A small n sequential multiple assignment randomized trial design for use in rare disease research

Tamura, Roy; Krischer, Jeffrey P.; Pagnoux, Christian; Micheletti, Robert G.; Grayson, Peter C.; Chen, Yeh-Fong; Merkel, Peter A.

doi:10.1016/j.cct.2015.11.010

Cited by 35 publications

(31 citation statements)

References 10 publications

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“…Some adaptive designs are now used for rare cancers [ 53 ]. Other sequential adaptive methods are proposed for testing different therapeutic possibilities in a small population [ 54 , 55 ]. Regulators accept or recommend some of these designs [ 56 ].…”

Section: Resultsmentioning

confidence: 99%

A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?

Rath

Salamon

Peixoto

et al. 2017

Trials

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BackgroundEvidence-based clinical practice is challenging in all fields, but poses special barriers in the field of rare diseases. The present paper summarises the main barriers faced by clinical research in rare diseases, and highlights opportunities for improvement.MethodsSystematic literature searches without meta-analyses and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project.ResultsBarriers specific to rare diseases comprise the difficulty to recruit participants because of rarity, scattering of patients, limited knowledge on natural history of diseases, difficulties to achieve accurate diagnosis and identify patients in health information systems, and difficulties choosing clinically relevant outcomes.ConclusionsEvidence-based clinical practice for rare diseases should start by collecting clinical data in databases and registries; defining measurable patient-centred outcomes; and selecting appropriate study designs adapted to small study populations. Rare diseases constitute one of the most paradigmatic fields in which multi-stakeholder engagement, especially from patients, is needed for success. Clinical research infrastructures and expertise networks offer opportunities for establishing evidence-based clinical practice within rare diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2287-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?

Rath

Salamon

Peixoto

et al. 2017

Trials

View full text Add to dashboard Cite

show abstract

“…A comparative effectiveness trial based at the University of Pennsylvania is attempting to identify which of azathioprine, colchicine, or dapsone is most effective in treatment of leukocytoclastic cutaneous vasculitis. These investigators have initially chosen a small n sequential multiple assessment randomized trial design (Tamura et al, 2016). We believe that adaptive trial principles will offer useful strategies for developing evidence-based treatment guidelines to improve patient care.…”

Section: Discussionmentioning

confidence: 99%

Adaptive Clinical Trial Design: An Overview and Potential Applications in Dermatology

Elman

Ware

Gottlieb

et al. 2016

Journal of Investigative Dermatology

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The challenges of drug development, including increasing costs, late-stage drug failures, and the decline in the number of drugs being approved by the US Food and Drug Administration over time, have generated interest in adaptive study designs that have the potential to address these problems. Adaptive trial designs use interim data analysis to amend trials, and have been recognized for more than a decade as a way to increase trial efficiency, partly by the increased probability of demonstrating a drug effect if one exists. In this article, we define adaptive trials; give examples of the most common types; highlight the pros, cons, and ethical considerations of these designs; and illustrate how these tools can be applied to drug development in dermatology.

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“…Workshop participants emphasized the need to evaluate any intervention critically with regard to the inclusion criteria and stratification of subjects, dose and duration of treatment, and study endpoints. The value of crossover designs, which allow patients to serve as their own control, was noted, as was the need for creative strategies to address studies with very small enrollments such as individualized “n=1” or small cohort trials [139]. …”

Section: Developing a Research Agendamentioning

confidence: 99%

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

Camp

Krotoski

Parisi

et al. 2016

Molecular Genetics and Metabolism

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In December 2014, a workshop entitled “Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base” was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

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A small n sequential multiple assignment randomized trial design for use in rare disease research

Cited by 35 publications

References 10 publications

A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?

A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?

Adaptive Clinical Trial Design: An Overview and Potential Applications in Dermatology

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

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