Abstract
BackgroundThe unmet medical needs of individuals with very rare diseases are high. The clinical trial designs and evaluation methods used for ‘regular’ drugs are not applicable in the clinical development of ultra-orphan drugs (<1000 patients) in many cases. In order to improve the clinical development of ultra-orphan drugs, we examined several points regarding the efficient evaluations of drug efficacy and safety that could be conducted even with very small sample sizes, based on the review reports of orphan drugs approved in Japan.ResultsThe clinical data packages of 43 ultra-orphan drugs approved in Japan from January 2001 to December 2014 were investigated. Japanese clinical trial data were not included in the clinical data package for eight ultra-orphan drugs, and non-Japanese clinical trial data were included for six of these eight drug. Japanese supportive data that included retrospective studies, published literature, clinical research and Japanese survey results were clinical data package attachments in 22 of the 43 ultra-orphan drugs. Multinational trials were conducted for three ultra-orphan drugs. More than two randomized controlled trials (RCTs) were conducted for only 11 of the 43 ultra-orphan drugs. The smaller the number of patients, the greater the proportion of forced titration and optional titration trials were conducted. Extension trials were carried out for enzyme preparations and monoclonal antibodies with high ratio. Post-marketing surveillance of all patients was required in 36 of the 43 ultra-orphan drugs.For ultra-orphan drugs, clinical endpoints were used as the primary efficacy endpoint of the pivotal trial only for two drugs. The control groups in RCTs were classified as follows: placebo groups different dosage groups, and active controls groups. Sample sizes have been determined on the basis of feasibility for some ultra-orphan drugs.We provide “Draft Guidance on the Clinical Development of Ultra-Orphan Drugs” based on this research.ConclusionsThe development of ultra-orphan drugs requires various arrangements regarding evidence collection, data sources and the clinical trial design. We expect that this draft guidance is useful for ultra-orphan drugs developments in future.
Highlights
In the clinical development of ultra-orphan drugs for the treatment of very rare diseases, it is often difficult to conduct clinical trials that aim to confirm the efficacy and safety of the drugs
We obtained review reports of orphan drugs that were approved in Japan in the period from January 2001 to December 2014 from the Pharmaceutical and Medical Devices Agency (PMDA) website, and we investigated the clinical data packages of the drugs
We investigated attachment of Japanese and non-Japanese data, randomized controlled trials (RCTs), dose-response trials, extension trials and postmarketing surveillances as the constitution of clinical data package, and efficacy end points, control arms and target sample sizes setting as the design of pivotal trials, The data of clinical trials with healthy volunteers and those for other approved indications were not treated as evaluation data
Summary
In the clinical development of ultra-orphan drugs for the treatment of very rare diseases, it is often difficult to conduct clinical trials that aim to confirm the efficacy and safety of the drugs. This is partly because very limited patient populations hinder the recruitment of a sufficient number of trial subjects. The unmet medical needs of the individuals with very rare disease are increasing, to the point where a rare-disease patient group submitted “A request for ultra-orphan drug development support and drug discovery/intractable disease measures in Japan” [17]
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