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Hemming et al. (“Ethical Implications of Excessive Cluster Sizes in Cluster Randomized Trials,” 20 February 2018) cite the FIRST Trial as an example of a “higher risk” cluster-randomized trial in which large cluster sizes pose unjustifiable excess risk. The authors state, “[t]he obvious way to reduce the cluster size in this study is to reduce the duration of the trial…”
We believe this to be an inappropriate recommendation stemming from an inaccurate appraisal of the FIRST Trial.
The FIRST Trial was designed to inform a potential policy change in U.S. resident duty hours. In the Statistical Analysis Plan, which was made available at www.nejm.org, we clearly and prospectively stated that “[t]his study is a trial-based evaluation of potential policy effects on patient safety and resident wellbeing... this study is intended to inform real-world policy decision-making with respect to resident duty hours regulation.” The SAP and Supplemental Appendix (www.nejm.org) also provides all assumptions for our power calculations and cluster sizes, which were not large in the case of resident outcomes.
As such, it was important that the trial closely resemble real-world conditions in which residency training occurs and duty hour policies are implemented. A shorter study would pose risks owing to non-standard, multiple policy shifts and would increase administrative/organizational bu...
As such, it was important that the trial closely resemble real-world conditions in which residency training occurs and duty hour policies are implemented. A shorter study would pose risks owing to non-standard, multiple policy shifts and would increase administrative/organizational burdens of staff workflow coordination. Moreover, a shorter period would threaten external validity, rendering evidence from the study potentially uninformative for policy decisions that could affect the lives of millions. Thus, a shorter study would be of little social benefit while imposing unjustifiable risks and burden. A planned interim analysis was independently reviewed by a Data Safety Monitoring Board out of consideration for patient safety, but termination was unwarranted.
If the policy intervention is ethically unacceptable, the study should not be done under any time frame. Yet, the debate over U.S. resident duty hours is marked by equipoise: it is not at all clear that flexible duty hours pose greater risk than duty hour regulations that interrupt critical patient care (e.g., leaving during an operation) or lead to more patient care hand offs. Considerable literature demonstrates adverse effects on patient outcomes of excessive care transitions [5,6] along with residents’ concerns that training may suffer with reductions in duty hours.[7-10]
Hemming et al. are well-intentioned in articulating ethical concerns arising from gratuitously large clusters. However, in trials designed to inform policy, the importance of external validity may justify ostensibly “large” cluster sizes.
Karl Y. Bilimoria, M.D., M.S.
Jeanette W. Chung, Ph.D.
Larry V. Hedges, Ph.D.
 Page 4 of the FIRST Trial Statistical Analysis Plan (March 2014) Available at: https://www.nejm.org/doi/suppl/10.1056/NEJMoa1515724/suppl_file/nejmoa15...
 Page 26 of the FIRST Trial Statistical Analysis Plan (March 2014) Available at: https://www.nejm.org/doi/suppl/10.1056/NEJMoa1515724/suppl_file/nejmoa15...
 Philibert I, Nasca T, Brigham T, Shapiro J. Duty-hour limits and patient care and resident outcomes: can high-quality studies offer insight into complex relationships? Ann Rev Med. 2013;64:467-483
 Denson JL, Jensen A, Saag HS, et al. Association between end-of-rotation resident transition in care and mortality among hospitalized patients. JAMA. 2016;316(21):2204-2213
 Denson JL, McCarty M, Fang Y, et al. Increased mortality rates during resident handoff periods and the effect of ACGME duty hour regulations. Am J Med. 2015;128(9):994-1000
 Ahmed N, Devitt KS, Kshet I, et al. A systematic review of the effects of resident duty hour restrictions in surgery: impact on resident wellness, training, and patient outcomes. Ann Surg. 2014;259(6):1041-1053
 Drolet BC, Spalluto LB, Fischer SB. Residents’ perspectives on ACGME regulation of supervision and duty horus – a national survey. N Engl J Med. 2010;363:e34
 Drolet BC, Christopher DA, Fischer SA. Residents’ response to duty-hour regulations – a follow-up national survey. N Engl J Med. 2012;366:e35
 Fargen KM, Chakraborty A, Friedman WA. Results of a national neurosurgery resident survey on duty hour regulations. Neurosurgery. 2011;69(6):1162-1170