HomeCirculationVol. 120, No. 21Ethical Issues in Cardiovascular Research Involving Humans Free AccessAnnouncementPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAnnouncementPDF/EPUBEthical Issues in Cardiovascular Research Involving Humans Robert L. Frye, Robert D. Simari, Bernard J. Gersh, John C. Burnett, Shari Brumm, Kathleen Myerle, Allan S. Jaffe, David R. Holmes, Amir Lerman and Andre Terzic Robert L. FryeRobert L. Frye From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , Robert D. SimariRobert D. Simari From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , Bernard J. GershBernard J. Gersh From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , John C. BurnettJohn C. Burnett From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , Shari BrummShari Brumm From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , Kathleen MyerleKathleen Myerle From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , Allan S. JaffeAllan S. Jaffe From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , David R. HolmesDavid R. Holmes From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author , Amir LermanAmir Lerman From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author and Andre TerzicAndre Terzic From the Division of Cardiovascular Diseases, College of Medicine (R.L.F., R.D.S., B.J.G., J.C.B., A.S.J., D.R.H., A.L., A.T.); Center for Translational Research (S.B.); and Legal Department, Mayo Clinic (K.M.), Rochester, Minn. Search for more papers by this author Originally published24 Nov 2009https://doi.org/10.1161/CIRCULATIONAHA.107.752766Circulation. 2009;120:2113–2121This component of the series “Careers in Cardiovascular Research: A Primer for New Investigators” will address ethical conduct of research involving humans. The dramatic decline in cardiovascular mortality (Figure) provides testimony to the societal benefits of research leading to new therapies and systems of care.1 In concert with these rapid developments, changing expectations have resulted in the emergence of ethical issues with highly publicized examples of concern over conduct of research in humans.2–5 Whereas professional ethics should, and for most physicians do, “regulate” conduct of biomedical research, “self-regulation” does not always meet societal expectations. Dr Barry Coller6 has pointed out that science lacks intrinsic morality. Thus, the laudable goals of improving patient care, understanding mechanisms of disease, or protecting society from perceived external threats do not justify ignoring fundamental human rights that guide (and regulate) the conduct of research. Download figureDownload PowerPointFigure. Death rates for cardiovascular disease in the United States, 1900 to 2005 (not adjusted for age).At the same time it is important to reflect on the importance of physicians participating in research and providing the opportunity for their patients to do so. Although some have argued this compromises the basic physician responsibility to a patient,7 we believe the best interest of the patient can and must be protected in the research setting. Two brief examples demonstrate the fundamental changes in understanding that may arise from direct involvement of physicians in research. As late as the 1970s, the prevailing wisdom to explain the presence of intracoronary thrombus on postmortem examination of patients after myocardial infarction was simply wrong; pathologists studying hearts in this setting found evidence to “suggest that coronary thrombi are consequences rather than causes of acute myocardial infarction”8 and “consideration is given to the possibility that some thrombi may follow rather than precede myocardial necrosis.”9 The primary role of thrombus in the genesis of acute myocardial infarction was subsequently established by physicians caring for their patients and by the observations from coronary arteriography and coronary artery bypass surgery during the acute phase of the event.10 The subsequent proof that intervention early in the course of myocardial infarction with thrombolysis or primary angioplasty reduces mortality could not have been accomplished without individual physicians on the front line of practice involving their patients in those investigations. A dramatic reduction in mortality with acute myocardial infarction has been achieved.A more recent example of a clinical trial that had a fundamental impact on practice and that depended on physicians involving their patients as subjects in research is the Cardiac Arrhythmia Suppression Trial (CAST).11 It was known that cardiac death was related to ventricular arrhythmias and that drugs were widely used that reduced ventricular premature contractions. The assumption had been made clinically that treatment of ventricular premature contractions with antiarrhythmic drugs would therefore decrease mortality. Many patients received these drugs in anticipation of benefit. Finally, CAST was performed as a large clinical trial, which documented that the drugs used clinically to prevent cardiac death actually increased mortality. This research has dramatically changed practice and saved lives. We use these examples to emphasize the critical role of physicians caring for their own patients also engaging in the effort to advance knowledge and improve care. In both examples, the established opinion influencing care was proved to be wrong, confirming the need for continued questioning of established dogma. At the same time we believe that rights of patients and subjects must be respected.The National Institutes of Health Roadmap12 recognizes the importance of clinical research and the need to “reengineer” the process with an emphasis on collaboration and translation of new knowledge to the community. An essential element will be specific training of clinicians in research methodology, the ethics of research, and the regulations that govern these activities. New discoveries such as gene and cell repair therapy, the patent process, and physician involvement in the biotechnology industry introduce the potential for a multiplicity of potential conflicts of interest.13 Our goal is to provoke reflection by investigators on the basis for current regulations governing research in humans and to urge careful attention to these regulations in the planning and conduct of their own research.Informed ConsentAdequate informed consent is fundamental to the ethical conduct of research in humans. Society has demanded greater efforts to protect individual rights of patients and human subjects. This is an evolving and complex area. We must understand and appreciate the historical basis for society’s concerns, including the real and perceived nature of physician authority, to deal with the current regulatory environment.History of Informed ConsentHistories of informed consent14–17 include efforts to inform patients like the efforts of Dr William Beaumont in 1833 for studies on Alexis St. Martin.18 The key elements included provisions that consent of the subject is essential, and withdrawal from the study is allowed if the subject is dissatisfied. Dr Walter Reed, in his yellow fever investigations, also developed a consent form in 1900, which included payment for participation in this research program.19Most consider the Nuremberg Code as the initial basis for our concept of informed consent. Vollmann and Winau20 document concepts of informed consent based on autonomy and enhanced risk of violation of individual rights in vulnerable populations, which were articulated in Germany during the latter part of the 19th century as scientific medicine was beginning to flourish. A directive issued in 1891 by the Prussian minister of the interior to all prisons stated that tuberculin “must in no case be used against the patient’s will.”21 In 1898, public concern over syphilis experiments performed in prostitutes without their consent by Neisser (discoverer of the gonococcus) led to a commission that dealt with issues of beneficence and autonomy, concluding that individual consent was essential before any human experimentation.20 Though most academics supported Neisser, he was fined on the basis of failure to obtain consent of those in his trials. Legal opinion at the time established liability under criminal law for studies without consent.20As late as 1931, the Weimar government issued “guidelines for new therapy and human experimentation” based on principles of informed consent.22 Dr Albert Moll,23 who was critical of Neisser’s experiments and other human investigations in Germany, published 600 examples of research involving humans he considered unethical. He was an early proponent of the concept of informed consent.20 Why these historical facts are ignored is unclear; they provoke reflection on how ethical principles may become compromised. Barodness has addressed these issues in a thoughtful manner.24Even before the Nazis came to power, eugenics to eliminate or sterilize those perceived to be “inferior” was gaining support. The United States was perceived by some as leading in this effort. Indiana was the first state to pass legislation in 1907 to allow involuntary sterilization of mentally defective and some criminal individuals, and by 1926, 23 states had implemented similar legislation.25 One finds in Science26 the opening address of the president of the American Eugenics Society asking for understanding and reflecting dismay that the program was misunderstood. Sofair and Kaldjian25 explored opinion in the United States on human research, including the activities in Germany, by analyzing editorials in the Journal of the American Medical Association (JAMA) and the New England Journal of Medicine (NEJM) between 1930 and 1945. The authors found a surprising scarcity of concern in this review and the following statement: “Germany is perhaps the most progressive nation in restricting fecundity among the unfit” by editors of the NEJM in 1934, a year after Hitler became chancellor.25 How do such trends in ethical compromise occur, and how do we ensure that violations of human rights do not occur in our own time? Marks has pointed out these hazards in a thought-provoking review of “doctors from hell” in the Journal of Clinical Investigation.27After World War II, the Nuremberg Tribunal was formed to prosecute Nazis charged with war crimes in an international court of law. This included a doctors’ trial, which began on December 9, 1946. Of 23 defendants, 20 were physicians charged with atrocious human experimentation. The deliberations of the tribunal led to the articulation of 10 directives for human experimentation that constitute the Nuremberg Code. The Declaration of Helsinki followed in 1964 and was endorsed by most countries as a guide to human research. The Declaration of Helsinki distinguishes between therapeutic and nontherapeutic research and provides that informed consent is not necessary in therapeutic research if “not consistent with patient psychology” and “approved by a review committee.”28 This principle is consistent with the plan implemented in the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarcto miocardico (GISSI) trial to enroll patients without informed consent to “protect the right of the patient not to be exposed to an emotionally burdensome request for informed consent”—a design approved by the responsible ethics committees, which included judges.29Because of growing concern amid a rapidly expanding biomedical research effort, a survey by the Law-Medicine Research Institute of Boston University, with the support of the United States Public Health Service (USPHS), addressed in 1962 the conduct of clinical research at that time.30 Of 52 departments of medicine responding to the survey, few had any procedural guidelines for conduct of research. The prevailing opinion held that the responsibility for regulation should be left to the investigator rather than a committee. The Advisory Committee on Human Radiation Experiments appointed by President Clinton in 1994 documented an environment in the years after World War II when research involving patients was performed without formal consent, in contrast to research involving normal volunteers.31 The equanimity of those times had been challenged in 1966 by Dr Henry K. Beecher32 in an article describing 22 published studies that in his opinion had ethical problems. His goal was to “call attention to a variety of ethical problems found in experimental medicine.” (In the spirit of full disclosure, one of the authors [R.L.F.] is a coauthor of one or more of the citations).Subsequent revelations of experiments at the Jewish Chronic Disease Hospital33 and Willowbrook School involving mentally defective children34 aroused great consternation, based in part on issues of consent. However, it was the Tuskegee Syphilis Study that shocked Congress into action. The Tuskegee study,35 started in 1932, initially to determine incidence of syphilis in Macon County, Alabama, subsequently shifted focus to observe the natural history of untreated syphilis with support by the USPHS including the Centers for Disease Control. An article in the New York Times36 describing the project led to congressional hearings. Lack of consent, inclusion only of a poorly educated black population, and obtaining spinal fluid examination under the guise of receiving a new treatment while actively withholding effective therapy were among the list of violations of ethical principles. Ultimately, Congress passed the National Research Act in 1974, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to advise on ethical conduct of research in humans. In 1979 the Commission published the Belmont Report, which was named after the Smithsonian Institute Conference Center where the Commission met.37 The report identified three fundamental principles for all human subject research: respect for persons, beneficence, and justice. The end result is the Code of Federal Regulations (CFR), Title 45, Part 46, which now encompasses a uniform set of regulations known as the Common Rule, which governs all research involving humans supported by federal funds. With limited exceptions, these regulations and those at 21 CFR 50 and 56 governing research under the US Food and Drug Administration cover basically all research activities involving humans.Given the above history, it is sobering to reflect on the Total Body Irradiation Study38 carried out at the University of Cincinnati after the Nuremberg Code and the Declaration of Helsinki. The study was supported by the Department of Defense. Started at the height of the Cold War, the objective was to determine how total body radiation might affect military personnel after a nuclear explosion. Though disapproved by the Atomic Energy Commission and the National Institutes of Health on ethical grounds and receipt of critical reviews within the University of Cincinnati, the project was implemented and continued in operation from 1960 to 1972. Dr Eugene Saenger directed the project in cancer patients seeking treatment for their cancer. Total body irradiation was performed under the guise of cancer treatment, though the purpose was research for which the patients had not consented.38 In 1966, it was reported that 10 patients died within 37 days of the treatment. There are estimates that 20 patients out of 87 died as a result of the experiment.39 An investigation by the American College of Radiology in 1971 to 1972 apparently found no ethical concerns. However, in subsequent litigation and a settlement with the subjects’ families, the following statement is displayed in the University of Cincinnati Hospital: “The Cincinnati citizens listed below were the innocent victims of human radiation experiments in this hospital from 1960 to 1972. Their names are placed here so that all may remember their injuries and afflictions, and their unwitting sacrifice in a project sponsored by the US Department of Defense and carried out by professors in the University of Cincinnati College of Medicine.”40Perceptions of the Autocratic Physician and the Failure of Self RegulationThe understanding of societal concerns relative to research involving humans and the process of informed consent requires reflection on physician behavior and the negative impact of the autocratic and/or insensitive physician as a serious barrier to the process of informed consent. Andrew Scull, in his 2005 book entitled Madhouse: A Tragic Tale of Megalomania and Modern Medicine,41 provides a frightening portrayal from the first half of the 20th century of the power of an individual physician to inflict brutal and horrifying surgical interventions on mentally impaired patients without consent. Convinced that removing “foci of infection” would cure mental illness, Dr Henry Cotton and his colleagues performed colectomies, total dental extractions, and other procedures without consent on those impaired with mental illness.41 Descriptions are provided of patients being literally dragged to the operating room against their will and forced to undergo surgical interventions on the basis of Dr Cotton’s certainty that this was in the best interest of the patient and society. Support for these surgical interventions was evident in the United Kingdom and Europe, and Cotton received warm welcomes on several tours presenting his data. Skepticism and outright criticism were expressed in some quarters of the medical profession, but major leaders of medicine were loath to criticize. In particular, Dr Adolph Meyer, Chief of Psychiatry at the Johns Hopkins Hospital, who was a mentor of Dr Cotton, suppressed an investigation by one of his own faculty proving that that Cotton’s claims for success were bogus. Even after Cotton’s death, Meyer lauded Cotton for his “remarkable achievement of the pioneer spirit.” Scull42 comments as follows: “How could such horrors occur in American medicine under the guise of clinical practice in the best interest of the patient?” Though Cotton never convinced most of his peers, Scull again notes, “But scarcely anyone doubted his right to experiment on his patients or raised in any serious or sustained manner any questions about the propriety of maiming and mangling the bodies of the mad—not even when Cotton confessed on occasion, that his surgical interventions proceeded notwithstanding verbal and physical resistance from their victims.”43 This frightening example of the power of physicians to inflict great harm under the banner of doing what they perceive is in the best interest of the patient, even when the patient strongly disagrees, is profoundly disturbing. It is also an example of failure of the profession to self regulate.Another example of attitudes to informed consent later in the 20th century is evident in an editorial after the publicity of the Tuskegee experiments: “In the days of the Tuskegee Study we used to walk into a patient’s room and announce ‘We’re going to take out your gallbladder tomorrow morning’; the answer was commonly OK and that was it—no informed consent, no signed paper of permission—ergo Jenner, the Hunters, Pasteur and hundreds of thousands of physicians of the past have been unethical in terms of informed consent.”44 Note that these comments were published in 1974.This review of landmarks in the evolution of informed consent and the examples of autocratic physicians, combined with the failure of the profession to self regulate, may help in understanding the extensive regulatory environment that now exists in the conduct of research involving humans.Informed Consent, Clinical Practice, and Research Involving PatientsProfessor Jay Katz, in his plenary address entitled “Human Sacrifice and Human Experimentation: Reflections at Nuremberg on the 50th Anniversary of the Nazi Doctors Trial,”7 concludes that regulations requiring informed consent will fail to achieve the goal of protecting individual rights of patients and human subjects “unless physician investigators embrace these rights as a new Hippocratic commitment.” He also challenged acceptance of medical research as part of medical practice: “When medical science and medical practice became intertwined, a new ethical question should have been raised: Are physicians’ obligations to their patient-subjects different from their obligations to their patients?” We believe our obligations as physicians to subjects are the same as those to our patients41: that physicians must still care for their patients involved in clinical trials or other research while adhering to protocols for creating generalized new knowledge. The natural history of patients in long-term trials will change with time, and the physician-investigator must make judgments about conflicts between protocol and the best interest of the patient. Involvement of a colleague without a commitment to the trial may be of value in such settings. Random assignment to the medical arm of a revascularization trial does not mean that one is denied appropriate revascularization therapy if clinical conditions change with time. Thus, many trials test treatment strategies rather than a rigid comparison of one treatment versus another.Fundamental to the process is equipoise. Clinical trials require equipoise—ie, real uncertainty as to the outcomes associated with the intervention or treatment strategy under investigation.45 We believe this is appropriate and consistent with physician responsibility of caring for individual patients to be honest when there is uncertainty and providing the opportunity for patients to participate in resolving the uncertainty in properly designed trials. Refusal to admit uncertainty in clinical practice when it exists, particularly when it is in the financial interest of the physician to deliver care that is of uncertain value, raises equally important ethical issues.Although equipoise is essential to conduct a clinical trial, it is not possible to address all uncertainties in medicine with randomized trials. How, then, should an investigator decide whether the risks are worthwhile to define equivalence of practice? In essence, such risks must be intrinsic to the finding of equipoise: the risks of both approaches are similar. What are the considerations in determining that an “uncertainty” be proposed for a clinical trial? Relevance to current practice and patterns of disease is essential. Those dealing with major public health issues deserve attention. Feasibility is a crucial determinant; although a question may be unresolved, it may be impossible to actually implement a clinical trial. Some may question commitment of resources to study equivalence of treatment interventions, but we believe these trials are still important when properly designed and implemented. Examples include direct comparison of different stents and efforts to determine whether less-invasive therapies such as percutaneous interventions are “no worse” than cardiac surgery. All current trials must include an effort to provide ongoing established therapy for all participants. The following questions focus on addressing the realities of informed consent:What Are the Necessary Elements of Informed Consent?The first principle of the Nuremberg Code46 identifies the elements of informed consent: “The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him/her to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him/her the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonable to be expected; and the effects on his/her health or person which may possibly come from his/her participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests on each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.”Current regulations on essential elements of informed consent can be found in 45CFR 46.116. Table 1 summarizes components of informed consent. Table 1. Components of Informed ConsentExplanation of research purpose, including experimental parts, procedures and durationClarify risks and discomfort to subjectIdentify potential benefits to subjectExplain alternative treatment optionsWhat happens if injury or complications?Contacts for subject if questionsParticipation voluntary, will not influence other care, and may terminate at any timeWhat Is the Process of Informed Consent?The process to achieve informed consent ideally provides these conditions: Time and an environment to establish a relationship of trust.Information on which consent is based.Multimedia materials to enhance understanding.Presentation of the written consent document.An opportunity for questions and discussion with the responsible physician investigator and those to whom initial responsibility for consenting has been delegated.Providing information during and after conclusion of the trial.Focus on a consent document alone is misplaced. In part, this relates to our experience at the Mayo Clinic, where consent forms for clinical practice were never used until recently, when they were required by the Centers for Medicare and Medicaid Services. The emphasis has been on direct face-to-face communication with patient and family to discuss risks and objectives of any intervention and in doing so to establish trust and understanding. It seems the longer the consent document the less likely it will be read completely. More important in the process of consent is the verbal direct contact with the patient and establishment of trust. The process of consent should include continuing efforts during the conduct of the trial to ensure understanding of the research protocol.Recognition of the powerful influence of the physician responsible for the care of the patient on decisions to participate in research is most important. Although concern about consent in vulnerable populations is clear, including those in acute care settings, note the comments of Dr Uwe Reinhardt, a Princeton professor and health economist, who agreed to participate in a trial so he would not upset his physician, as reported in an article from the New York Times,47 “The physician has enormous power over you. You want to keep his favor. If you say no, you’ll worry that he may not like you.” The process of consent then must be sensitive to the concern that the patient–physician relationship will be a form of coercion leading to inappropriate consent. Involving another colleague in the consent process and identifying other physician availability for management of usual care in such settings is of value in dealing with this dilemma. The following excerpt from a letter to patients considering participation in a research protocol in psychiatric studies may be considered: “Your health care provider may be an investigator of this research protocol, and as an investigator, is interested in both your clinical welfare and in the conduct of this study. Before entering this study or at any time during the research, you may ask for a second opinion about your care from another doctor who is in no way associated with this project. You are not under any obligation to participate in any research pr