Objective To examine methods for generating evidence on health outcomes in patients with rare diseases.Design Methodological review of existing literature.Setting PubMed, Embase, and Academic Search Premier searched for articles describing innovative approaches to randomized trial design and analysis methods and methods for conducting observational research in patients with rare diseases. Main outcome measuresWe assessed information related to the proposed methods, the specific rare disease being studied, and outcomes from the application of the methods. We summarize methods with respect to their advantages in studying health outcomes in rare diseases and provide examples of their application. ResultsWe identified 46 articles that proposed or described methods for studying patient health outcomes in rare diseases. Articles covered a wide range of rare diseases and most (72%) were published in 2008 or later. We identified 16 research strategies for studying rare disease. Innovative clinical trial methods minimize sample size requirements (n=4) and maximize the proportion of patients who receive active treatment (n=2), strategies crucial to studying small populations of patients with limited treatment choices. No studies describing unique methods for conducting observational studies in patients with rare diseases were identified.Conclusions Though numerous studies apply unique clinical trial designs and considerations to assess patient health outcomes in rare diseases, less attention has been paid to innovative methods for studying rare diseases using observational data.

With limited therapeutic options, rare disease patients often considered off-label treatments or novel drugs that posed substantial risk. Nonetheless, rare disease patients generally appreciated the rigor of the research underlying the drugs and supported the FDA's gatekeeping role.

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