阶段，看来DMOAD与安慰剂相比应该有显著的差异。收益应该通过3个共同的主要终点来衡量：关节突触、疼痛和功能。次要终点应包括“应答者”(或“失败”)患者的百分比。根据有效的临界值，失败患者的定义是JSN和GT；0.5 mm在2-3年内进展，或者疼痛和/或功能显著恶化。疼痛和功能的临床相关界点的定义必须基于评估疾病自然病史的数据(来自长期研究的流行病学队列或安慰剂组)。这些临界点应该反映出个体患者以后需要关节置换的高倾向。结论：GREES概述了一套开发骨关节炎DMOAD的指南。虽然这些准则可能会随着新信息的出现而变化，但上述信息是以目前的实地知识为基础，并加入了专家意见。(C)2004年国际骨性关节炎研究会。爱思唯尔有限公司出版。保留所有权利。
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.