Corneal Confocal Microscopy: a Surrogate Endpoint for Neurodegeneration in Clinical Trials


Why Have Clinical Trials for Diabetic Neuropathy Failed?

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Approximately one of three people with diabetes is affected by diabetic distal symmetric polyneuropathy (DSPN). Its clinical manifestations such as excruciating neuropathic pain, diabetic foot ulceration, and amputations are associated with substantial morbidity, reduced quality of life, and increased mortality. However, there is substantial unmet medical need due to the following reasons: 1.) inadequate awareness of DSPN by patients, physicians, and funding bodies, 2.) no standardized criteria for screening and diagnosis, 3.) paucity of surrogate markers to predict development and progression of clinical DSPN, 4.) no agreement on how best to address the hierarchy from surrogate endpoints to ultimate clinical benefit in randomized clinical trials (RCTs), 5.) limited efficacy or unfavorable safety profile of symptomatic analgesic treatments and no disease-modifying treatment approved by FDA/EMA. It has been suggested that the main reasons why RCTs for DSPN failed are that DSPN worsens very slowly within the frame of an RCT and that many endpoints are not sufficiently sensitive, accurate, representative, reproducible, and especially monotonic to reliably recognize the small worsening occurring even over a relatively long period of 4 years. Moreover, placebo effects for both neuropathic symptoms and signs (deficits) may result in improvement rather than worsening. Other reasons include too short study durations, too advanced DSPN stages, and inhomogeneous study populations. Finally, thus far disease-modifying agents target only single aspects of the putative pathogenetic pathways rather than offering a holistic approach. It remains to be established whether novel diagnostic techniques and biomarkers can be successfully used as long-term surrogate RCT endpoints. However, new treatments will ultimately be measured by their favorable impact on major clinical endpoints and mortality