Critical appraisal of arguments for the delayed-start design proposed as alternative to the parallel-group randomized cl
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Critical appraisal of arguments for the delayed-start design proposed as alternative to the parallel-group randomized clinical trial design in the field of rare disease Loukia M. Spineli, Eva Jenz, Anika Großhennig and Armin Koch*
Abstract Background: A number of papers have proposed or evaluated the delayed-start design as an alternative to the standard two-arm parallel group randomized clinical trial (RCT) design in the field of rare disease. However the discussion is felt to lack a sufficient degree of consideration devoted to the true virtues of the delayed start design and the implications either in terms of required sample-size, overall information, or interpretation of the estimate in the context of small populations. Objectives: To evaluate whether there are real advantages of the delayed-start design particularly in terms of overall efficacy and sample size requirements as a proposed alternative to the standard parallel group RCT in the field of rare disease. Methods: We used a real-life example to compare the delayed-start design with the standard RCT in terms of sample size requirements. Then, based on three scenarios regarding the development of the treatment effect over time, the advantages, limitations and potential costs of the delayed-start design are discussed. Results: We clarify that delayed-start design is not suitable for drugs that establish an immediate treatment effect, but for drugs with effects developing over time, instead. In addition, the sample size will always increase as an implication for a reduced time on placebo resulting in a decreased treatment effect. Conclusions: A number of papers have repeated well-known arguments to justify the delayed-start design as appropriate alternative to the standard parallel group RCT in the field of rare disease and do not discuss the specific needs of research methodology in this field. The main point is that a limited time on placebo will result in an underestimated treatment effect and, in consequence, in larger sample size requirements compared to those expected under a standard parallelgroup design. This also impacts on benefit-risk assessment. Keywords: Delayed-start, Randomized trial, Orphan drug, Rare disease, Sample size, Treatment effect
* Correspondence: [email protected] Institute for Biostatistics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Spineli et al. Orphanet J
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