Restoring Balance to the Cancer Research Regulation Equation

Colin Gittens

November/December 2010, Vol 1, No 6 - Clinical Research

Clinical cancer research is hampered by an overly complex and cautious regulatory system, which slows the development of lifesaving drugs, increases costs, and may be unethical, according to David J. Stewart,MD, of the University of Texas M.D. Anderson Cancer Center and colleagues (Stewart DJ, et al. Equipoise lost: ethics, costs, and the regulation of cancer clinical research. J Clin Oncol. 2010;28:2925-2935). Because of the urgency associated with a lethal disease such as cancer, there is a need to restore the balance between adequate safety regulation and innovation, say the authors.

Among the many agencies, laws, and regulations that govern clinical research are institutional review boards (IRBs), the US Food and Drug Administration, the Office of Human Research Protections, the National Cancer Institute, the Cancer Therapy Evaluation Pro gram, the Clinical Laboratory Improve ment Amendments (CLIA) section of the Centers for Medicare & Medicaid Services, the Department of Health and Human Services, the Department of Veterans Affairs, the Internal Revenue Service, the Office of the Inspector General, the Patent and Trademark Office, and the Joint Commission. Although these overseeing bodies serve to prevent patient harm, the combined impact of this regulatory oversight is large—and negative—say the authors.

The Scope of the Problem
The slow pace of clinical trials resulting from regulatory bottlenecks hinders activation of trials and wastes researcher and patient time. Regulatory requirements also drive up research costs. In examining whether regulation has actually increased patient safety, the authors looked at mortality in phase 1 clinical research between 1972 and 2002 and found that the more stringent regulations reduced the toxic death rate by no more than 0.3%. Increasing protocol complexity and the number of tests mandated by protocol have served to push the average cost to $26,000 to enter a patient into a clinical trial. The cost per life-year saved when all regulations are factored in is approximately $2.7 million; the consensus among oncologists is that $100,000 per life-year gained is good value.

Higher costs also mean that fewer organizations are able to conduct trials, and that the number of testable ideas is reduced. Concentrating research in the hands of a few pharmaceutical firms can limit combined testing of agents from different firms, lessen explorations for rare diseases, and curb higherrisk strategies.

Regulations have slowed the pace of research; time from drug discovery to marketing has reached 12 to 15 years today compared with 8 years in the 1960s. This slowing discourages patient participation through restrictive eligibility and impractical study schedules. The number of physician-researchers has also declined, perhaps because of the burdens of running a trial.

Streamlining the Regulatory Approach
In terms of general principles, the authors argue that acceptable risk in clinical research should be substantially higher for uniformly fatal diseases compared with potentially curable conditions. The key is to inform patients of the risk, rather than presume for them what risks they should be allowed to take. The regulatory burden should also be adjusted based on the population under study, and the authors push for a new, single regulatory body focusing on lethal diseases only to streamline this process.

Other, more specific recommendations include:

  • Reform toxicology and pharmacology procedures, testing subjects only for P450 interactions
  • Streamline study review to no more than 2 agencies, and centralize IRB review in multiinstitutional studies
  • Streamline reporting of adverse events, and centralize information on drug toxicity
  • Modify protocol adherence to acknowledge degrees of deviation. The definition of protocol violation should be changed to an event where the patient was harmed or the integrity of the data was compromised
  • Refocus documentation requirements on what truly matters, not trivial events
  • Simplify healthcare payment systems for patients in trials
  • Allow assignment of patients for therapy, even when laboratory tests are not CLIA-certified
  • Adjust study randomization so that studies are capable of showing large gains in a small population
  • Efficacy biomarkers should be identified initially based on their correlation with tumor shrinkage, not survival.

The authors conclude that the current process “seems to be unethical and squanders research resources.” Targeting the subpopulations likely to benefit most from a therapy at the outset (ie, from the earliest phase 1 and 2 studies), among other strategies, would help restore the imbalance between the costs of life-years lost and gained as it exists under the current system. Regulations that do not add large demonstrable value should be discarded, they say