Rare disease registries: potential applications towards impact on development of new drug treatments

Abstract

BackgroundLow prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design.ResultsBefore and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry.ConclusionsA RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.

Post-hoc analyses of the edaravone clinical trials Study 16 and Study 19: a step toward more efficient clinical trial designs in amyotrophic lateral sclerosis

“…Conducting clinical trials in rare diseases such as ALS can be particularly challenging due to significant disease heterogeneity, low numbers of patients, and the lack of reliable biomarkers, among other factors (1). One approach to addressing these challenges is the use of patient data from rare disease registries as historical controls; however, the applicability of these approaches is currently limited and under debate (16). To improve trial efficiency, clinical study enrichment strategies have been utilized to enhance signal detection (4,17,18).…”

“…The designs and outcomes for Study MCI186- 16 and Study MCI186-19 have been previously published (8,11). Post-hoc analyses of these studies were performed to analyze the distributions of the changes from baseline ALSFRS-R scores at week 24 for the full analysis set (FAS) for each study and for the Step 1 and Step 2 subgroups of Study MCI186-16.…”

Limited data to evaluate real‐world effectiveness of enzyme replacement therapy for mucopolysaccharidosis type I

“…Improving the system of postmarketing analysis could restore this trust in potentially beneficial therapies. The lack of natural course data implies that such changes of the system should also involve earlier systematic analyses, preferably based on high quality registries of untreated disease progression. Therefore, marketing approval for orphan drugs should in the future be accompanied by rigorous and independent post‐marketing studies including core outcome sets, enforced by marketing and/or reimbursing authorities aiming to demonstrate real‐world effectiveness within a reasonable time frame.…”

An international registry of patients with plasminogen deficiency (HISTORY)

“…geneity affect recruitment, interpretation of data and applicability of conclusions to the larger real-world population of patients; in many cases it may not be possible to design a clinical trial accurately because of insufficient knowledge of the disease. 2 Instead clinicians have often relied on personal experience, case studies/series and patient registries to understand the natural history of these diseases and to collect data on therapeutic interventions and patient outcomes. Patient registries may be national, regional or international, each with its own advantages and disadvantages.…”