Equipoise lost: ethics, costs, and the regulation of cancer clinical research

Cancer is the leading cause of death in Americans younger than 85 years of age and kills one American every 56 seconds. Advances in understanding of cancer biology have given us the potential to develop new, effective targeted therapies. However, progress is slowed by suboptimal/outdated clinical trial design paradigms and by regulatory complexity and rigidity. For instance, simulations suggest that restricting randomized trials to patients expressing drug target, instead of using unselected patient populations, could substantially reduce patient numbers required to demonstrate efficacy. High response rates that are achievable when patients and drugs are matched on the basis of molecular profiles may also make some randomized trials unnecessary or unjustifiable. Moreover, increasing the regulatory rigidity of clinical trials (regulatory fundamentalism) augments trial complexity and costs while slowing progress without demonstrating meaningful safety benefits. Time from drug discovery to marketing increased from 8 years in 1960 to 12 to 15 years currently. Toxic death rates on phase I trials have decreased from 0.8% in 1979 to 0.5% by 2002, but the estimated cost per life-year gained by tighter regulations is $2,700,000 (far higher than costs of other health measures), and simulations suggest that regulatory delays in development of effective therapies result in tens to hundreds of thousands of life-years lost, whereas stringent regulations save extremely few. Dysregulation is also a major disincentive to patient and clinician participation in clinical research. In summary, current approaches squander research resources and discourage research participation, and the marked imbalance between potential life-years lost versus saved renders the regulatory burden potentially unethical. We outline suggested solutions.