Informed Consent
Research on Humans The Federal Regulations for the Protection of Human Subjects Title 45 Part 46 of the Code of Federal Regulations (45CFR46) Title 21 Part 50, 56, 312, 812 of the Code of Federal Regulations (21 CFR 50,56, 312, 812) State Law Local IRB policies and procedures
Hypothetical Research Collaboration Project Dr. B, an oncologist in a poor third-world country, has been conducting a trial of a vaccine against gastric cancer, a highly prevalent disease in her country. Before she began the study, Dr. B called and asked if you would be willing to perform some research analyses of blood samples obtained from the subjects in the proposed vaccine trial and to help with the data evaluation. She offered you a co-authorship on any relevant publications which might be generated. You have a long professional association with Dr. B. She was a research fellow in your laboratory a decade ago, and you have collaborated on several other research projects since her return to her home country. You are co-authors on a number of publications which have been the results of other collaborative projects
Hypothetical Research Collaboration Project Your Position You judged that your role in the research was peripheral, since you would have no actual contact with human subjects and would only be performing the blood analyses requested by Dr. B. You agreed to help and have been receiving and analyzing data and blood samples monthly for a year.
Hypothetical Research Collaboration Project Trouble? During a recent interview by the news media, Dr. B said, "Without the important input of my colleague at the Institution, these vaccine trials would not have been possible." A clinical trial of the same vaccine had been planned by researchers in the United States, but was not conducted because of irresolvable concerns over scientific validity and ethical permissibility. A journalists' interest is aroused when he learns that four of the ten people in Dr. B's trial died, allegedly from reactions to the vaccine.
Hypothetical Research Collaboration Project Trouble? When Dr. B notifies you that four subjects died, you become concerned and question whether or not you have followed the Institution s policies and procedures related to collaborations. You become even more concerned when the journalist calls you for more information about the vaccine trial and your role in it. The journalist tells you he has also placed an inquiry with the federal Freedom of Information Office for details about FDA involvement in the vaccine trial and details about your research collaboration. The journalist asks you for a copy of the research protocol and the minutes of the Institutional Review Board (IRB) that approved the study. You know that IRBs are responsible for reviewing and approving research involving human subjects, but you did not think that IRB approval of this collaboration was necessary because you were only receiving and analyzing blood samples, and neither you nor the institution would have any contact with the human subjects involved in the research.
Hypothetical Research Collaboration Project What You Should Have Done The collaborative research activities, the analyses of blood samples drawn specifically for research and analyses of research data, are considered research with human subjects as defined by the Department of Health and Human Services. Before starting the research, you should have sought review and approval by the institution s IRB. In this case, you did not follow the policies and procedures of the Institution. People were apparently seriously harmed by their participation in research in which you were a collaborator.
Hypothetical Research Collaboration Project Ramifications You were incorrect in your judgment that the IRB did not need to review and approve the research just because you would not have any direct contact with the subjects. There will be consequences of your behavior, which may result in your personal sanctioning by local or federal officials or may adversely impact on the Institution s Multiple Project Assurance, jeopardizing the federal funding of all investigators at this Institution.
SOME HISTORY The formal codification of ethical guidelines for the conduct of research involving humans began in the late 1940's as a result of the War Crimes of World War II. In 1946, 23 Nazi physicians were tried by a military tribunal at Nuremberg because of atrocities performed on inmates of concentration camps, captured soldiers and other prisoners of war. As a result, the Nazi War Crimes tribunal issued the Nuremberg Code, the first internationally recognized code of research ethics. While the Nuremberg Code and subsequent ethical guidelines, such as the Declaration of Helsinki, represented the most enlightened way of thinking of the time, many well-intentioned researchers did not know about them or did not apply this guidance to their research activities. A series of research subjects abuses came to public attention in the U.S. between 1953 and 1972, including the infamous Tuskegee Study*, a study conducted by the Public Health Service employees on the natural history of Syphilis. These abuses led some people to conclude that medical researchers were not to be trusted to conduct ethical studies involving humans.
SOME HISTORY In the 1950's and 1960's, as federal funding for bio-medical research increased dramatically, ethical safeguards and legal requirements were imposed on research activities involving human subjects. The U.S. Government, in dialogue with the re-search community, gradually designed one of the most comprehensive systems in the world for protecting human subjects. Laws, regulations, and public opinion challenged the research community to make the system operable and accountable. By congressional mandate, the National Commission for the Protection of Human Subjects was established in 1974 to make recommendations for the conduct of research involving humans. Oversight of the system was assigned, by law, to the Secretary of the Department of Health and Human Services (DHHS). DHHS set standards for high quality research accompanied by high standards of research ethics as their goal. The primary task of the National Commission was to identify the ethical principles that would guide all research involving humans.
Belmont Report The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects was published in 1978 The principles of The Belmont Report govern all research involving human subjects at this institution.
Belmont Report Principles Respect for persons: which acknowledges the dignity and freedom of every person, dictating the need for informed consent from all potential research subjects (or their legally authorized representatives). Beneficence: which requires that the researcher maximize the benefits and minimize the harm or risk associated with research. Research related risks must be reasonable when weighed against the expected benefits. Justice: which requires equitable participant (subject) selection and recruitment, and fair treatment of research subjects.
Belmont Report and Federal Regulations In the early 1980's and again in 1991, DHHS revised regulations for the conduct of research with humans were published, entitled Title 45 Code of Federal Regulations Part 46, Protection of Human Subjects (45 CFR 46). Similarly, the FDA revised their regulations, entitled Protection of Human Subjects (21 CFR 50) and Institutional Review Boards (21 CFR 56). The ethical principles of The Belmont Report are embodied in these regulations. Taken together, The Belmont Report, the 45 CFR 46 and 21 CFR 50, 56 articulate the minimum ethical and legal obligations of those who conduct or support research involving human subjects.
Belmont Report and Federal Regulations Among other things, these regulations require that each institution conducting federally funded research adheres to the principles of The Belmont Report and sets forth, in writing, their ethical principles, practices, and procedures for protecting the rights and welfare of human research subjects. The Institution's policies place the responsibility for protecting the rights of human subjects directly on you, as a research investigator, and the Institution. If you find the Institution's policies application unclear in a given situation, you should ask the IRB for resolution. Not knowing or not understanding what the policy requires of you is not an acceptable reason for ignoring or circumventing its policies. Failure to comply with the policies may constitute unethical behavior and violation of the law. Such violations can lead to loss of research privileges for an individual, a laboratory, or for an entire research program.
The Institutional Policy Applies to all research activities involving human subjects conducted by Investigators, or staff. Requires that all research activities involving human subjects follow the ethical principles of The Belmont Report and the legal requirements of 45 CFR 46 and or 21 CFR 56. Collaborations with other researchers in human subjects' research activities at other institutions is subject to the requirements of the Institution s Policies. For example, collaborative research activities in which subjects are enrolled entirely at a non-institutional site, such as a facility in another country, must meet the same ethical standards as those conducted at your institution.
Research Federal regulations, Institutional Policies apply to all research involving human subjects. "Research" means a systematic collection of information, designed to produce generalizable knowledge. Research may involve direct interactions or interventions with subjects, health service research, program evaluation, interviews, oral histories, human factor evaluations, quality control methodologies, obtaining blood samples, urine sampling, diagnostic procedures, or treating patients, at least in part, for the purpose of gaining generalizable information. Research may also involve indirect activities such as the analysis of previously collected specimens or data Participation in these kinds of indirect activities, particularly if if the results will be published constitutes human subjects research.
Your Responsibilities Research investigators have a fundamental responsibility to safeguard the rights and welfare of the people participating in their research activities. In addition, our society has decided by law that an objective review of human subjects research by a group of diverse individuals is most likely to protect human subjects and promote ethnically sound research. Therefore, when conducting research involving humans, federal regulations, institutional policy and the Institution s policies require prospective and continuing review and approval of the research by a committee called an Institutional Review Board (IRB).
IRBs IRBs have one paramount responsibility: to protect the rights and welfare of human research subjects. IRBs are very important to the conduct of human subjects research at this institution and other research institutions, both inside and outside the U.S. IRB review and approval relieves us of making that onerous decision and obviates our potential conflict of interest. IRBs take into account national and, when appropriate, international ethical standards of research on a study-by-study basis. Protecting human research subjects is their sole responsibility. IRBs rarely disapprove proposed research activities. Instead, they strive to work interactively with investigators to assure that the research design is optimal, that risks are minimized benefits maximized, and that outlined study procedures are adequate. The IRB staff and IRB Chairpersons are available to assist you. If you need advice or guidance, contact your IRB.
Infamous Cases, Ethical Violations in Research Involving Humans Nazi War Crimes of Medical Nature The Willowbrook Studies The Tuskegee Syphilis Study Radiation Test on Mentally Impaired Boys The Jewish Chronic Disease Hospital Study
Infamous Cases: Nazi War Crimes During the trial at Nuremberg, fundamental ethical principles for the conduct of research involving humans were codified into the Nuremberg Code which set forth ten conditions that must be met before research involving humans is ethically permissible (e.g., the basis for voluntary informed consent of subjects, and a scientifically valid research design that could produce fruitful results for the good of society). The Nuremberg Code became the first international standard for the conduct of research. If you would like a copy of the Nuremberg Code, you may obtain it through OHRP's web site.
The Tuskegee Syphilis Study This study was conducted in the United States and was designed to determine the natural history of untreated latent syphilis. Over 400 black men with syphilis and about 200 men without syphilis, who served as the controls, were the subjects. Men were recruited without informed consent. In fact, they were misinformed and told that some of the procedures done in the interest of research (e.g., spinal taps) were actually " special free treatment." In the 1940 s when penicillin, known to be effective in the treatment of syphilis, became available, the men were neither informed of this, nor treated with the antibiotic. The government continues to pay millions of dollars yearly to surviving subjects and the families of deceased subjects.
The Jewish Chronic Disease Hospital Study In 1963, studies were undertaken at New York City s Jewish Chronic Disease Hospital to develop information on the nature of the human transplant rejection process. These studies involved the injection of live cancer cells. Patients who were hospitalized with various chronic debilitating diseases. Previous studies had indicated that healthy persons rejected cancer implants promptly. Patients with widespread cancer also rejected homographs, however, rejection is delayed substantially when compared with healthy subjects. Researchers said that consent had been given orally, but it was not documented. They felt that documentation was unnecessary because it was customary to undertake much more dangerous medical procedures without the use of written informed consent. Furthermore, patients were not told that they would receive cancer cells because, in the view of the investigators; this would frighten the patients unnecessarily. Investigators defended this view on the basis that they had good cause to predict that the cancer cells were going to be rejected.
Infamous Cases: The Willowbrook Study From 1963 through 1966, studies were carried out at the Willowbrook State School, a New York State institution for "mentally defective persons." The studies were designed to gain an understanding of the natural history of infectious hepatitis and subsequently to test the effects of gamma globulin in preventing complications of hepatitis or ameliorating the disease. The subjects, all children, were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations. This case caused a public outcry because of the perception that parents and their children were given little choice about whether or not to participate in research.
Radiation Test on Impaired Boys From 1946 to 1956, 19 boys who thought they were participating in a science club were fed radioactive milk by researchers who wanted to learn about the digestive system. Experiments were performed at the Fernald State School in Massachusetts. Researchers from Harvard University and the Massachusetts Institute of Technology fed radioactive forms of iron and calcium to the boys, sometimes in their breakfast milk, to study the body s ability to digest minerals.
The three ethical principles of The Belmont Report Respect for persons that individuals should be treated as autonomous agents, that persons with diminished autonomy are entitled to protection. Beneficence do not harm maximize possible benefits, and minimize possible harms. Justice fairness in distribution Willing participants
Applications Applications of the general principles to the conduct of research leads to consideration of the following requirements: informed consent, risk / benefit assessment the selection of subjects of research
Informed Consent Information Most codes of research establish specific items for disclosure, intended to assure that subjects are given sufficient information. These items generally include: the research procedure, their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Additional items have been proposed, including how subjects are selected, the person responsible for the research, etc. A special problem of consent arises, where informing subjects of some pertinent aspect of the research is likely to impair the validity of the research. In many cases, it is sufficient to indicate to subjects that they are being invited to participate in research, of which some features will not be revealed until the research is concluded. In all cases of research involving incomplete disclosure, such research is justified, only if it is clear that (1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them.
Informed Consent Comprehension The manner and context, in which information is conveyed is as important as the information itself. Because the subject's ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject's capacities. On occasion, it may be suitable to give some oral or written tests of comprehension. Special provision may need to be made, when comprehension is severely limited --for example, by conditions of immaturity or mental disability. Each class of subjects that one might consider as incompetent should be considered on its own terms. Such persons are thus respected, both by acknowledging their own wishes, and by the use of third parties to protect them from harm. The third parties chosen should be those, who are most likely to understand the incompetent subject's situation, and to act in that person's best interest. The person authorized to act on behalf of the subject should be given an opportunity to observe the research, as it proceeds, in order to be able to withdraw the subject from the research, if such action appears in the subject's best interest.
Informed Consent Voluntariness An agreement to participate in research constitutes a valid consent, only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence. Unjustifiable pressures usually occur, when persons in positions of authority or commanding influence -- especially where possible sanctions are involved-- urge a course of action for a subject. But undue influence would include actions, such as manipulating a person's choice through the controlling influence of a close relative, and threatening to withdraw health services to which an individual would otherwise be entitled.
Assessment of Risks and Benefits The Nature and Scope of Risks and Benefits Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and society at large (or special groups of subjects in society). Previous codes and Federal regulations have required that risks to subjects be outweighed by the sum of both the anticipated benefit to the subject, if any, and the anticipated benefit to society in the form of knowledge to be gained from the research. In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight. Beneficence thus requires that we protect against risk of harm to subjects, and also that we be concerned about the loss of the substantial benefits that might be gained from research
Assessment of Risks and Benefits The Systematic Assessment of Risks and Benefits It is commonly said that benefits and risks must be "balanced", and shown to be "in a favorable ratio". It should also be determined whether an investigator's estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies. Finally, assessment of the justifiability of research should reflect at least the following considerations: (i) Brutal or inhumane treatment of human subjects is never morally justified. (ii) Risks should be reduced to those necessary to achieve the research objective. (iii) When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject --or, in some rare cases, to the manifest voluntariness of the participation). (iv) When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits. ( v) Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process.
Selection of Subjects Justice is relevant to the selection of subjects of research at two levels: Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some patients, who are in their favor, or select only "undesirable" persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens, and on the appropriateness of placing further burdens on already burdened persons. Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators, and treated fairly in the course of research. Thus, injustice arises from social, racial, sexual and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, and even if institutional review boards are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects.
IRB Review Criteria Vulnerable populations: Fetuses and human in vitro fertilization Children and minors Prisoners (additional protections in 45 CFR 46 subpart C) Traumatized and comatose patients Terminally ill patients Elderly/aged persons Cognitively impaired individuals Students, employees and normal volunteers International research Minorities
Case Study One Your colleague at another institution calls you on the phone to ask if you will analyze some human blood samples. She says the samples were collected from cancer patients and, are currently stored in her laboratory freezer. You are very interested in doing the research analyses. She says she can send them to you by overnight delivery. Choose the best course of action: 1. You encourage your colleague to send the sample as soon as possible. You plan to begin analyzing them as soon as they arrive. 2. You ask her for more information about the samples. 3. You tell her you will consider the matter and call her back after seeking advice, but you are not sure whom to ask for advice. 4. You tell her you are not permitted to receive or analyze them unless you first prepared a research protocol and get IRB approval for it. The process in too cumbersome and too complicated to bother with and so you are not interested in collaborating with her.
Case Study One Choice 2: You ask her for more information about the samples, The information you should seek would be: Are these specimens currently in an IRB approved repository? Are there identifiers on these samples? Were these samples collected with appropriate informed consent? This the best choice!
Important Points in Case Study One Before you begin research analyses of existing human samples (i.e., frozen/stored blood/tissue specimens) or existing private data about humans, ASK YOURSELF: Do the samples/data contain identifiers (codes, initials, etc.) that either or someone else could link to a living individual? If the answer is "yes" then your proposed activity is considered research with human subjects and you need IRB review and approval before you begin. If the human samples/data do not contain identifiers, then the research may be exempt from IRB continuing review and approval. Contact the IRB Office. If you are not sure whether your research involves human subjects, discuss it with your IRB.
Case Study Two Dr. B. an oncologist in an economically poor third-world country, is conducting a controversial trial to develop a vaccine against gastric cancer which is highly prevalent in her country. You have a long, professional association with Dr. B. She was a research fellow in your laboratory. In the past, you have collaborated on several research projects, and you are co-authors on a number of publications. She called and asked you to perform some research analyses of blood samples that will be drawn from subjects in the proposed vaccine trial and to help with the data evaluation. She suggested that you be identified as a co-author on relevant research publications. You want very much to work with her on this project. Choose the best course of action: 1. You ask her to write a research protocol for you to review because you must get IRB approval before you collaborate in this research. 2. You are not sure what to do. You want advice but are not sure whom to ask. 3. You tell her you want to work with her on the research project and you agree to have her send the first batch of blood samples to you next week.
Case Study Two Choice 1: You ask her to write a research protocol for you to review because you must get IRB approval before you collaborate in this research. This is the best course of action.
Important Points of Case Study Two When investigators collaborate in research, they and the institution accept some measure of responsibility for protecting the rights and welfare of human subjects at the collaborating institution(s). In all research involving humans, including collaborative activities, the IRB and the investigators are expected to follow the requirements of the institutional policies. The IRB and the investigators should be familiar with the institutions guidelines on what constitutes "collaborative research".
Case Study Three Dr. C., a psychologist working in the county school system, asks you to collaborate with his study to evaluate the prevalence of drug usage in the high schools. You have a long professional association with Dr. C. He was a fellow student during your postdoctoral years and you have collaborated on several research projects, and you are a co-author on a number of publications. He called and asked you to assist in the development of the survey instruments, perform fieldwork with him and to help with the data analysis. He informed you that all of the preliminary approvals have been obtained and the superintendent of the country school systems was anxious for this study to begin. The superintendent authorized the study to go forward with passive parental consent. Choose the best course of action 1. You ask him to write a research protocol, including a process for active parental consent and student assent, for you to review because you must get IRB approval before you collaborate in this research. 2. You are not sure what to do, because as a parent, you believe that an active consent process is required, but don t know how to proceed. 3. You tell him you want to work with him on the research project and you agree to begin next week.
Case Study Three Choice 1 You ask him to write a research protocol, including a process for active parental consent and student assent, for you to review because you must get IRB approval before you collaborate in this research. This is the best course of action.
NJIT IRB http://www5.njit.edu/research/compliance/re view-board/forms.phpcomplete a IRB Research Review Form for your project.
OHRP (Office of Human Research Protections) 1. HHS Regulations & Institutional Responsibilities 2. Investigator Responsibilities & Informed Consent 3. Human Research Protections Program https://www.hhs.gov/ohrp/education-and-outreach/humanresearch-protection-programfundamentals/index.html/assurance-training