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

University Of California, San Francisco, San Francisco CA

Investigators

Linked publications, trials & patents

Abstract

Project Summary Very effective therapies for osteoporosis are available which can reduce spine fracture risk by 50-75% and devastating hip fracture risk by 40-50%. However, due to fears about very rare side effects, their use as greatly decreased from 2008 by > 50%. Therefore, there is a strong need for new therapies without these side effects. However, new trials require fracture endpoints and must be very large: as long as 5 years with > 16,000 patients making development of new medications extremely expensive and no longer feasible. The FNIH Bone Quality Study began in 2013 with a primary aim of finding surrogate markers that could lead to drug approvals with as few as 500 patients for 2 years. This could greatly facilitate new drug development. After working with several potential biomarkers, we have focused on change in DXA BMD as a surrogate endpoint to replace fracture in future randomized trials. The project has collected individual patient data from >150,000 patients in >50 randomized trials and used this unique resource to perform analyses to determine the extent to which BMD increases in trials are predictive of fracture reductions. Our results, currently under consideration for publication, show a strong and quantitative relationship between larger BMD increase in trials and larger fracture reductions in those trials. Starting in 2016, we began work with the FDA to obtain formal qualification for change in DXA BMD as a surrogate for fracture in future trials. This proposal will fund our continued work with FDA to complete the steps outlined in the 2017 Biomarker Qualification Guidelines which will involve significant on-going discussion with FDA. The specific aims are to 1) Finalize the Statistical Analysis Plan; 2) Complete, submit and obtain FDA acceptance of a Qualification Plan and 3) Draft and Submit a Full Qualification Package. It will also fund writing of a BMD quality control plan for future studies and creation and submission of data documentation according to FDA specification. The qualification of BMD change as a surrogate marker for fracture 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.