Letters

the subtleties in judging whether these criteria are met, we believe this decision is best left to an IRB. David W. Baker, MD, MPH Stephen D. Persell, MD, MPH Author Affiliations: Division of General Internal Medicine and Geriatrics, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Corresponding Author: David W. Baker, MD, MPH, Division of General Internal Medicine and Geriatrics, Department of Medicine, Feinberg School of Medicine, Northwestern University, 750 N Lake Shore Dr, 10th Floor, Chicago, IL 60611 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pletcher MJ, Lo B, Grady D. Informed consent in randomized quality improvement trials: a critical barrier for learning health systems. JAMA Intern Med. 2014;174(5):668-670. 2. Baker DW, Brown T, Buchanan DR, et al. Design of a randomized controlled trial to assess the comparative effectiveness of a multifaceted intervention to improve adherence to colorectal cancer screening among patients cared for in a community health center. BMC Health Serv Res. 2013;13:153. 3. Tang JW, Kushner RF, Cameron KA, Hicks B, Cooper AJ, Baker DW. Electronic tools to assist with identification and counseling for overweight patients: a randomized controlled trial. J Gen Intern Med. 2012;27(8):933-939.

In Reply We thank Baker and Persell for their thoughtful response. It is indeed useful to consider specific criteria for deciding when a waiver of consent is justified, and we generally agree with the criteria they propose. We also wish to emphasize their and our recommendation that an institutional review board be involved in decision making. The decision to waive consent in a randomized clinical trial is an important one that should be vetted carefully by a disinterested panel, even if the study can be considered a “quality improvement” project. While the minimal risk criterion proposed is clearly a very important consideration, we take issue with one aspect of their discussion. When the control group receives pure usual care such that there is no perturbation whatsoever in the best judgment of the treating clinicians, and also no added burden to patients in the study, we would argue that this control group would not be at any increased risk from participation in the study besides the loss of confidentiality that may come from analysis of health records. The fact that some other patients (those randomized to the intervention) receive an intervention that might improve health does not itself place those randomized to control at any increased risk. We do agree, however, with the importance of planning explicitly to offer the intervention to all participants (and presumably the rest of the eligible population) after the criterion for proving benefit has been met. The time has come for serious dialogue on these topics, with input not only from medical professionals and ethicists but also from patients, health system administrators, institutional review boards, and regulators. We believe consensus can be reached that would help us realize the goal of creating a learning health system.1 Mark J. Pletcher, MD, MPH Bernard Lo, MD Deborah Grady, MD

Author Affiliations: Department of Epidemiology and Biostatistics, University of California, San Francisco (Pletcher); Department of Medicine, University of California, San Francisco (Pletcher, Grady); Clinical and Translational Science Institute, University of California, San Francisco (Pletcher, Grady); The Greenwall Foundation, New York, New York (Lo); Deputy Editor, JAMA Internal Medicine (Grady). Corresponding Author: Mark J. Pletcher, MD, MPH, Department of Epidemiology and Biostatistics, University of California, San Francisco, 185 Berry St, Ste 5700, San Francisco, CA 94107 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Institute of Medicine. Large Simple Trials and Knowledge Generation in a Learning Health System: Workshop Summary. Washington, DC: Institute of Medicine; 2012.

Is There More Than Just 1 Ethical Standard for Clinical Trials? To the Editor Two recent articles in JAMA Internal Medicine1 and JAMA2 addressed ethical issues of health care interventional research with respect to seeking informed consent from patients, but they argue from quite different angles, questioning or in favor of fully informed patients. The Viewpoint by Nayak et al2 argues that patients should also be fully informed about the economic motivation for the study when trials are conducted predominantly (or exclusively) for economic reasons of otherwise comparable therapies, referring to a comparative effectiveness drug trial in agerelated macular degeneration.3 The Editorial by Pletcher et al1 argues that for quality improvement (QI) trials based on electronic medical records such as the one discussed in the same issue of JAMA Internal Medicine,4 informed consent prior to study inclusion may be dispensed because of the increased risk to loose patients not willing to participate (and thus biasing the sample) and because the QI does not pose patients to an additional risk beyond treatment as usual but normally improves their individual well-being. These 2 positions are incompatible. While researchers may appreciate the occurrence of novel designs that move toward testing therapeutic interventions “in the real world” of everyday medicine rather than in artificial randomized clinical trial situations, especially since these are at risk for becoming severely biased by the use of social media of recruited patients, not every novel design appears to meet the same ethical standards. If cost arguments for a clinical trial need to be disclosed to patients, this request is even more valid for QI trials, which are performed more often for economic than for any other reasons. For example, in the cited “Veterans Victory over Tobacco Study,”4 improving patient care is not only an intervention that may improve individual health conditions of smokers but also prevents secondary costs of smoking and thus benefits the health care system in general and health insurance plans specifically. The dropout rates reported following fully informed consent2,4 demonstrate that the commercial and/or societal benefit may be much more relevant than the individual benefit as seen from a patients perspective, at least for a substantial subgroup of those approached via their electronic medical records. Therefore, if the ethical standards of the Declaration of Helsinki recently renewed for randomized interventions5 (and not for QI assessments only) remain valid, there cannot be differ-

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ent ethical standards for different types of clinical trials but only one: fully informed consent. Paul Enck, PhD Author Affiliation: Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany. Corresponding Author: Paul Enck, PhD, Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Frondsbergstr 23, 72076 Tübingen, Germany ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pletcher MJ, Lo B, Grady D. Informed consent in randomized quality improvement trials: a critical barrier for learning health systems. JAMA Intern Med. 2014;174(5):668-670. 2. Nayak RK, Pearson SD, Miller FG. Cost-related motivations for conducting research: participants should be informed. JAMA. 2014;311(15):1491-1492. 3. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ; CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908. 4. Fu SS, van Ryn M, Sherman SE, et al. Proactive tobacco treatment and population-level cessation: a pragmatic randomized clinical trial. JAMA Intern Med. 2014;174(5):671-677. 5. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194.

Faster Brain Shrinkage in the ACCORD MIND Study: An Unexpected Result? To the Editor In the context of the current controversy regarding the optimal goal for blood pressure (BP) control triggered by the publication of “JNC 8” (Eighth Joint National Committee),1 one more dismaying finding from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial published in JAMA Internal Medicine has cast additional doubts on the potential benefits of intensive BP lowering in older adults. The ACCORD Memory in Diabetes (MIND) study, a substudy of the main ACCORD trial, reported that intensive lowering of systolic BP to a target of lower than 120 mm Hg caused more declines in total brain volume (TBV) measured with magnetic resonance imaging, a surrogate of neurodegeneration, in older adults with established type 2 diabetes mellitus (T2DM) compared with those who received a standard therapy of lowering systolic BP below 140 mm Hg.2 No differences in cognitive function were observed between the intensive and standard BP interventions. These observations are “unexpected” in that the study authors hypothesized that intensive BP lowering would result in less, rather than more, declines in TBV and thus better brain health. We congratulate the authors for such an important study. However, we believe that an important link is missing regarding how these findings should be interpreted in the setting of intensive BP lowering in older adults. Previous studies have demonstrated that cerebral autoregulation— the capacity of the cerebral vasculature to maintain stability of brain blood flow during changes in BP—is impaired in older adults with T2DM.3 Thus, brain perfusion could have been compromised substantially during intensive BP lowering in those with established T2DM. This possibility is consistent with the observed greater decline in TBV because a 144

fundamental coupling relationship exists between TBV (metabolism) and blood flow supply. Conversely, we have shown that intensive BP lowering did not reduce brain blood flow, and cerebral autoregulation was intact in middle-aged and older adults without diabetes.4 In fact, brain gray matter perfusion was increased during intensive BP lowering (

Is there more than just 1 ethical standard for clinical trials?

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