• Shona Kalkman, KimScott Y HSYHDepartment of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA., van ThielGhislaine J M WGJMWJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands., Diederick E Grobbee, and van DeldenJohannes J MJJMJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands..
• Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: s.kalkman@umcutrecht.nl.
• Value Health. 2017 Jul 1; 20 (7): 902-908.

ObjectivesPragmatic trials evaluate the comparative benefits, risks, and burdens of health care interventions in real-world conditions. Such studies are now recognized as valuable to the perimarketing stage of drug development and evaluation, with early pragmatic trials (EPTs) being explored as a means to generate real-world evidence at the time of regulatory market approval. In this article, we present an analysis of the ethical issues involved in informed consent for EPTs, in light of the generally recognized concern that traditional ethical rules governing randomized clinical trials, such as lengthy informed consent procedures, could threaten the "real world" nature of such trials. Specifically, we examine to what extent modifications (waivers or alterations) to regulatory consent for EPTs would be ethical.MethodsWe first identify broadly accepted necessary conditions for modifications of informed consent (namely, the research involves no more than minimal risk of harm, the research is impracticable with regulatory consent, and the alternative to regulatory consent does not violate legitimate patient expectations) and then apply those criteria to the premarket and early postmarket contexts.Results And ConclusionsThe analysis shows that neither waivers nor alterations of regulatory consent for premarket EPTs will be ethically permissible. For postmarket EPTs with newly approved interventions, waivers of consent will be ethically problematic, but some studies might be conducted in an ethical manner with alterations to regulatory consent.Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

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