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首页> 外文期刊>Osteoarthritis and cartilage >Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.
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Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.

机译：关于使用新方法评估疾病缓解药物治疗骨关节炎疗效的建议。

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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>0.5mm 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.
机译：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's）的疾病改良药物。监管机构承认，可以证明此类化合物可以减慢疾病进程，但可以授予DMOAD适应症。可以通过替代性结构改变来校正进展，方法是在普通X射线片上测量关节间隙变窄（JSN），但要注意，这种延迟的JSN可以为患者带来临床益处。近来，已经开发了新技术以比传统的X射线更早地检测OA关节的结构变化。目的：道德与科学卓越小组（GREES）成立了一个工作组，以评估这些新技术是否可以用作普通X射线的替代品，以评估DMOAD。方法：GREES包括学术科学家，监管机构成员和制药行业代表。在广泛搜索国际文献之后，从1980年到2002年，组织了两次专家会议，为监管机构准备了一份资源文件。该文件包括有关骨关节炎中新化学实体注册指南可能更新的建议。结果：磁共振成像（MRI）现在用于测量OA患者的软骨形态和完整性参数。尽管一些数据令人鼓舞，但需要用MRI观察到的软骨结构的短期变化与放射线或临床长期变化之间的相关性。因此，GREES建议在II期研究中可以将MRI用作结果，但是在将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。骨骼和软骨重塑的生化标志物正在测试中，以预测OA和测量疾病进展。最近发表的数据很有希望，但作为OA疾病进展的替代终点的验证尚需进一步研究。 GREES表明，生化标志物仍限于“概念验证”研究或作为第二和第三阶段临床试验的次要终点。但是，GREES强调获取有关生化标记物的其他信息的重要性，以帮助更好地了解用于OA的药物的作用方式。监管机构认为，临床结果改善的证据对于批准DMOAD至关重要。全关节置换手术的时间可能是评估DMOAD疗效最相关的临床终点。但是，由于非疾病相关因素（例如患者对手术的意愿或经济因素）的影响，目前无法在临床试验中使用手术时间。在此阶段，与安慰剂相比，DMOAD似乎应显示出显着差异。收益应通过3个主要共同终点来衡量：JSN，疼痛和功能。次要终点应包括“有反应”（或“失败”）的患者百分比。根据验证的临界值，“失败”患者的定义是在2-3年内JSN> 0.5mm进展或疼痛和/或功能明显恶化的患者。疼痛和功能的临床相关临界点的定义必须基于评估疾病自然史的数据（流行病学队列或长期研究的安慰剂组）。对于每个患者，这些临界点应反映出较高的倾向，以后需要进行关节置换。结论：GREES概述了一套为OA开发DMOAD的准则。尽管这些指南可能会随着新信息的发布而发生变化，但以上信息是基于本领域的现有知识并加上专家意见。

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