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

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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.