Journal of Surgical Research 128, 221–225 (2005) doi:10.1016/j.jss.2005.07.003
Research Ethics Primer Karen J. Brasel, M.D., M.P.H.1 Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin Submitted for publication December 15, 2004
According to Webster’s dictionary, “ethics” can be defined as a set of moral principles or values, the principles of conduct governing an individual or group, or a guiding philosophy. The following is a short primer on research ethics for those beginning careers in surgical research, either basic or clinical. It is not meant to be a comprehensive treatise, and Web sites used to put the primer together are annotated at the end for those desiring more information. BIOETHICAL PRINCIPLES GOVERNING HUMAN SUBJECTS RESEARCH
The principles behind human subjects research have been codified in publications at least three different times. The first, the Nuremberg code written in 1947, was in response to the appalling experiments done during World War II . There are 10 principles of the Nuremberg code. These include willing consent, expectation of societal good, solid scientific basis, avoidance of injury and suffering, balance of risks and benefits, protection of subjects, basis on sound animal studies, qualifications of the researcher, ability for subject to withdraw, and interim analysis or ability of investigator to terminate study. This list of principles was expanded in the Declaration of Helsinki to 29 principles. The Declaration of Helsinki (Document 17.C) is an official policy document of the World Medical Association, the global representative body for physicians . It was first adopted in 1964 and revised in 1975, 1983, 1989, 1996, 2000, and 2002. The third document was published on July 12, 1974. It is the National Research Act (Public Law 93348) and created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The underlying report, called the Belmont re1
To whom correspondence and reprint requests should be addressed at Department of Surgery, The Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226. E-Mail: [email protected]
port, outlines the basic ethical principles that serve as justification for the many particular ethical prescriptions and evaluations of human actions . Applications of the general principles to the conduct of research lead to consideration of the following requirements: informed consent, risk/benefit assessment, and the selection of subjects of research. The bioethical principles that underlie the Belmont report are respect for persons (encompassing dignity and autonomy), beneficence, and justice. The principle of respect for persons has a dual requirement: the requirement to acknowledge autonomy, and the requirement to protect those with diminished autonomy. Acknowledging autonomy involves recognizing that all people who have the capacity for selfdetermination are able to make their own decisions. Respect for persons demands that subjects enter into the research voluntarily and with adequate information. An example of coercion, violating this principle, would be providing standard medical care to those that participate but withholding care from those who do not. Extreme circumstances, where a family member is grieving or a patient is in shock, are examples where processing and understanding information may be impaired and the principle of autonomy violated. The involvement of prisoners as subjects of research is less clear cut and an example of how this principle needs to be carefully applied. The principle of respect for persons suggests that prisoners not be deprived of the opportunity to volunteer for research. However, they may be subject to subtle coercion or undue influence to engage in research activities. Respect for persons would then suggest that prisoners be protected. Those who do not have the capacity for selfdetermination (children, the mentally disabled) are under special protection. This protection may necessitate excluding them from activities that may harm them. It may simply require additional safeguards to make sure they undertake activities freely and with awareness of possible adverse consequences. The extent of protec-
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tion should depend upon the risk of harm, and the likelihood of benefit. The judgment that any individual lacks autonomy should be periodically reevaluated, and will vary in different situations. The principle of beneficence requires that the potential treatments must not harm patients, and that the study must maximize possible benefits for the greatest number of people while minimizing possible harms for the greatest number of people. Some of the conflict posed by the principle of beneficence is illustrated by the fact that learning potential benefits may require exposing persons to risk. Additional conflict arises in deciding when it is justifiable to seek benefits despite the risks involved, and when the benefits should be foregone because of the risks. The obligations of beneficence require not only individual investigators, but society at large to recognize the longer-term benefits and risks that may result from the improvement of knowledge, and from the development of novel medical, psychotherapeutic, and social procedures. Studies that present more than minimal risk without immediate prospect of direct benefit to the subjects involved might be judged ethically inadmissible. However, a rigid application of this approach could eliminate much research with promise for significant future benefit. The principle of justice requires that the burdens and benefits must be equally distributed across all people and populations. There are several widely accepted formulations of just ways to distribute burdens and benefits. These formulations are: 1) to each person an equal share, 2) to each person according to individual need, 3) to each person according to individual effort, 4) to each person according to societal contribution, and 5) to each person according to merit. The principle of justice requires careful scrutiny of the selection of research subjects to avoid systematic selection of some classes for reasons not directly related to the problem being studied. Justice also demands that these advantages gained from research be available to all, not only to those who can afford them. EXAMPLES OF RESEARCH MISCONDUCT
The Tuskegee syphilis study is the most flagrant example of research misconduct in our history. It began in 1932 as a study of 399 African-American men with tertiary syphilis and 201 without syphilis and was aimed to show the need for treatment. No subjects of other racial or ethnic backgrounds were used. At the initiation of the study, determining the need for treatment was a worthwhile goal. However, in 1945, penicillin was accepted as the treatment of choice for syphilis, but the physicians were asked to withhold treatment. It should be noted that this treatment is effective for primary syphilis; it would not have changed the course of tertiary syphilis. In 1947, Rapid Treatment Centers for syphilis were established; yet
none of these men in the Tuskegee study received treatment. It was in 1947 that the Nuremberg code was issued. Furthermore, in 1969, 5 years after the Helsinki declaration, the CDC reaffirmed the need for the Tuskegee study. Two years later, congressional hearings were held, and the study ended. Participants, their families, or both were compensated. Not until 25 years later was an apology made to the participants and their families. So, what are the ethical problems with the Tuskegee study? First of all, it was and is illegal not to report persons infected with syphilis to public health authorities, and these people were not reported. The subjects were blocked from the WWII draft—the risks and benefits were not distributed equally, violating the principle of justice. The subjects were not told about the purpose of the experiment and were told they were being treated, violating the principle of autonomy. They were coerced into participation, again violating the principle of autonomy. There was no effort made to prevent disease spread, violating the principle of beneficence. Finally, there was not consistent long-term plan for the study, again violating the principle of beneficence. Unfortunately, the Tuskegee study was not an isolated incident. The Willowbrook State School was a school in New York for mentally disabled children, where there was an extraordinarily high rate of hepatitis. From 1963 through 1966, seven studies were carried out under the direction of Dr. Saul Krugman, the director of research. The purpose was to gain an understanding of the natural history of infectious hepatitis and subsequently to test the effects of gamma globulin in preventing or ameliorating the disease. One study involved feeding healthy, uninfected children extracts of stools from infected individuals; in another subjects were injected with purified virus preparations. All experiments were done with parental consent. Results were published in the Journal of the American Medical Association, and led to an understanding of the differences between hepatitis A and B. There are several ethical concerns with this study. Children and the mentally ill are not fully autonomous, as they do not have full capacity for self-determination or the ability to understand adequate information. The surrogate decision-makers were not truly informed of the purpose of the study, and in some cases they were told their child was being immunized. Perhaps of greatest concern is that participation was coerced. During the course of these studies, Willowbrook closed its doors to new children because of overcrowding. The hepatitis program was housed in the research wing, and was not subject to the same overcrowded conditions, so it was able to continue to admit new patients while the remainder of the institution was closed. Parents were forced to choose between finding alternative care for their child or participation in the studies. This
KAREN J. BRASEL: RESEARCH ETHICS PRIMER
study violated the principle of beneficence, as there was no potential benefit for the children enrolled. The benefit of understanding the differences between hepatitis A and B is not likely to offset the risks inherent in the study, particularly given the vulnerable population studied. The institution’s failings, a high rate of hepatitis, were exploited rather than addressed. INSTITUTIONAL REVIEW BOARDS AND INFORMED CONSENT
In 1966, Henry Knowles Beecher, a Harvard researcher and anesthesiologist, described 22 representative unethical studies conducted by prominent United States researchers in the New England Journal of Medicine. This helped bring the issue of research misconduct to the attention of the American public and research community. After publication of the article, the National Institutes of Health and the Food and Drug Administration altered their investigator guidelines to require peer-reviewed supervision and evidence of informed consent in all human experiments. Under the Federal Policy (Common Rule) for the protection of human subjects, Section 103(a) requires that each institution engaged in federally supported human subject research file an Assurance of Protection for Human Subjects. The Assurance formalizes an institution’s commitment to protect human subjects. The Assurance facilitates efforts of the Department of Health and Human Service (DHHS) to establish effective communication with the Institutional Review Boards (IRBs) working to protect human subjects, especially when the research is regulated or supported by DHHS. These IRBs were established by the National Research Act of 1974. Although the IRBs were created by and function under federal authority, they are located in each individual research institution. IRBs are responsible for review and approval of all institutional research activities involving human subjects. The purpose of this review is to ensure that the rights and welfare of the subjects are adequately protected and that all research involving human subjects is in compliance with applicable institutional policies and external regulations. IRBs must include at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas. They must also include at least one member who is not otherwise affiliated with the institution. Much of the responsibility of the IRB pertains to the informed consent process. The required elements of informed consent stipulated by the Common Rule are summarized as follows: 1. A statement that the study involves research, an explanation of the purposes of the research, and a description of the procedures to be followed;
2. A description of any reasonably foreseeable risks or discomforts to the subject; 3. A description of any benefits to the subjects or to others that might reasonably be expected; 4. A disclosure of alternative procedures or courses of treatment; 5. A statement describing the extent to which confidentiality of records identifying the subject will be maintained; 6. For research involving more than minimal risk, an explanation of the availability and nature of any compensation or medical treatment if injury occurs; 7. Identification of whom to contact for further information about the research and about subjects’ rights, and whom to contact in the event of a researchrelated injury; and 8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time. Under the Common Rule, consent can be waived for nonemergent studies only if one of the following four requirements is met: 1) the research involves no more than minimal risk; 2) the waiver or alteration will not adversely affect the rights and welfare of the subjects; 3) the research could not practicably be carried out without the waiver or alteration; and 4) whenever appropriate, the subjects will be provided with additional pertinent information after participation. Exception to informed consent for research in life-threatening medical conditions has been possible since 1996. This complex process is both federally regulated and regulated by the local IRBs using a structured process of community consultation and notification. IRB documents, including consent forms, are institution-specific. Interpretations of the Common Rule and the ethical principles outlined above may also differ by institution. HIPAA
HIPAA, or the Health Insurance Portability and Accountability Act, was issued by the Department of Health and Human Services in 1996. The final Privacy Rule was published in 2002. Its’ goal is to ensure that health information is protected while allowing adequate flow of health information needed to provide high quality health care. All individually identifiable health information is protected by this rule. With respect to research, the Privacy Rule permits protected health information to be disclosed for research purposes provided it is authorized by the individual(s) participating in research. Protected health information may also be used to prepare a research protocol or other purpose preparatory to research, provided the researcher does
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not remove protected health information from the site of research and that is essential for conducting the research. Privacy Boards at each institution are responsible for overseeing implementation of the Privacy Rule; as a practical matter, most IRBs also function as Privacy Boards.
The IACUC consists of at least three members, one of whom is the attending veterinarian of the research facility and one of whom is not affiliated in any way with the facility other than as a member of the committee. FEDERAL POLICY ON RESEARCH MISCONDUCT
One of the principles of the Nuremberg code establishes that ethical human research be based on sound evidence from animal studies. Ethical research involving animals is regulated by the Animal Welfare Act, signed into law in 1966 (amended in 1970, 1976, 1985, and 1990). It regulates the treatment of animals in research, exhibition, transport, and by dealers in the United States. All animal species are covered with the exception of rats of the genus Rattus, mice of the genus Mus, and birds. Standards include those for facilities and operations, health and husbandry systems, and transportation. Other applicable policies and guidelines include the Health Research Extension Act of 1985 and the Guide for the Care and Use of Laboratory Animals, published by the National Academy of Science in 1996. The Office of Laboratory Animal Welfare governs research ethics specific to animals. The principles governing animal research are as follows: 1. Transportation, care and use of animals should be in accordance with the Animal Welfare Act and other applicable laws, guidelines, and policies. 2. Procedures should be designed and performed with consideration of their relevance to human or animal health, the advancement of knowledge, or societal good. 3. The animals should be of an appropriate species and quality, using the minimum number possible. 4. Avoidance or minimization of discomfort, distress, and pain is imperative. 5. Appropriate sedation, analgesia, and/or anesthesia should be used. 6. Procedures resulting in severe or chronic pain that cannot be relieved should result in the animal being painlessly killed during or at the end of the procedure. 7. Living conditions should be appropriate, and veterinary care should be provided as indicated. 8. All investigators should have appropriate qualifications with sufficient training on humane care and use of laboratory animals. The Animal Welfare Act established Institutional Animal Care and Use Committees (IACUC), similar to IRBs for human research. The IACUC is responsible for evaluating the care, treatment, housing, and use of animals in research. It is also responsible for certifying institutional compliance with the Animal Welfare Act.
The government has taken the approach of defining research misconduct rather than attempting to define the more nebulous concept of research ethics. The federal policy on research misconduct has been in existence for more than 4 years. This policy is originated from the Office of Science and Technology and is available on their Web site, and prohibits the fabrication, falsification, or plagiarism in proposing, performing, reviewing, or reporting research. Fabrication is defined as completely making up data. Falsification implies that the data have been falsified or altered in some way. Plagiarism is taking someone else’s idea, data, or proposal. A finding of research misconduct, violation of one of these three precepts, requires significant departure from accepted community standard. It also requires that the violation was done recklessly, knowingly, and intentionally, and that there is a preponderance of evidence supporting the claim. Importantly, the government puts the responsibility for policing individual researchers on individual institutions. Inadequate oversight can result in some significant sanctions against these institutions, as well as against individual researchers. According to federal policy, a claim of research misconduct first requires an inquiry by the institution. If federal money supports the research, the Office of Research Integrity and Office of Science and Technology must be notified. The purpose of the “Inquiry” is to make a preliminary evaluation of the available evidence and testimony of key witnesses, including the person making the allegation of misconduct and the respondent. This allows a determination as to whether there is sufficient credible evidence of possible scientific misconduct to warrant a formal “Investigation”. This step does not reach a final conclusion about whether misconduct has or has not occurred. The findings of the “Inquiry” are set forth in an “Inquiry Report”. If the Inquiry finds that there is enough substance to the claim to warrant further investigation, an “Investigation” is initiated; again, the government must be notified. The purpose of the Investigation is to explore in detail the allegations, to examine the evidence in depth, and to determine specifically whether misconduct has been committed, by whom, and to what extent. The Investigation also determines whether there are circumstances that would justify adding additional charges of misconduct and identifies these circumstances. The findings of the Investigation are set forth
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in an “Investigation Report”. When the investigation is complete, the findings are reported and action taken, again with notification. If misconduct is found, possible actions include:
above and a certificate of completion of the NIH program. It continues with incorporating and embracing these principles during the responsible conduct of all research.
Removal from a particular project Letter of reprimand to be included in the individual’s personnel file ● Special monitoring of work ● Decrease in laboratory support (e.g., loss of a Fellow position or technical support position) ● Probation ● Suspension without pay ● Denial of a raise in salary or salary/rank reduction ● Termination of employment If no misconduct is found, all individuals who knew of the allegation because they were involved in or knew of the Inquiry and Investigation (e.g., witnesses, attorneys, supervisors, lab members and colleagues of the defendant, journal editors who received complaints, etc.) must be formally notified of the exoneration. INVESTIGATOR TRAINING
Appropriately trained investigators are the cornerstone for the conduct of ethical research. Several venues are available to obtain this training. There is a collaborative IRB training initiative developed by the University of Miami that includes 17 Web-based modules on biomedical research and other modules on social and behavioral research (CITI program). This comprehensive training is being required of all researchers by many institutions. The VA also has a comprehensive program. The NIH has a single Web-based module required of anyone applying for federal research funding. In summary, the principles of respect for persons, beneficence and justice are the basic bioethical principles that underlie all aspects of human subjects research. The principles of animal research emphasize humane treatment of all species and their judicious use under institutional and veterinary oversight. Research has become a highly regulated endeavor, with protections in place, so some of the horrors of our recent past are not repeated. Training in research ethics begins with familiarizing yourself with the rules discussed
NIH bioethics home page. Available online at: http:// www.nih.gov/sigs/bioethics/. Office of Laboratory Animal Welfare. Regulates animal research. Available online at: http://grants.nih. gov/grants/olaw/olaw.htm. Office of Human Subjects Research. Regulates research involving human subjects. Available online at: http://ohsr.od.nih.gov/. Course to fulfill NIH requirement for research training in bioethics. Available online at: http://cme.nci. nih.gov/. President’s Council on Bioethics site for research. Available online at: http://bioethics.gov/topics/experiment_ index.html. Read more about the Tuskegee Syphilis study and its’ aftermath. Available online at: www.med.virginia. edu/hs-library/historical/apology/report.html. Comprehensive bibliography of publication on research bioethics. Available online at: www.nlm.nih. gov/pubs/cbm/hum_exp.html. Office of Research Integrity. Defines misconduct, penalties. Available online at: www.ori.dhhs.gov/html/ policies/fed_research_misconduct.asp. CITI—Course in the protection of human research subjects. Available online at: http://www.citiprogram. org. Summary of HIPAA law and regulations. Available online at: www.hhs.gov/ocr/hipaa. REFERENCES 1.
The Nuremberg Code (1947). In Mitscherlich A, Mielke F, (Eds.), Doctors of Infamy: The Story of the Nazi Medical Crimes. New York: Schuman, 1949. Pp. xxiii-xxv. 2. World Medical Organization. Declaration of Helsinki. Br Med J 1996;313:1448. 3. Department of Health, Education and Welfare Publication No. (OS) 780013 and No. (OS) 78-0014. U.S. Government Printing Office, Washington, D.C. April 18, 1979.