This paper explains why informed consent for randomized comparative effectiveness research (CER) must include risks of standard care. Disclosures of such risks are both legally and ethically required and, for reasons discussed in the paper, should remain so.
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References
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R. R.Faden, T. L.Beauchamp, and N. E.Kass, “Informed Consent, Comparative Effectiveness, and Learning Health Care,”New England Journal of Medicine370, no. 8 (2014): 766-67, at 766.
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Comparative effectiveness research can also refer to purely observational studies in which patients receive usual clinical care from their physicians or other health care providers but data on their outcomes is prospectively tracked for research purposes. This article focuses on CER studies in which patient care is altered for research purposes, such as in randomized trials.
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See Kass et al., supra note 9.
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See Lantos and Feudtner, supra note 1.
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Id. See also L.Shepherd, “SUPPORT and Comparative Effectiveness Trials: What's At Stake,”Hastings Center Report45, no. 1 (2014): 44-45 (arguing the opposite).
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In this respect, I believe John Lantos and I are in agreement. “We believe strongly in the need for voluntary and informed consent for clinical research.”J. D.Lantos and J. A.Spertus, “The Concept of Risk in Comparative-Effectiveness Research,”New England Journal of Medicine371, no. 22 (2014): 2129-2130.
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2 Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10 181-82 (1946-1949).
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“The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research,” Pub. No. 78-0012; The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (1979), at 7, available at <http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html> (last visited August 2, 2017).
18.
Id., at 4. “To show lack of respect for an autonomous agent is to repudiate that person's considered judgments, to deny an individual the freedom to act on those considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so.”
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Id., at 7.
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R. J.Morse and R. F.Wilson, “Realizing ‘Informed’ Consent in Times of Controversy: Lessons from the SUPPORT Study,”Journal of Law, Medicine & Ethics44, no. 3 (2016): 402-418.
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Grimes v. Kennedy Krieger Institute, Inc., 366 Md. 29, 90 (2001).
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Federal regulations governing human subjects research were first proposed in 1978 by the Department of Health, Education, and Welfare (DHEW). The final rules were put into place in 1981 by DHEW's successor agency, the Department of Health and Human Services (HHS). In 1991, most federal agencies involved in supporting biomedical research adopted the HHS regulations, thus establishing a “Common Rule” that applies to all of those agencies. FDA “concurs” with the Common Rule, but has not adopted it entirely. E. D.Williams, Congressional Research Service (CRS), “Federal Protection for Human Research Subjects: An Analysis of the Common Rule and Its Interactions with FDA Regulations and the HIPAA Privacy Rule 14-15,” (2005): at 65.
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21 C.F.R. 50.25.
28.
The requirements for informed consent under the Common Rule can be found at 45 C.F.R. 46.116. For the FDA requirements, see 21 C.F.R. 50.25.
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I.Cortes-Puch, R. A.Wesley, M. A.Carome, R. L.Danner, S. M.Wolfe, and C.Natanson, “Usual Care and Informed Consent in Clinical Trials of Oxygen Management in Extremely Premature Infants,”PLOSOne, May18, 2016, available at <http://dx.doi.org/10.1371/journal.pone.0155005> (last visited August 2, 2017); see also R.Macklin and L.Shepherd, “Informed Consent and Standard of Care: What Must Be Disclosed,”American Journal of Bioethics13, no. 12 (2013): 9-13 (summarizing the consent forms).
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Id. (Macklin and Shepherd).
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S.Pratt, Comments at U.S. Department of Health & Human Services OHRP Public Meeting on Matters Related to Protection of Human Subjects and Research Considering Standard of Care Interventions (August28, 2013) [hereinafter OHRP Public Meeting], transcript available at <http://www.hhs.gov/ohrp/regulations-and-policy/requests-for-comments/public-meeting-08-28-2013-transcript/index.html> (last visited August 2, 2017) [hereinafter OHRP Public Meeting Transcript] (comment of parent of a child in SUPPORT who believed he had provided permission “to record Dagan's oxygen saturation measurements” and was surprised to learn that their child “was placed into a random oxygen saturation category, instead of a study to monitor her natural oxygen saturation.”)
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Letter from Lisa R.Buchanan, Compliance Oversight Coordinator, OHRP Div. of Compliance Oversight, to Richard B. Marchase, Vice President for Research & Economic Development, University of Alabama, Birmingham (March7, 2013), available at <www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf> (last visited August 2, 2017).
42.
See Cortes-Puchet al., supra note 38 (discussing, among other things, the use of untested, altered oximeters); J. F.Merz and D.Yerramilli, “SUPPORT Asked the Wrong Question,”American Journal of Bioethics13, no. 12 (2013): 25-26 (criticizing the trial design for being “powered to detect a clinically meaningful decrease in incidence and severity of ROP,” in a way that “ignored the trade-off in mortality risk”); J. F.Merz and N. M. P.King, “Letter to the editor,”British Medical Journal347 (2013): f4198, available at <http://www.bmj.com/content/347/bmj.f4198/rr/653401> (explaining why a composite primary endpoint was inappropriate); C. Natanson, “Comments at OHRP Public Meeting, OHRP Public Meeting Transcript,”supra note 40 (questioning whether experiments of titrated treatments comparing the extreme ends of usual care ranges have scientific merit and are ethical).
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Letter from Michael A. Carome et al. to The Honorable Daniel R. Levinson, Inspector General U.S. Department of Health and Human Services, May20, 2014, available at <http://www.citizen.org/documents/2201.pdf> (last visited August 3, 2017) (detailing evidence of involvement of NIH in suspension of OHRP's compliance action against UAB).
Only very limited exceptions from the general requirements for informed consent have been allowed under the FDA regulations. See 21 C.F.R. 50.23 & 50.24. M. S.Schreiner, “Letter to the Editor,”New England Journal of Medicine370, no. 20 (2014): 1958. The Department of Health and Human Services has recently revised its waiver guidance following implementation of the 21st Century Cures Act to allow waivers or alternations of informed consent for “minimal risk” research. See U.S. Food and Drug Administration, “IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects,” July 2017, available at <https://www.fda.gov/RegulatoryInformation/Guidances/ucm566474.htm> (last visited September 16, 2017).
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W.Rich, N. N.Finer, and M.G.Gantzet al., “Enrollment of Extremely Low Birth Weight Infants in a Clinical Research Study May Not Be Representative,”Pediatrics129, no. 3 (2012): 480-484; S. N.Whitney, “The Python's Embrace: Clinical Research Regulation by Institutional Review Boards,”Pediatrics129, no. 3 (2012): 576-578.
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B. S.Wilfondet al., “The OHRP and SUPPORT,”New England Journal of Medicine368 (2013): e36-e36(3), available at <http://www.nejm.org/doi/full/10.1056/NEJMc1307008> (last visited September 16, 2017).
51.
For babies in the study cared for in NICUs that normally allowed oxygen levels to range from 85% to 95%, or that normally aimed for the middle of that range, we have less information about the comparative risks and benefits of the targeted oxygen levels in the study versus outside the study, because in those sites usual care was not studied. But altering the oxygen targets altered the risks.
52.
See Macklin and Shepherd, supra note 38.
53.
45 C.F.R. 46.116(a)(2).
54.
45 C.F.R. 46.111(a)(2).
55.
S.Joffe and A.Wertheimer, “Determining Minimal Risk for Comparative Effectiveness Research,”IRB: Ethics & Human Research36, no. 3 (2014): 16-18; D.Magnus and B. S.Wilfond, “Research on Medical Practices and the Ethics of Disclosure,”Pediatrics135, no. 2 (2015): 208-210.
56.
See Morse and Wilson, supra note 21.
57.
Looney v. Moore, 2015 WL 4773747 at *8 (N.D. AL. 2015); see Morse and Wilson, supra note 21.
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R.Macklinet al., “The OHRP and SUPPORT — Another View,”New England Journal of Medicine369, no. 3 (2013): available at <http://www.nejm.org/doi/full/10.1056/NEJMc1308015> (last visited August 3, 2017).
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BenWilfond, Comments at Meeting of American Society of Bioethics and Humanities, October27, 2013.
When combined with the four other concurrent trials taking place internationally, the study was powered to detect signifi-cant differences in mortality.
C. H.Cole, K. W.Wright, W.Tarnow-Mordi, and D. L.Phelps, “Resolving Our Uncertainty about Oxygen Therapy,”Pediatrics112, no. 6 (2003): 1415-1419.
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Id.
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See SUPPORT Protocol, supra note 63.
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Magnus and Wilfond, supra note 55.
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J. M.Drazen, C. G.Solomon, and M. F.Greene, “Informed Consent and SUPPORT,”New England Journal of Medicine368, no. 20 (2013): 1929-1931.
72.
B.Freedman, “Equipoise and the Ethics of Clinical Research,”New England Journal of Medicine317, no. 3 (1987): 141-145.
73.
See Trifiletti et al., supra note 4.
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75.
See generally R.Macklin, “More on SUPPORT: The Controversy Continues,”Indian Journal of Medical Ethics12, no. 3 (2015): 169-172.
76.
David Wendler seems to be arguing for some variation of this idea. D.Wendler, “What Should Be Disclosed to Participants?”American Journal of Bioethics13, no. 12 (2013): 3-8.
77.
H.Brody, “Transparency: Informed Consent in Primary Care,”Hastings Center Report19, no. 5 (1989): 5-9.
78.
L.Shepherd, “SUPPORT and Comparative Effectiveness Trials: What's at Stake?”Hastings Center Report45, no. 1 (2015): 44-45.
