DDTBMQ000054: Regulatory qualification for DXA bone mineral density as a surrogate endpoint for fracture risk in osteoporosis trials

总结 目前批准的骨质疏松症治疗方法可将脊柱骨折风险降低50-75%， 骨折风险高达50%。然而，由于担心非常罕见的副作用，使用 自2008年以来，治疗骨质疏松症的药物减少了50%。因此，有强烈的需要 对于具有强安全性的新疗法，可能更有效， 病人然而，新的试验需要骨折终点，并且必须非常大：只要5 超过16，000名患者，使得新药的开发极其昂贵 不再可行。 FNIH-ASBMR-SABRE（将高级BMD作为监管终点的研究）始于2013年 主要目的是将治疗相关的骨矿物质密度（BMD）变化定性为 在未来的新的抗骨质疏松症治疗试验的替代终点。成功完成 这一目标的实现将促进创新并促进新药开发。为此我们 在>50项随机试验中收集了> 150，000例患者的个体患者数据，并使用该数据 独特的资源来执行分析，以确定较大BMD之间的强关系 在这些试验中骨折复位率越来越高。 从2016年开始，我们开始与FDA合作，以获得DXA变更的正式资格 BMD作为未来试验中骨折的替代终点。迄今为止，我们的意向书和 鉴定计划已获得FDA批准。目前的提案将资助我们继续 与FDA合作完成2017年生物标志物鉴定中概述的最后步骤 指导方针，即提交完整的资格文件包。为此，我们需要 定期与FDA会面，对资格审查计划中的建议做出回应， 根据FDA的规范，最终确定CROP并提交数据文件。 骨密度变化作为未来抗骨关节炎试验中骨折替代终点的资格 骨质疏松症治疗将是该领域的一个突破， 新药物的开发和骨质疏松症患者和公众的巨大利益 健康

SUMMARY Currently approved therapies for osteoporosis can reduce spine fracture risk by 50-75% and hip fracture risk by up to 50%. However, due to fears about very rare side effects, use of osteoporosis medications has declined by 50% since 2008. Therefore, there is a strong need for new therapies that have a strong safety profile, perhaps greater efficacy and convenient for the patient. However, new trials require fracture endpoints and must be very large: as long as 5 years with > 16,000 patients making the development of new medications extremely expensive and no longer feasible. The FNIH-ASBMR-SABRE (Study to Advanced BMD as a Regulatory Endpoint) began in 2013 with a primary goal of qualifying the treatment-related change in bone mineral density (BMD) as a surrogate endpoint in future trials of new anti-osteoporosis therapies. Successful completion of this goal would prompt innovation and facilitate new drug development. To this end, we have collected individual patient data from >150,000 patients in >50 randomized trials and used this unique resource to perform analyses to determine a strong relationship between larger BMD increase and greater fracture reductions in those trials. Starting in 2016, we began work with the FDA to obtain formal qualification of change in DXA BMD as a surrogate endpoint for fracture in future trials. To date, our Letter of Intent and Qualification Plan have been approved by the FDA. The current proposal will fund our continued work with FDA to complete the final steps outlined in the 2017 Biomarker Qualification Guidelines, namely submission of the Full Qualification Package. To do so, we will need to meet regularly with the FDA, respond to the suggestions in the review of the Qualification Plan, finalize the FQP and the submission of data documentation according to FDA specifications. The qualification of BMD change as a surrogate endpoint for fracture in future trials of anti- osteoporosis therapies would be a breakthrough in the field that would lead to expedited development of new medications and enormous benefits for osteoporosis patients and public health.