Abstract
A systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using annual incidence ≤6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications between December 1987 and May 2011. We characterized each selected trial for study design, sample size, primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of submission, review designation, and approval type. Our results indicated that, of 99 trials that supported the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of approvals relied on objective response rate as the primary efficacy endpoint; and 63% were based on a single trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety findings, relative to drugs approved under the regular approval. Data collected across clinical trials were robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare cancers. Postmarketing safety data may relate to trial design and approval type. An operational definition of "rare cancer" can be useful for the analysis of trial data and for the path toward harmonizing the terminology in the area of clinical research on rare cancers.
Highlights
Rare cancers are rare diseases and pose particular challenges to programs of drug development
The information in this database was independently verified by 4 Food and Drug Administration (FDA) staff members from the Office of Hematology and Oncology Products (OHOP), Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER) who were not associated with this research
Because the annual incidence of this subset is unknown, we estimated the incidence rate for vandetanib’s indication at 2,000 cases per 100,000 per year on the basis of all stages of medullary thyroid cancer instead of the subset of symptomatic or progressive medullary thyroid cancer. One exception to this rule is the incidence of non–Hodgkin lymphoma (NHL), in which the incidence rate was estimated on the basis of the subtypes
Summary
Rare cancers are rare diseases and pose particular challenges to programs of drug development. Rare cancers are further problematic owing to their poorly understood natural histories, their phenotypic heterogeneity, and to a range of manifestations that, even within a given phenotype, can be diverse. Rare cancers represent a particular unmet need in clinical oncology. The U.S Food and Drug Administration (FDA) has recognized the importance of addressing unmet needs by Authors' Affiliations: 1Food and Drug Administration (FDA)-National Cancer Institute Interagency Oncology Task Force, 2Office of Hematology and Oncology Products, Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER), and 3OND, CDER, FDA, Silver Spring, Maryland. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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