Flaxman, Linda

Background: Concern for underrepresentation of minorities in clinical trials has focused on enrollment proportions and generalizability. The interplay of trial event-rates with diversity has not been emphasized. Methods: The Carotid Revascularization Endarterectomy vs Stent Trial (CREST) randomized 2502 patients and compared them by race, ethnicity, baseline characteristics, and primary outcome (any peri-procedural stroke, death or MI and subsequent ipsilateral stroke up to 10 years); those with unknown race or ethnicity were excluded. Proportional hazards models adjusting for age, sex, symptomatic status and treatment were used to test for a treatment by race/ethnicity interaction. Results: One-hundred-nine patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other by self-report, and 18 (0.7%) unknown; 90 (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. Compared to whites, racial minorities were younger (mean age 67±8.9 vs 69±8.8, p=0.004), more often female (44% vs 34%, p=0.01), symptomatic (63 vs 52%, p=0.01), and diabetic (51% vs 29%, p<0.0001), but less often dyslipidemic (76% vs 85%, p=0.004), current smokers (19% vs 27%, p=0.04), or had a history of cardiovascular disease (34% vs 46%, p=0.007). Hispanics were more often diabetic (48% vs 30%, p=0.0002). The rate of the primary endpoint was 10.9%±0.9% at 10 years, and did not differ by race or ethnicity (p inter >0.24). In the context of this low rate, even if minority recruitment were increased to represent 50% of study participants, and if the treatment difference in one race were a greater hazard of HR = 1.49 (anticipated alternative hypothesis), then the hazard ratio in the other group would need to be <0.73, or >3.31, to have 90% power of detection. Conclusions: The proportion of racial and ethnicity participation in CREST was suboptimal at < 10%. Primary outcomes did not differ by minority or ethnic status. However, in low event-rate trials very high and even unrealistic enrollment goals for diversity, for example ≥50%, may still be insufficient for detection of outcome differences by race or ethnicity.

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites. Aims Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. Methods Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. Results Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5·5%) were randomized during the first five years and 1387(55·5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model. Conclusions Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity.