Equipoise lost: Ethics, costs, and the regulation of cancer clinical research.
Authors: D. J. Stewart, R. Kurzrock, S. Whitney
Journal: Journal of Clinical Oncology (2010)

6052 Background: Published data indicate: (1) New therapies are gradually improving outcome in localized and metastatic cancers. (2) U.S. lifetime probability of developing cancer is 44% for males and 37% for females. (3) Cancer will kill 562,340 Americans in 2009. (4) The toxic death rate for patients on NCI phase I trials 1991-2002 was 0.5%. (5) Clinical research regulation has become increasingly stringent. (6) It takes 370-481 steps and 26-27 months to take co-operative group trials from conception to activation. (7) The inflation-adjusted annual rate of increase in clinical trials costs is itself increasing, from 7.3% for 1970-1980 to 12.2% for 1980-1990. (8) The average cost per patient on a trial is now $20,000-$30,000. (9) On average, drug approval processes now take 5 years longer than in the 1960s and require 5,435 study patients. Methods: We reviewed toxic death rates in older phase I trials. We calculated: 1) cost per life-year gained by newer, stringent regulations; 2) life-years gained vs lost. Results: In phase I trials published 1979-1990, there were 52 toxic deaths (0.8%) in 6,639 patients entered. Hence, increasingly stringent regulations reduced toxic death rates by no more than 0.3%. They also increased costs by $8,000 per study patient. If estimated average life-expectancy of study patients is one year, cost per life-year gained is $2,700,000, far higher than other therapies and preventive measures. With an average of 5,435 study patients required for drug approval, the increasingly stringent regulations save 16.3 life-years. However, if the new therapy increased lung cancer cure rates by 1% through adjuvant therapy, if cured patients survived 5 years, and the new therapy increased life-expectancy in uncured patients by 3 months, then the 5-year regulation-induced delay would cost 282,529 life-years in the US (4,709 per month of regulatory delay) and 2,000,000 worldwide. The potential losses are much larger if one also considers other factors, such as other malignancies, larger possible therapy gains and new therapies that are never even tested because of costs. Conclusions: Current regulation of cancer clinical research is neither cost-effective nor ethical. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Align 2 Action, Inc., AstraZeneca, Bridger Capital, LLC, Centocor Ortho Biotech, Gascon Associates, Johnson & Johnson, Liquid Technologies, Maxygen, Meda Corp, Merck, Nektar Therapeutics Amgen, AstraZeneca, Center for Biomedical Continuing Education (CBCE), Enzon, Genentech, IDSC, ImClone Systems, Johnson & Johnson, Maxygen, Merck, Pharmion, Roche Abraxis, Amgen, AmpliMed, Antigenics, AstraZeneca, Bayer, BMS, Callisto, Celgene, Centocor, Centocor Ortho Biotech, Concordia, Curagen, Eisai, Eli Lilly, EMD Serono, Enzon, Exelixis, Genentech, GlaxoSmithKline, Globomax, Kinex, Merck, Metastatix, MGI Pharmaceuticals, Millennium, Myriad, Myriad Genetics, NCI, Nereus, NIH, Novartis, Oncothyreon, Pfizer, Pharmacyclics, Pharmion, Phoenix Biotech, Reata, Roche, Taiho, Vioquest, Ziopharm