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doi:10.1111/jgh.12755
REVIEW
Ethical issues in gastroenterology research* Gregory L Eastwood Center for Bioethics and Humanities, State University of New York Upstate Medical University, Syracuse, New York, USA
Key words bioethics, conflicts of interest, ethics, human subjects, research ethics. Correspondence Gregory L. Eastwood, Office of the President, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Email: eastwood@upstate .edu *Presented at the 15th Taishotoyama International Symposium on Gastroenterology, September 26, 2013, Tokyo, Japan. Funding: The author has received no funding for the development of this paper. Potential conflict of interest: The author declares no conflicts of interest.
Abstract Ethical issues have become increasingly important in gastroenterology research. This is for several reasons, including (i) an understanding of how conflicts of interest might affect research, (ii) the influence of the drug and device industries on research, (iii) ghostwriting (taking credit for something you did not write), (iv) the occurrence of ethically inappropriate research and scientific misconduct, and (v) respect for the rights of research subjects. These include the rights (i) to give informed consent to participate after understanding the purposes, risks, and benefits of the research; (ii) to ask questions; and (iii) to withdraw from participation at any time. Notions of doing good (beneficence), avoiding harm (nonmaleficence), confidentiality, and, most important, the primacy of the welfare of the patient or research subject can be traced to antiquity. In the modern era, the Nuremburg Code (1947), the Declaration of Helsinki (1964), the Belmont report (1979), and other events and reports have led to the refinement of ethical practices in both clinical and research domains, have reinforced those long observed principles, and have given rise to the newer principles of autonomy and justice. The ethical conduct of research not only promotes good research but also is in the best interests of research subjects, investigators, sponsors, patients, and the public.
Ethical issues have become increasingly important in gastroenterology research, particularly research that involves human subjects. This is the consequence of a number of interrelated issues, such as the growing awareness of potential conflicts of interest, concerns about the influence of industry on the conduct and outcomes of research, the practice of so-called ghost writing, revelations of ethically questionable research and scientific misconduct, and a heightened emphasis on the rights of research subjects. Contemporary notions of appropriate ethical behavior in research are derived from ethical principles and values that have their roots in the practice of medicine in ancient times, but which have been modified and expanded by events in the contemporary era. In the following, I first will review the development of ethical principles that apply to the conduct of human research today and then examine several of the important ethical issues in gastroenterology research.
Development of contemporary ethical principles in human research Ethics asks, What is the right thing to do in this situation?, taking into account the law, moral values, personal beliefs, and social norms. To a large extent, our ideas of what is the right thing to do have their roots in the practice of medicine and the philosophic and religious teachings from ancient times. 8
Hippocrates (470–410 BC), in the Oath that bears his name, proclaimed: “I will come for the benefit of the sick . . .” This describes the ethical principle of beneficence or doing good. Hippocrates also said, “I will keep them from harm and injustice,” which is non-maleficence, the notion of avoiding or minimizing harm. “What I see or hear in the course of treatment or even outside . . . I will keep to myself,” speaks to confidentiality of information relating to patients. And “The health and life of my patient will be my first consideration” is, in my view, the fundamental principle of medicine. It means that physicians commit to putting the welfare of the patient, and thus the research subject, first, above their own interests and the interests of the institution and research sponsor. This principle is not only why we practice medicine, but also why we educate students, engage in administrative activities, promote social actions, and, of course, perform biomedical research—all to foster the welfare of patients. In Japan, Confucian ethics has had a large influence on contemporary ethical thought. Confucius (551–479 BC) advocated that physicians should have jin, meaning benevolence, and that they should value life, show concern for suffering, practice medicine with honesty, and treat all patients equally.1–3 To Confucius, medicine was the art of jin. In Buddhism, the concepts of daiji, the mercy of Buddha, and sokuin, meaning sympathy or benevolence, which is similar to the jin of Confucius, were combined; physicians need to have daiji-sokuin, a mix of mercy, sympathy, and benevolence.2 The Christian influence in Japan, with its emphasis
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 8–11 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
GL Eastwood
on mercy, benevolence, compassion, and healing, reinforces these concepts. With foundations in ancient practices, bioethical concepts have matured and changed in the contemporary era. Events in the research domain have raised ethical questions and helped clarify our notions of appropriate research and the rights of research subjects. In 1947, the Nuremberg Code was developed as a consequence of the Nuremberg doctors’ trial, which was one of 13 Nuremberg trials after World War II in which the leaders of the Nazi regime were prosecuted for crimes against humanity. The 1947 doctors’ trial resulted from the Nazi medical research atrocities in the 1930s–1940s in which physicians and their assistants had conducted experiments that included shooting, infecting, freezing, starving, and sterilizing prisoners and others.4,5 Some of the important elements of the Nuremberg Code were (i) consent of subjects must be voluntary, informed, and without coercion; (ii) the benefit to society must be greater than the risk to the subject; (iii) subjects must be protected against possibilities of injury, disability, or death; (iv) the research must be performed by scientifically qualified persons; and (v) subjects have a right to withdraw from the research without repercussions.4,6 In 1953, the description of the structure of DNA by Francis Crick, Rosalind Franklin, and James Watson led to the remarkable expansion of genetics and the new field of genomics and a better understanding of how DNA might be damaged spontaneously and by radiation and chemicals. It also raised many ethical issues related to gene manipulation, selection for desired traits, and eugenics. E. O. Wilson has raised the possibility of controlling the future evolution of humans. He says, “Thanks to advances in genetics and molecular biology underway, hereditary change will soon depend less on natural selection than on social choice. Possessing exact knowledge of its own genes, collective humanity in a few decades can, if it wishes, select a new direction in its evolution and move there quickly . . . The prospect of this ‘volitional evolution’—a species deciding what to do about its own heredity—will present the most profound intellectual and ethical choices humanity has ever faced.”7 In 1964, the Declaration of Helsinki acknowledged the need to study people who cannot consent, such as infants, children, the mentally disabled, and the critically ill, but still need to be involved in research studies. This introduced the notion of identifying surrogates or guardians who can make decisions on behalf of those who cannot speak for themselves, according to their wishes or best interests. In 1979, the Belmont Report on Ethical Principles and Guidelines for Human Subjects Research, commissioned by the US Congress, drew distinctions between medical practice and research. The report declared that in the practice of medicine, interventions are intended to benefit the patient, whereas research is to test a question and thus the subject may not benefit. In fact, research subjects bear the risks of research, although others are likely to benefit from it. The report also affirmed the principle of beneficence, meaning all efforts should be made to secure the subject’s well-being, and the principle of respect for persons, that people are autonomous, and if autonomy is diminished, the person is entitled to protection. These events and reports, although not exhaustive, are sufficient to appreciate the essential contemporary ethical principles that
GLE: Ethical issues in GI research
guide clinical research. They include beneficence (the intent to do good), non-maleficence (the avoidance of harm), justice (treating subjects fairly and raising the question, Who will benefit from the research?), autonomy (respecting the right of persons to choose for themselves and act freely), and, the fundamental principle, putting the interests and welfare of the subject first before the interests of the investigator, the interests of the institution in which the research is conducted, the interests of the sponsor of the research, or other interests. The principles seem to reflect similar ethical values both in Japan and in so-called Western culture, particularly with regard to a common emphasis on benevolence and the welfare of the patient. However, how those values are expressed may be different in degree and nuance. For example, in Japan, the values placed on deference to authority, striving for harmony with others, and thinking of oneself as part of a family or group, each may affect the expression of these ethical principles, perhaps diminishing the expression of autonomy and favoring the roles of authority, harmony, family, and tradition. The following scenario illustrates an ethical dilemma in which the rights of a patient or research subject come in conflict with the ethical duties of a physician researcher in training as they may be affected by the desire to respect the instructions of the person in authority. Prof. M, chair of Gastroenterology at a respected medical center, is known around the world for his research on nitric oxide (NO). To provide a control group and to investigate NO in various clinical conditions, Prof. M instructs his fellow, Dr. S, to obtain gastric and duodenal biopsies in patients who are undergoing upper GI endoscopy for clinical reasons. Prof. M says that it is not necessary to ask permission for additional research biopsies, because the patients already have consented to endoscopy and possible biopsy for clinical reasons. This scenario raises several questions that are broadly relevant, such as, Is it necessary for patients to consent to additional research biopsies, thus consenting to participate as a research subject, when they already have consented to biopsies for clinical purposes? (Yes, it is necessary.) What should a person in a subordinate position do when that person questions the judgment or actions of a person in authority? Is the person in authority always right?
Some important ethical issues in gastroenterology research Conflicts of interest. Conflicts of interest occur when researchers “are tempted to deviate or do deviate from their professional obligations for economic or other personal gain.”8 I believe that a conflict of interest is anything that comes between the investigator and the welfare of the research subject or between the investigator and the proper conduct of the research. Often one thinks of a conflict of interest as being a financial benefit to the conflicted person, such as receiving compensation for services by the sponsoring company or owning stock in the company or having some other pecuniary interest. Conflicts of interest also can arise from other self-interest, such as the prospect of promotion, prestige, fame, or other career advancement.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 8–11 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Receiving a gift sometimes can create a conflict of interest because of the human need to reciprocate, to give back, to the giver, even if the gift is trivial or has low monetary value.9 Influence of industry on research. Partnerships between industry and non-industry researchers are important in the discovery and dissemination of new knowledge. Yet, industrysponsored research brings potential conflicts and other ethical issues to the conduct of research, as explained in the following. “Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer . . . Sponsoring companies . . . often design the studies; perform the analysis; write the papers; and decide whether, when, and in what form to publish the results . . . Faculty investigators often . . . serve as paid consultants and members of speakers’ bureaus and advisory boards and sometimes even have equity interest.”10 To avoid conflicts of interest and assure the proper conduct of research and publication of its results, most institutions have implemented policies to address these issues. For example, my university requires all those involved in the conduct and reporting of research to declare their relationships with industry and other conflicts, limits the contact of students and trainees with representatives of industry, does not allow the acceptance of gifts, and prohibits ghostwriting (see following).11 Ghostwriting. Ghostwriting is both the failure to identify the person who actually wrote or made a substantial contribution to a manuscript, article, book, or the like12 and the practice of taking credit for something you did not write or contribute to in a substantive manner. The prevalence of ghostwriting is difficult to ascertain but, as inferred from the following example, it does not seem rare. During litigation against Merck related to rofecoxib, internal company documents became available through the court.12 Those documents indicated that the company had performed a number of clinical drug trials, had written manuscripts describing the studies and proposed titles for them, had recruited outside academic investigators to be guest authors, and had designated intended journals for publication. The first author of a study that was published13 spoke with a New York Times reporter in 2005,14 2 years after the publication of the article. He said, “Merck designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing.”14 It is deceptive to take credit for something you did not write or contribute to substantively. Yet, the conduct and reporting of research is a complex undertaking that often involves many people who contribute different important portions of the overall work. More than one person may write the manuscript on behalf of others. What is important is that each author has made a substantive contribution to the work and understands the manuscript in its entirety. Ethically questionable research and scientific misconduct. The Tuskegee Syphilis Study (1932–1972), in Tuskegee, Alabama, USA, under the auspices of the US Public 10
Health Service, and the Willowbrook Hepatitis Study (1956–1970), at a state hospital for disabled children on Staten Island, New York, USA are examples of research that have been regarded as ethically flawed and that have influenced the conduct of contemporary research. In the Tuskegee Study, 399 poor black men with syphilis, who were told they had “bad blood,” were followed for many years to study the natural history of syphilis, in comparison with 201 men without syphilis. The men with syphilis were not treated for the disease even after an effective treatment, penicillin, became available in 1947. In 1974, a $10 million court settlement included lifetime medical benefits and burial services to all living participants. A year later, those benefits were applied to wives, widows, and children of the study participants. In 1997, President Clinton apologized on behalf of the nation. In the Willowbrook Study, children who were newly admitted to the facility were intentionally infected with hepatitis A to study the effect of gamma globulin on the disease and develop a vaccine. The deliberate infection of the children was rationalized because the historical record indicated that ordinarily nearly all children contracted hepatitis A within a short time after admission. Although the results were presented at scientific meetings and published in journals, the study was criticized because the children were not able to give consent and parents received inadequate information before they were asked to give consent. These and other studies have reinforced the principles of autonomy, beneficence, non-maleficence, and justice, as well as the practices of informed consent and having a responsible person act on behalf of persons who cannot make decisions for themselves. Further, instances of scientific misconduct have accentuated the need for greater attention to these principles and practices and the need for tighter regulation of research as well as education in the ethical conduct and reporting of research. Scientific misconduct is defined variously, but may be thought of as distortion of the research process by intention or gross negligence and may involve plagiarism or fabrication of the hypothesis, methods, data, text, or other aspects of research.15 Unfortunately, examples of scientific misconduct abound, ranging from plagiarism to gross ineptitude to intentional fabrication of data. A survey of over 3200 early- and mid-career scientists in the United States who were funded by the National Institutes of Health indicated that research misconduct is not rare.16 Thirty-three percent of the respondents said they had engaged during the previous 3 years in at least 1 of 10 behaviors that were deemed to be sanctionable if discovered.16 Some of the behaviors were falsifying data; ignoring major aspects of human subject requirements; using the ideas of someone else without obtaining permission or giving credit; and changing the design, methodology, or results of a study in response to pressure from a funding source. The reasons why investigators and others engage in research misconduct vary and are not always clear, but sometimes it seems related to a desire for recognition, the need for promotion or professional advancement, laziness or lack of ability, or perhaps simply because it can be done. Regardless of the reason, scientific misconduct violates a fundamental principle of research, namely the truth and reliability of the results, and undermines public trust in research.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 8–11 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Rights of research subjects. The contemporary conduct of research, taking into account ethical principles, the law, policies, and regulations, requires respect for the rights of research subjects. Research subjects have the right: • to understand the purposes, risks, and benefits of the research before they consent to participate and to do so without coercion • to be protected against possibilities of injury, disability, or death • to participate in research that is conducted by qualified people • to ask questions at any time • to withdraw from participation at any time without repercussions • to be represented, if they are unable to understand the conditions or consequences of the research, by surrogates who can consent and otherwise act on their behalf and make decisions for them according to their wishes or best interests.
A final word The ethical conduct of research is in accord with the fundamental principle of medicine—the primacy of the welfare of the patient as research subject. It not only promotes good research but also is in the best interests of research subjects, investigators, sponsors, patients, and the public.
References 1 Kitagawa JM. 1. Japan through the nineteenth century. In: Warren T. Reich, ed. Encyclopedia of Bioethics. London: Macmillan Publishing Company, 1995; 1491–6. 2 Kimura R, Bishop L. Contemporary Japan. In: Warren T. Reich, ed. Encyclopedia of Bioethics. London: Macmillan Publishing Company, 1995; 1496–505. 3 Tsai DF-C. The bioethical principles and Confucius’ moral philosophy. J. Med. Ethics 2005; 31: 159–63.
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4 Rice TW. The historical, ethical, and legal background of human-subjects research. Respir. Care 2008; 53: 1325–9. 5 Reicher H. Medicine in the Third Reich: the 65th anniversary of the doctors’ trial at Nuremberg. Penn Med 2012; 23: 28–37. 6 The Nuremberg Code. Directives for Human Experimentation. Available from URL: http://www.hhs.gov/ohrp/archive/nurcode.html (Accessed: October 16, 2014) 7 Wilson EO. Consilience: The Unity of Knowledge. New York: Alfred A. Knopf, Inc., 1998. 8 Brennan TA, Rothman DJ, Blank L et al. Health industry practices that create conflicts of interest. A policy proposal for academic medical centers. JAMA 2006; 295: 429–33. 9 Katz D, Caplan AL, Merz JF. All gifts large and small. Toward an understanding of the ethics of pharmaceutical industry gift-giving. Am. J. Bioeth. 2003; 3: 39–46. 10 Angell M. Industry-sponsored clinical research. A broken system. JAMA 2008; 300: 1069–71. 11 Policy on Relations with the Pharmaceutical, Medical Device, and Biotechnology Industries. SUNY Upstate Medical University. 2010. Available from URL: http://www.upstate.edu/policies/documents/ CAMP_A-24.pdf (Accessed: October 16, 2014) 12 Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghost-writing in publications related to rofecoxib. A case study of industry documents from rofecoxib litigation. JAMA 2008; 299: 1800–12. 13 Lisse JR, Perlman M, Johansson G et al. Gastrointestinal tolerability and effectiveness of rofecoxib vs naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann. Intern. Med. 2003; 139: 539–46. 14 Berenson A. Evidence in Vioxx suits shows intervention by Merck officials. New York Times April 24, 2005:A1. 15 Nylenna M, Andersen D, Dahlquist G, Sarvas M, Aakvaag A. Handling of scientific dishonesty in the Nordic countries. Lancet 1999; 354: 57–61. 16 Martinson BC, Anderson MS, de Vries R. Scientists behaving badly. Nature 2005; 435: 737–8.
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doi:10.1111/jgh.12755
REVIEW
Ethical issues in gastroenterology research* Gregory L Eastwood Center for Bioethics and Humanities, State University of New York Upstate Medical University, Syracuse, New York, USA
Key words bioethics, conflicts of interest, ethics, human subjects, research ethics. Correspondence Gregory L. Eastwood, Office of the President, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Email: eastwood@upstate .edu *Presented at the 15th Taishotoyama International Symposium on Gastroenterology, September 26, 2013, Tokyo, Japan. Funding: The author has received no funding for the development of this paper. Potential conflict of interest: The author declares no conflicts of interest.
Abstract Ethical issues have become increasingly important in gastroenterology research. This is for several reasons, including (i) an understanding of how conflicts of interest might affect research, (ii) the influence of the drug and device industries on research, (iii) ghostwriting (taking credit for something you did not write), (iv) the occurrence of ethically inappropriate research and scientific misconduct, and (v) respect for the rights of research subjects. These include the rights (i) to give informed consent to participate after understanding the purposes, risks, and benefits of the research; (ii) to ask questions; and (iii) to withdraw from participation at any time. Notions of doing good (beneficence), avoiding harm (nonmaleficence), confidentiality, and, most important, the primacy of the welfare of the patient or research subject can be traced to antiquity. In the modern era, the Nuremburg Code (1947), the Declaration of Helsinki (1964), the Belmont report (1979), and other events and reports have led to the refinement of ethical practices in both clinical and research domains, have reinforced those long observed principles, and have given rise to the newer principles of autonomy and justice. The ethical conduct of research not only promotes good research but also is in the best interests of research subjects, investigators, sponsors, patients, and the public.
Ethical issues have become increasingly important in gastroenterology research, particularly research that involves human subjects. This is the consequence of a number of interrelated issues, such as the growing awareness of potential conflicts of interest, concerns about the influence of industry on the conduct and outcomes of research, the practice of so-called ghost writing, revelations of ethically questionable research and scientific misconduct, and a heightened emphasis on the rights of research subjects. Contemporary notions of appropriate ethical behavior in research are derived from ethical principles and values that have their roots in the practice of medicine in ancient times, but which have been modified and expanded by events in the contemporary era. In the following, I first will review the development of ethical principles that apply to the conduct of human research today and then examine several of the important ethical issues in gastroenterology research.
Development of contemporary ethical principles in human research Ethics asks, What is the right thing to do in this situation?, taking into account the law, moral values, personal beliefs, and social norms. To a large extent, our ideas of what is the right thing to do have their roots in the practice of medicine and the philosophic and religious teachings from ancient times. 8
Hippocrates (470–410 BC), in the Oath that bears his name, proclaimed: “I will come for the benefit of the sick . . .” This describes the ethical principle of beneficence or doing good. Hippocrates also said, “I will keep them from harm and injustice,” which is non-maleficence, the notion of avoiding or minimizing harm. “What I see or hear in the course of treatment or even outside . . . I will keep to myself,” speaks to confidentiality of information relating to patients. And “The health and life of my patient will be my first consideration” is, in my view, the fundamental principle of medicine. It means that physicians commit to putting the welfare of the patient, and thus the research subject, first, above their own interests and the interests of the institution and research sponsor. This principle is not only why we practice medicine, but also why we educate students, engage in administrative activities, promote social actions, and, of course, perform biomedical research—all to foster the welfare of patients. In Japan, Confucian ethics has had a large influence on contemporary ethical thought. Confucius (551–479 BC) advocated that physicians should have jin, meaning benevolence, and that they should value life, show concern for suffering, practice medicine with honesty, and treat all patients equally.1–3 To Confucius, medicine was the art of jin. In Buddhism, the concepts of daiji, the mercy of Buddha, and sokuin, meaning sympathy or benevolence, which is similar to the jin of Confucius, were combined; physicians need to have daiji-sokuin, a mix of mercy, sympathy, and benevolence.2 The Christian influence in Japan, with its emphasis
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 8–11 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
GL Eastwood
on mercy, benevolence, compassion, and healing, reinforces these concepts. With foundations in ancient practices, bioethical concepts have matured and changed in the contemporary era. Events in the research domain have raised ethical questions and helped clarify our notions of appropriate research and the rights of research subjects. In 1947, the Nuremberg Code was developed as a consequence of the Nuremberg doctors’ trial, which was one of 13 Nuremberg trials after World War II in which the leaders of the Nazi regime were prosecuted for crimes against humanity. The 1947 doctors’ trial resulted from the Nazi medical research atrocities in the 1930s–1940s in which physicians and their assistants had conducted experiments that included shooting, infecting, freezing, starving, and sterilizing prisoners and others.4,5 Some of the important elements of the Nuremberg Code were (i) consent of subjects must be voluntary, informed, and without coercion; (ii) the benefit to society must be greater than the risk to the subject; (iii) subjects must be protected against possibilities of injury, disability, or death; (iv) the research must be performed by scientifically qualified persons; and (v) subjects have a right to withdraw from the research without repercussions.4,6 In 1953, the description of the structure of DNA by Francis Crick, Rosalind Franklin, and James Watson led to the remarkable expansion of genetics and the new field of genomics and a better understanding of how DNA might be damaged spontaneously and by radiation and chemicals. It also raised many ethical issues related to gene manipulation, selection for desired traits, and eugenics. E. O. Wilson has raised the possibility of controlling the future evolution of humans. He says, “Thanks to advances in genetics and molecular biology underway, hereditary change will soon depend less on natural selection than on social choice. Possessing exact knowledge of its own genes, collective humanity in a few decades can, if it wishes, select a new direction in its evolution and move there quickly . . . The prospect of this ‘volitional evolution’—a species deciding what to do about its own heredity—will present the most profound intellectual and ethical choices humanity has ever faced.”7 In 1964, the Declaration of Helsinki acknowledged the need to study people who cannot consent, such as infants, children, the mentally disabled, and the critically ill, but still need to be involved in research studies. This introduced the notion of identifying surrogates or guardians who can make decisions on behalf of those who cannot speak for themselves, according to their wishes or best interests. In 1979, the Belmont Report on Ethical Principles and Guidelines for Human Subjects Research, commissioned by the US Congress, drew distinctions between medical practice and research. The report declared that in the practice of medicine, interventions are intended to benefit the patient, whereas research is to test a question and thus the subject may not benefit. In fact, research subjects bear the risks of research, although others are likely to benefit from it. The report also affirmed the principle of beneficence, meaning all efforts should be made to secure the subject’s well-being, and the principle of respect for persons, that people are autonomous, and if autonomy is diminished, the person is entitled to protection. These events and reports, although not exhaustive, are sufficient to appreciate the essential contemporary ethical principles that
GLE: Ethical issues in GI research
guide clinical research. They include beneficence (the intent to do good), non-maleficence (the avoidance of harm), justice (treating subjects fairly and raising the question, Who will benefit from the research?), autonomy (respecting the right of persons to choose for themselves and act freely), and, the fundamental principle, putting the interests and welfare of the subject first before the interests of the investigator, the interests of the institution in which the research is conducted, the interests of the sponsor of the research, or other interests. The principles seem to reflect similar ethical values both in Japan and in so-called Western culture, particularly with regard to a common emphasis on benevolence and the welfare of the patient. However, how those values are expressed may be different in degree and nuance. For example, in Japan, the values placed on deference to authority, striving for harmony with others, and thinking of oneself as part of a family or group, each may affect the expression of these ethical principles, perhaps diminishing the expression of autonomy and favoring the roles of authority, harmony, family, and tradition. The following scenario illustrates an ethical dilemma in which the rights of a patient or research subject come in conflict with the ethical duties of a physician researcher in training as they may be affected by the desire to respect the instructions of the person in authority. Prof. M, chair of Gastroenterology at a respected medical center, is known around the world for his research on nitric oxide (NO). To provide a control group and to investigate NO in various clinical conditions, Prof. M instructs his fellow, Dr. S, to obtain gastric and duodenal biopsies in patients who are undergoing upper GI endoscopy for clinical reasons. Prof. M says that it is not necessary to ask permission for additional research biopsies, because the patients already have consented to endoscopy and possible biopsy for clinical reasons. This scenario raises several questions that are broadly relevant, such as, Is it necessary for patients to consent to additional research biopsies, thus consenting to participate as a research subject, when they already have consented to biopsies for clinical purposes? (Yes, it is necessary.) What should a person in a subordinate position do when that person questions the judgment or actions of a person in authority? Is the person in authority always right?
Some important ethical issues in gastroenterology research Conflicts of interest. Conflicts of interest occur when researchers “are tempted to deviate or do deviate from their professional obligations for economic or other personal gain.”8 I believe that a conflict of interest is anything that comes between the investigator and the welfare of the research subject or between the investigator and the proper conduct of the research. Often one thinks of a conflict of interest as being a financial benefit to the conflicted person, such as receiving compensation for services by the sponsoring company or owning stock in the company or having some other pecuniary interest. Conflicts of interest also can arise from other self-interest, such as the prospect of promotion, prestige, fame, or other career advancement.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 8–11 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Receiving a gift sometimes can create a conflict of interest because of the human need to reciprocate, to give back, to the giver, even if the gift is trivial or has low monetary value.9 Influence of industry on research. Partnerships between industry and non-industry researchers are important in the discovery and dissemination of new knowledge. Yet, industrysponsored research brings potential conflicts and other ethical issues to the conduct of research, as explained in the following. “Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer . . . Sponsoring companies . . . often design the studies; perform the analysis; write the papers; and decide whether, when, and in what form to publish the results . . . Faculty investigators often . . . serve as paid consultants and members of speakers’ bureaus and advisory boards and sometimes even have equity interest.”10 To avoid conflicts of interest and assure the proper conduct of research and publication of its results, most institutions have implemented policies to address these issues. For example, my university requires all those involved in the conduct and reporting of research to declare their relationships with industry and other conflicts, limits the contact of students and trainees with representatives of industry, does not allow the acceptance of gifts, and prohibits ghostwriting (see following).11 Ghostwriting. Ghostwriting is both the failure to identify the person who actually wrote or made a substantial contribution to a manuscript, article, book, or the like12 and the practice of taking credit for something you did not write or contribute to in a substantive manner. The prevalence of ghostwriting is difficult to ascertain but, as inferred from the following example, it does not seem rare. During litigation against Merck related to rofecoxib, internal company documents became available through the court.12 Those documents indicated that the company had performed a number of clinical drug trials, had written manuscripts describing the studies and proposed titles for them, had recruited outside academic investigators to be guest authors, and had designated intended journals for publication. The first author of a study that was published13 spoke with a New York Times reporter in 2005,14 2 years after the publication of the article. He said, “Merck designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing.”14 It is deceptive to take credit for something you did not write or contribute to substantively. Yet, the conduct and reporting of research is a complex undertaking that often involves many people who contribute different important portions of the overall work. More than one person may write the manuscript on behalf of others. What is important is that each author has made a substantive contribution to the work and understands the manuscript in its entirety. Ethically questionable research and scientific misconduct. The Tuskegee Syphilis Study (1932–1972), in Tuskegee, Alabama, USA, under the auspices of the US Public 10
Health Service, and the Willowbrook Hepatitis Study (1956–1970), at a state hospital for disabled children on Staten Island, New York, USA are examples of research that have been regarded as ethically flawed and that have influenced the conduct of contemporary research. In the Tuskegee Study, 399 poor black men with syphilis, who were told they had “bad blood,” were followed for many years to study the natural history of syphilis, in comparison with 201 men without syphilis. The men with syphilis were not treated for the disease even after an effective treatment, penicillin, became available in 1947. In 1974, a $10 million court settlement included lifetime medical benefits and burial services to all living participants. A year later, those benefits were applied to wives, widows, and children of the study participants. In 1997, President Clinton apologized on behalf of the nation. In the Willowbrook Study, children who were newly admitted to the facility were intentionally infected with hepatitis A to study the effect of gamma globulin on the disease and develop a vaccine. The deliberate infection of the children was rationalized because the historical record indicated that ordinarily nearly all children contracted hepatitis A within a short time after admission. Although the results were presented at scientific meetings and published in journals, the study was criticized because the children were not able to give consent and parents received inadequate information before they were asked to give consent. These and other studies have reinforced the principles of autonomy, beneficence, non-maleficence, and justice, as well as the practices of informed consent and having a responsible person act on behalf of persons who cannot make decisions for themselves. Further, instances of scientific misconduct have accentuated the need for greater attention to these principles and practices and the need for tighter regulation of research as well as education in the ethical conduct and reporting of research. Scientific misconduct is defined variously, but may be thought of as distortion of the research process by intention or gross negligence and may involve plagiarism or fabrication of the hypothesis, methods, data, text, or other aspects of research.15 Unfortunately, examples of scientific misconduct abound, ranging from plagiarism to gross ineptitude to intentional fabrication of data. A survey of over 3200 early- and mid-career scientists in the United States who were funded by the National Institutes of Health indicated that research misconduct is not rare.16 Thirty-three percent of the respondents said they had engaged during the previous 3 years in at least 1 of 10 behaviors that were deemed to be sanctionable if discovered.16 Some of the behaviors were falsifying data; ignoring major aspects of human subject requirements; using the ideas of someone else without obtaining permission or giving credit; and changing the design, methodology, or results of a study in response to pressure from a funding source. The reasons why investigators and others engage in research misconduct vary and are not always clear, but sometimes it seems related to a desire for recognition, the need for promotion or professional advancement, laziness or lack of ability, or perhaps simply because it can be done. Regardless of the reason, scientific misconduct violates a fundamental principle of research, namely the truth and reliability of the results, and undermines public trust in research.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 8–11 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Rights of research subjects. The contemporary conduct of research, taking into account ethical principles, the law, policies, and regulations, requires respect for the rights of research subjects. Research subjects have the right: • to understand the purposes, risks, and benefits of the research before they consent to participate and to do so without coercion • to be protected against possibilities of injury, disability, or death • to participate in research that is conducted by qualified people • to ask questions at any time • to withdraw from participation at any time without repercussions • to be represented, if they are unable to understand the conditions or consequences of the research, by surrogates who can consent and otherwise act on their behalf and make decisions for them according to their wishes or best interests.
A final word The ethical conduct of research is in accord with the fundamental principle of medicine—the primacy of the welfare of the patient as research subject. It not only promotes good research but also is in the best interests of research subjects, investigators, sponsors, patients, and the public.
References 1 Kitagawa JM. 1. Japan through the nineteenth century. In: Warren T. Reich, ed. Encyclopedia of Bioethics. London: Macmillan Publishing Company, 1995; 1491–6. 2 Kimura R, Bishop L. Contemporary Japan. In: Warren T. Reich, ed. Encyclopedia of Bioethics. London: Macmillan Publishing Company, 1995; 1496–505. 3 Tsai DF-C. The bioethical principles and Confucius’ moral philosophy. J. Med. Ethics 2005; 31: 159–63.
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4 Rice TW. The historical, ethical, and legal background of human-subjects research. Respir. Care 2008; 53: 1325–9. 5 Reicher H. Medicine in the Third Reich: the 65th anniversary of the doctors’ trial at Nuremberg. Penn Med 2012; 23: 28–37. 6 The Nuremberg Code. Directives for Human Experimentation. Available from URL: http://www.hhs.gov/ohrp/archive/nurcode.html (Accessed: October 16, 2014) 7 Wilson EO. Consilience: The Unity of Knowledge. New York: Alfred A. Knopf, Inc., 1998. 8 Brennan TA, Rothman DJ, Blank L et al. Health industry practices that create conflicts of interest. A policy proposal for academic medical centers. JAMA 2006; 295: 429–33. 9 Katz D, Caplan AL, Merz JF. All gifts large and small. Toward an understanding of the ethics of pharmaceutical industry gift-giving. Am. J. Bioeth. 2003; 3: 39–46. 10 Angell M. Industry-sponsored clinical research. A broken system. JAMA 2008; 300: 1069–71. 11 Policy on Relations with the Pharmaceutical, Medical Device, and Biotechnology Industries. SUNY Upstate Medical University. 2010. Available from URL: http://www.upstate.edu/policies/documents/ CAMP_A-24.pdf (Accessed: October 16, 2014) 12 Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghost-writing in publications related to rofecoxib. A case study of industry documents from rofecoxib litigation. JAMA 2008; 299: 1800–12. 13 Lisse JR, Perlman M, Johansson G et al. Gastrointestinal tolerability and effectiveness of rofecoxib vs naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann. Intern. Med. 2003; 139: 539–46. 14 Berenson A. Evidence in Vioxx suits shows intervention by Merck officials. New York Times April 24, 2005:A1. 15 Nylenna M, Andersen D, Dahlquist G, Sarvas M, Aakvaag A. Handling of scientific dishonesty in the Nordic countries. Lancet 1999; 354: 57–61. 16 Martinson BC, Anderson MS, de Vries R. Scientists behaving badly. Nature 2005; 435: 737–8.
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