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Sample size determinations in original research protocols for randomised clinical trials submitted to UK research ethics committees: review

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1135 (Published 21 March 2013) Cite this as: BMJ 2013;346:f1135
  1. Timothy Clark, research scientist,
  2. Ursula Berger, senior statistician,
  3. Ulrich Mansmann, director, and chair of biostatistics and bioinformatics
  1. 1Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
  1. Correspondence to: U Mansmann mansmann{at}ibe.med.uni-muenchen.de
  • Accepted 31 January 2013

Abstract

Objectives To assess the completeness of reporting of sample size determinations in unpublished research protocols and to develop guidance for research ethics committees and for statisticians advising these committees.

Design Review of original research protocols.

Study selection Unpublished research protocols for phase IIb, III, and IV randomised clinical trials of investigational medicinal products submitted to research ethics committees in the United Kingdom during 1 January to 31 December 2009.

Main outcome measures Completeness of reporting of the sample size determination, including the justification of design assumptions, and disagreement between reported and recalculated sample size.

Results 446 study protocols were reviewed. Of these, 190 (43%) justified the treatment effect and 213 (48%) justified the population variability or survival experience. Only 55 (12%) discussed the clinical importance of the treatment effect sought. Few protocols provided a reasoned explanation as to why the design assumptions were plausible for the planned study. Sensitivity analyses investigating how the sample size changed under different design assumptions were lacking; six (1%) protocols included a re-estimation of the sample size in the study design. Overall, 188 (42%) protocols reported all of the information to accurately recalculate the sample size; the assumed withdrawal or dropout rate was not given in 177 (40%) studies. Only 134 of the 446 (30%) sample size calculations could be accurately reproduced. Study size tended to be over-estimated rather than under-estimated. Studies with non-commercial sponsors justified the design assumptions used in the calculation more often than studies with commercial sponsors but less often reported all the components needed to reproduce the sample size calculation. Sample sizes for studies with non-commercial sponsors were less often reproduced.

Conclusions Most research protocols did not contain sufficient information to allow the sample size to be reproduced or the plausibility of the design assumptions to be assessed. Greater transparency in the reporting of the determination of the sample size and more focus on study design during the ethical review process would allow deficiencies to be resolved early, before the trial begins. Guidance for research ethics committees and statisticians advising these committees is needed.

Footnotes

  • We thank the National Research Ethics Service for its support; IBE research assistants Mathias Heibeck and Linda Hayanga for their contribution to this project; and Michael Campbell, Sir Iain Chalmers, Douglas Altman, Gary Collins, and Hugh Davies for their comments on this work.

  • Contributors: UM had full access to all of the study data and takes responsibility for the integrity of the data and the accuracy of the data analyses. He is guarantor. TC and UM conceived and designed the study. TC, Mathias Heibeck, and Linda Hayanga collected the data. TC and UB carried out the statistical analyses. TC, Mathias Heibeck, Linda Hayanga, and UM recalculated the sample sizes. TC, UM, and UB interpreted the data. TC drafted the manuscript. UM and UB critically reviewed the manuscript. The views expressed in the paper are those of the authors and do not necessarily reflect the views of the National Research Ethics Service, which became a part of the Health Research Authority in December 2011.

  • Funding: This study received no funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: TC received support for travel from the National Research Ethics Service and has worked as a consultant for the clinical research organisation ICON in the previous three years; they have no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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