needs to be carefully defined so neither the benefits nor risks differ appreciably from what would be expected in common use. Unless precluded by toxicity or tolerability, it would be expected that the dose of the comparator should be at least equal in effectiveness to the target agent. If no comparator treatment exists or no comparator has a well-defined benefit–risk profile, then typically at least one arm of the study should be some form of “usual care” or a placebo if usual care is not a proven or active treatment. If there are ethical reasons for not having a usual-care or placebo arm in the study—for example, if the treatment in question is for an irreversible and fatal disease—a treatment that does not have a well-defined benefit–risk profile might be the only ethically acceptable comparator. In such cases, FDA should take the questionable benefit–risk profiles of the drug and its comparator into account when interpreting the results of the study.

REFERENCES

Borer, J. S., H. Pouleur, E. Abadie, F. Follath, J. Wittes, M. A. Pfeffer, B. Pitt, and F. Zannad. 2007. Cardiovascular safety of drugs not intended for cardiovascular use: Need for a new conceptual basis for assessment and approval. European Heart Journal 28(15):1904-1909.

Flory, J., and E. Emanuel. 2004. Interventions to improve research participants’ understanding in informed consent for research. JAMA 292(13):1593-1601.

Hiatt, W. R. 2006. Observational studies of drug safety—aprotinin and the absence of transparency. New England Journal of Medicine 355(21):2171-2173.

IOM (Institute of Medicine). 2007. The future of drug safety: Promoting and protecting the health of the public. Washington, DC: The National Academies Press.

Kass, N. E., and H. A. Taylor. 2008. Empirical research on informed consent: A review of the literature prepared for the National Academies Workshop on Collecting, Storing, Accessing, and Protecting Data Containing Biological Measures (unpublished).

Lindegger, G., C. Milford, C. Slack, M. Quayle, X. Xaba, and E. Vardas. 2006. Beyond the checklist: Assessing understanding for HIV vaccine trial participation in South Africa. Journal of Acquired Immune Deficiency Syndromes 43(5):560-566.

NRC (National Research Council). 2009. Science and decisions: Advancing risk assessment. Washington, DC: The National Academies Press.

NRC. 2011. A risk-characterization framework for decision-making at the Food and Drug Administration. Washington, DC: The National Academies Press.

Psaty, B. M., and J. P. Vandenbroucke. 2008. Opportunities for enhancing the FDA guidance on pharmacovigilance. JAMA 300(8):952-954.

Ray, W. A., and C. M. Stein. 2006. Reform of drug regulation—beyond an independent drug-safety board. New England Journal of Medicine 354(2):194-201.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement