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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 370;20 nejm.org may 15, 20141958

Informed Consent for Comparative Effectiveness Trials To the Editor: We reject the argument by Faden et al. (Feb. 20 issue)1 that certain research with randomized assignment of interventions can be conducted without the consent of patients. Whether or not these studies are embedded in the routine processes of medical care, randomiza- tion equals research, and such studies are subject to all of the standard requirements for research, including approval by an institutional review board and patient consent. Patients have the right to choose whether to participate after they have been informed about the interventions, risks, and potential benefits and alternatives, ir- respective of the risk levels of the interventions. Patients are the ultimate arbiters of what is done to them.

Integrated consent, as proposed by Kim and Miller in the same issue of the Journal,2 is fine in theory but difficult in practice. Few studies in- volve the comparison of agents delivered in the same way with similar side effects. In most re- search settings, written disclosure of the treat- ments being compared, including their risks and potential benefits, is necessary. Written docu- mentation of the patient’s agreement to be a re- search subject remains essential. James R. Anderson, Ph.D. Frontier Science and Technology Research Foundation Madison, WI [email protected]

Toby L. Schonfeld, Ph.D. Emory University Atlanta, GA

No potential conflict of interest relevant to this letter was re- ported.

1. Faden RR, Beauchamp TL, Kass NE. Informed consent, com- parative effectiveness, and learning health care. N Engl J Med 2014;370:766-8. 2. Kim SYH, Miller FG. Informed consent for pragmatic trials — the integrated consent model. N Engl J Med 2014;370:769-72.

DOI: 10.1056/NEJMc1403310

To the Editor: In their articles, Faden et al. and Kim and Miller propose alternative approaches to consent for comparative-effectiveness trials. Both articles describe hypothetical studies com- paring two medications with risks and benefits that appear to be similar. Faden et al. recommend that prospective patients could be informed about the trial through streamlined procedures, where- as Kim and Miller suggest that an abbreviated

consent procedure would suffice, and they cite the requirements for alteration of informed con- sent as the justification.1

Unfortunately, even when study drugs are eli- gible for exemption from the investigational new drug requirements of the Food and Drug Ad- ministration (FDA), the investigator must ensure that the “investigation is conducted in compli- ance with the requirements for institutional re- view set forth in part 56 and with the require- ments for informed consent set forth in part 50” of the human-subjects protection regulations of the FDA.2 In contrast to the Common Rule, these FDA regulations do not permit alteration or waiver of consent except under very limited cir- cumstances. The informed-consent documenta- tion and process for the two hypothetical trials described by Faden and colleagues and Kim and Miller would need to fully comply with these regulatory requirements.3

Mark S. Schreiner, M.D. Children’s Hospital of Philadelphia Philadelphia, PA [email protected]

Dr. Schreiner reports serving as the chair of the committees for the protection of human subjects (the institutional review boards) of Children’s Hospital of Philadelphia. No other poten- tial conflict of interest relevant to this letter was reported.

1. Code of Federal Regulations, Title 45, Public Welfare. De- partment of Health and Human Services. Part 46, Protection of human subjects, Section 46.116. 2. Code of Federal Regulations, Title 21, Public Welfare. De- partment of Health and Human Services. Part 312, Investiga- tional new drug application, Section 312.2(b). 3. Code of Federal Regulations, Title 21, Public Welfare. De- partment of Health and Human Services. Part 50, Protection of human subjects, Section 50.25.

DOI: 10.1056/NEJMc1403310

To the Editor: Faden et al. claim that current consent and oversight practices too often under- protect patients from medical error because they make research to reduce these problems very burdensome to conduct. The authors use the pro- cedural difficulty of certain consent processes as part of their justification for their argument that informed-consent processes are not always ethi- cally necessary. However, the doctrine of in- formed consent is intended to protect a patient’s decision-making ability and to respect the per- son’s dignity.1 Although policymakers ought to minimize the difficulties researchers and physi-

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correspondence

n engl j med 370;20 nejm.org may 15, 2014 1959

cians face while conducting their studies, these difficulties are irrelevant to the topic of consent. Furthermore, although medical errors may result from the increased burdens of the consent pro- cesses, that does not mean that policymakers have reason to simply forgo the consent process in certain circumstances. Instead, they should attempt to find ways to better reduce these med- ical errors without potentially compromising a patient’s decision-making ability. Ahmed Elsayyad Johns Hopkins University Baltimore, MD [email protected]

No potential conflict of interest relevant to this letter was re- ported.

1. Wu WC, Pearlman RA. Consent in medical decision making: the role of communication. J Gen Intern Med 1988;3:9-14.

DOI: 10.1056/NEJMc1403310

To the Editor: Faden et al. propose that written, prospective informed consent is not ethically necessary for all comparative-effectiveness re- search (CER) in a mature learning health care system. Although their intention to make such research less burdensome is commendable, there are potential pitfalls to streamlining the informed- consent process. First, the authors propose “transparent mechanisms” to ensure that the public and patients will be aware of ongoing CER studies. Often, however, the patients who are most in need of the protection afforded by the current arduous informed-consent process have poor health literacy and are unable to navigate the complex health care system in the United States. Second, the current informed-consent dis- cussion serves a purpose beyond simply educat- ing the patient. The clinician-researcher wears two hats in the care of patients, and he or she must be cognizant of the different goals of these enterprises to be able to identify and avoid con- flicts of interest. A distinct consent process is a reminder to the researcher of this dual role.

Parth K. Modi, M.D. Rutgers Robert Wood Johnson Medical School New Brunswick, NJ [email protected]

No potential conflict of interest relevant to this letter was re- ported.

DOI: 10.1056/NEJMc1403310

To the Editor: In response to Kim and Miller: there are examples of pragmatic trials that replace physician selection of care with randomized se- lection and do not require individual informed consent. Enhanced Peri-Operative Care for High- risk patients,1 a cluster-randomized trial of a qual- ity intervention for patients undergoing emergency laparotomy, is currently recruiting patients in the United Kingdom. Patients undergo randomiza- tion at the institutional level. There is no require- ment for the physician to conceal inclusion in the study, since the patient receives the same care as any other patient in his or her care. Individualized consent is not a requirement, since the data will be collected by the National Emergency Laparot- omy Audit of the United Kingdom and returned anonymized for data analysis.

It is not unduly paternalistic to randomly as- sign patients this way, because their interests are democratically represented by a patient and pub- lic involvement group (the National Institute for Clinical Excellence Patient and Public Involvement Programme)2 and the intervention, a care path- way, presents little opportunity for meaningful objection. This method of randomization is un- suitable, but the requirement for independent lay members on research ethics committees acts as a check; this makes this method a useful tool for closely integrated health care trials.

Robin T.W. Williams, M.B., B.S. 15 Holmes Rd. London, United Kingdom

No potential conflict of interest relevant to this letter was re- ported.

1. Enhanced Peri-Operative Care for High-risk patients (EPOCH) trial home page (http://www.epochtrial.org/epoch.php). 2. INVOLVE briefing notes for researchers: involving the pub- lic in NHS, public health and social care research. Eastleigh, United Kingdom: INVOLVE (http://www.invo.org.uk/wp-content/ uploads/2012/04/INVOLVEBriefingNotesApr2012.pdf ).

DOI: 10.1056/NEJMc1403310

The Authors Reply: The criticism by Anderson and Schonfeld that randomization constitutes re- search misses our point. CER with randomiza- tion is undeniably research but, in ethically ma- ture learning health care systems, we challenge whether the use of randomization in CER should automatically trigger written informed-consent

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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 370;20 nejm.org may 15, 20141960

requirements. What matters morally in appropri- ate oversight and consent practices is not wheth- er an activity is labeled research, but how the activity affects the rights and interests of pa- tients.1 Even in the current health care context, we question the assumption that randomized CER always compromises these rights and interests. When CER introduces few if any compromises while furthering patients’ interests in improving care, a streamlined consent process is ethically acceptable.

As Schreiner notes, some of our views may not comport with federal regulations. Our arti- cle is not about current regulations or oversight practice; it is about what ethically should exist for CER, both in the future, when morally robust learning health care systems are in place, and in the current health care environment. Elsayyad rightly says that respecting the dignity of pa- tients should remain fundamental, and it is one of seven core obligations in our Common Pur- pose Framework.2 We merely challenge whether written informed consent is always the only or the best mechanism for respecting patients in CER.

Modi correctly states that attention must be devoted to low health literacy. A moral objective in developing transparent mechanisms for learn- ing health care systems and in soliciting in- formed consent is that patients acquire adequate understanding. Consent practices too often work against the goal of patient understanding, espe- cially among patients with low literacy.3,4 In one review, the median length of 124 consent forms was 27 pages.5 Our proposal for a learning health care system further requires that patients be substantively engaged in ethics oversight of research. The moral objective here is that the perspectives and interests of all patients, includ- ing those with low health literacy, figure promi- nently in ethics review.

Kim and Miller mischaracterize our view as a “no consent” model. We maintain that what should be required in the way of consent de- pends not only on characteristics of the research but also on the degree to which morally relevant background conditions are present, including patient engagement, transparency, and account-

ability, as well as on having all patients benefit from CER quality improvements. We support a fundamental obligation to respect the rights of patients that in many research contexts will continue to require individual informed consent. Kim and Miller ignore our core positions on these subjects. They also wrongly conclude that practices and policies grounded in our frame- work would condone or even require untruthful answers by physicians when patients ask why a particular treatment is chosen. We have consis- tently maintained that randomized CER without consent requires that patients appreciate that some learning activities, including those with randomization, occur routinely and always with appropriate review and oversight in which pa- tients are engaged. Physicians in this environ- ment must answer patients’ questions about randomization truthfully, as in all other matters. Concealment has no place in a learning health care system or any other health care system.

Ruth R. Faden, Ph.D., M.P.H. Johns Hopkins University Baltimore, MD

Tom L. Beauchamp, Ph.D. Georgetown University Washington, DC

Nancy E. Kass, Sc.D. Johns Hopkins University Baltimore, MD

Since publication of their article, the authors report no fur- ther potential conflict of interest.

1. Kass NE, Faden RR, Goodman SN, Pronovost P, Tunis S, Beauchamp TL. The research-treatment distinction: a problem- atic approach for determining which activities should have ethi- cal oversight. Hastings Cent Rep 2013;43(1):Spec No:S4-S15. 2. Faden RR, Kass NE, Goodman, SN, Pronovost P, Tunis S, Beauchamp TL. An ethics framework for a learning health care system: a departure from traditional research ethics and clinical ethics. Hastings Cent Rep 2013;43(1):Spec No:S16-S27. 3. Nishimura A, Carey J, Erwin PJ, Tilburt JC, Murad MH, Mc- Cormick JB. Improving understanding in the research informed consent process: a systematic review of 54 interventions tested in randomized control trials. BMC Med Ethics 2013;14:28. 4. Tamariz L, Palacio A, Robert M, Marcus EN. Improving the informed consent process for research subjects with low literacy: a systematic review. J Gen Intern Med 2013;28:121-6. 5. Kass NE, Chaisson L, Taylor HA, Lohse J. Length and com- plexity of US and international HIV consent forms from federal HIV network trials. J Gen Intern Med 2011;26:1324-8.

DOI: 10.1056/NEJMc1403310

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