Investigators commonly include more subjects in a CT to reach the statistical power required to see the effect of their drug (37). Regulators and statisticians encourage these practices to expose research hypotheses to diverse real-world conditions able to support generalizations of conclusions. Unfortunately, larger numbers of subjects also require additional locations for patient recruitment and hence additional monitoring and supervision of often inexperienced staff (30, 31). Investigators knowingly or unknowingly employ raters not experienced with the disease under study, not trained and familiar with the instruments used as outcome measures, and who use biased ratings and relaxed protocol conditions to meet quotas (28, 29, 32, 36, 40). One indicator that is consistent with an increased vulnerability of large CTs to errors is that placebo responses increase with industrial sponsorships and with added research sites (20, 41, 42).
