Sample size determinations in original research protocols for randomised clinical trials submitted to UK research...

To assess the completeness of reporting of sample size determinations in unpublished research protocols and to develop guidance for research ethics committees and for statisticians advising these committees.

Review of original research protocols.

Unpublished research protocols for phase IIb, III, and IV randomised clinical trials of investigational medicinal products submitted to research ethics committees in the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.

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

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.

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.