Points to consider: efficacy and safety evaluations in the clinical development of ultra-orphan drugs

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 Sample sizes have been determined on the basis of feasibility for some ultra-orphan drugs.We provide “Draft Guidance on the Clinical Development of Ultra-Orphan Drugs” based on this research.ConclusionsThe development of ultra-orphan drugs requires various arrangements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 We expect that this draft guidance is useful for ultra-orphan drugs developments in future.

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties

“…The process of clustering converged, resulting in six clusters: (1) conditions with single acute episodes, (2) conditions with recurrent acute episodes, (3) chronic slow or non-progressive conditions, (4) progressive conditions led by one organ-system, (5) progressive multidimensional conditions and (6) chronic staged conditions. The prevalence of the condition (rare: ≤5/10,000 and > 1/100,000 and ultrarare: ≤1/100,000) was taken into account due to potential implications of the limited feasibility of certain types of design and the implications for regulatory assessment [ 33 ] (Fig. 1 and Table 1 ).…”

Japan oncology market overview: Current and future perspectives

“…48 Utilization of nonrandomized, noncontrolled clinical trial designs with clinical data obtained from clinical trials conducted outside Japan has been reported in new allocations of rare cancer drugs in Japan. 49 In Europe and the United States, orphan drug legislation directed at incentivizing orphan drug development has worked well in securing the profitability of pharmaceutical companies; the same trend has been confirmed for limited types of rare cancers in Japan. 47,50 Continuation of these trends can be expected to boost the development of rare cancer drugs by Japanese pharmaceuticals.…”

“…49 In Europe and the United States, orphan drug legislation directed at incentivizing orphan drug development has worked well in securing the profitability of pharmaceutical companies; the same trend has been confirmed for limited types of rare cancers in Japan. 47,50 Continuation of these trends can be expected to boost the development of rare cancer drugs by Japanese pharmaceuticals. In such an environment, rare cancer drugs should be an important market in Japan in the not-too-distant future.…”

Factors distinguishing important identified risks from important potential risks in orphan and nonorphan drugs: An analysis of safety specifications of Japan and European Union risk management plans

“…However, previous studies have reported that pivotal trials of orphan drugs are more likely to include single‐arm, nonrandomized, and unblinded designs with smaller number of subjects compared to nonorphan drugs, suggesting that the assessment of safety and efficacy of orphan drugs is limited at the time of regulatory approval . Postmarketing pharmacovigilance is expected to play a critical role in characterizing a safety profile . However, recent postmarketing studies conducted for orphan drugs did not contribute to revising the initial decision of regulatory authority …”

“…[4][5][6][7] Postmarketing pharmacovigilance is expected to play a critical role in characterizing a safety profile. 8,9 However, recent postmarketing studies conducted for orphan drugs did not contribute to revising the initial decision of regulatory authority. 10 In 2004, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) agreed to the E2E guideline which provides instructions for summarizing safety specifications and pharmacovigilance planning.…”