Innovative research methods for studying treatments for rare diseases: methodological review

Abstract

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.

The role of systemic therapy in the management of sinonasal cancer: A critical review

“…Although some of these methods, already used in studies of common conditions, are gaining more and more interest in the field of randomized trials for rare disease, greater attention is needed in observational studies. The use of observational data such as patients' registry and electronic healthcare databases might in fact represent an important source of clinical information in rare diseases [41].…”

Combination Therapies for Traumatic Brain Injury: Retrospective Considerations

“…To reduce sample sizes and/or enhance power of including even modestly promising therapies for more rigorous subsequent evaluations, clinical trials now incorporate innovative study designs, (e.g., adaptive, factorial, crossover), and perform interim analyses to identify and eliminate futile dosing strategies from further study. 104 Population heterogeneity in TBI injured patients 7 undermines the potential to find a statistically significant therapeutic effect size; clinical trials in other fields are now reducing variability in the group by using genetic or biomarker screening. 104 All of these innovative approaches being added to enhance the statistical power and reduce costs of clinical studies should also be exploited for pre-clinical translational therapy research.…”

“…104 Population heterogeneity in TBI injured patients 7 undermines the potential to find a statistically significant therapeutic effect size; clinical trials in other fields are now reducing variability in the group by using genetic or biomarker screening. 104 All of these innovative approaches being added to enhance the statistical power and reduce costs of clinical studies should also be exploited for pre-clinical translational therapy research.…”

CONSORT extension for reporting N-of-1 trials (CENT) 2015: explanation and elaboration

“…Example: ''Our objectives were [1] to determine whether in children undergoing doxorubicin-containing chemotherapy, topical vitamin E decreases an objective measurement of oral mucositis compared to placebo and [2] to assess the feasibility of an innovative trial design of combining N-of-1 trials using Bayesian meta-analysis.'' [35].…”

“…Many scenarios exist where this holds true. As examples, unique challenges exist with respect to evaluating treatments in populations with rare diseases; adequate recruitment for group trials is not always feasible, retention may be difficult, and funding may be difficult to obtain [1,2]. Similarly, children, adolescents, and elderly people are typically excluded from or not studied in large scale RCTs [1,3].…”