Seeking impact: Global perspectives on outcome measure selection for translational and clinical research for primary mitochondrial disorders

Abstract

Primary mitochondrial disorders (PMDs) are challenging due to overall poor outcomes, no proven treatments, and a history of failed clinical trials, leading to a critical need to design future trials that can prove efficacy of an intervention. Selection of outcome measures for PMDs is complicated by extreme clinical, biochemical and genetic heterogeneity; PMDs are effectively a collection of nearly 400 individually ultrarare diseases. In clinical trials, outcome measures aim to evaluate, and ideally quantitate, the efficacy of an intervention in ameliorating clinical phenotype(s). The heterogeneity and multisystemic nature of PMDs makes it unlikely that a universal outcome measure will be applicable to all PMDs. Instead, a composite score of the individual's most worrisome symptoms may be a preferable endpoint. A further challenge arises from the tension between finding outcomes suitable for use in clinical trials (able to produce a measurable change in a relatively short period of time, namely the duration of a clinical trial) vs measures that are clinically meaningful to individual patients. A number of clinical rating scales and proposed biomarkers have emerged to capture the features of PMDs for natural history and interventional trials. Here we review our collective experiences with clinical rating scales, patient-reported outcome measures, and physiological, imaging, biochemical and muscle phenotypes as outcome measures in paediatric and adult PMDs in natural history studies and recent clinical trials. There is a pressing need to agree on a set of validated, robust, clinically meaningful outcome measures internationally, to facilitate the multicentre international clinical trials needed for optimal evaluation of novel therapies for these ultrarare diseases.

Research priorities for mitochondrial disorders: Current landscape and patient and professional views

“…The biomarker question was seen to be essential to the delivery of high‐quality clinical trials and the development of therapy 20,21 . It is possible that answering this question will also address Priority 4.…”

“…The biomarker question was seen to be essential to the delivery of high‐quality clinical trials and the development of therapy. 20 , 21 It is possible that answering this question will also address Priority 4. A number of putative biomarkers of mitochondrial dysfunction have been identified, including FGF21 and GDF15, 22 but none of these is sufficiently specific and sensitive for all mitochondrial diseases.…”

“…A number of putative biomarkers of mitochondrial dysfunction have been identified, including FGF21 and GDF15, 22 but none of these is sufficiently specific and sensitive for all mitochondrial diseases. 21 For mitochondrial disorders caused by mtDNA mutations, mtDNA heteroplasmy can in some cases be a clinically useful biomarker for assessment of disease and prognostication. 23 However, no equivalent biomarker has been identified for nuclear‐encoded mitochondrial disease.…”

Community Consensus Guidelines to Support FAIR Data Standards in Clinical Research Studies in Primary Mitochondrial Disease

“…[ 5 , 6 ] PMD are rare diseases, and hundreds are ultra-rare. PMD may impair the function of any organ system at any age, leading to chronic, complex, and progressively disabling conditions [ 2 , 7 ] Therapeutic development efforts for PMD face multiple challenges due to this phenotypic complexity, lack of predicable phenotype–genotype correlation, general lack of validated outcome measures or reliable biomarkers, [ 8 ] a wide spectrum of morbidity and mortality (with limited natural history studies), and fluctuating, episodic symptoms [ 9 ]…”

Editorial: Mitochondrial medicine special issue

“…This issue of JIMD provides a sampling of the gamut of presentations at this meeting, from fundamental research 1 to addressing practical hurdles in drug development, including how to work with regulatory agencies, 2 what is required by industry to move from an early concept to a licensed medicine, 3 and the critical need to develop reliable noninvasive biomarkers of disease progression 4 and other outcome measures to allow effective evaluation of new compounds. 5 Recent developments in animal models were presented, 6 including high throughput approaches for drug screening. 7 Novel and known biomarkers were discussed, backed up by large longitudinal studies involving patients with precisely defined molecular diagnoses.…”