Chapter 1. The Ethical Mandate to Protect Human Subjects

The following summarize important events in the development of protections for human subjects in research.

A. The Nuremberg Code. The modern history of human subject protections begins with the discovery after World War II of numerous atrocities committed by Nazi doctors in human-related research experiments. The Nuremberg Military Tribunal developed ten principles, known as The Nuremberg Code, to judge the Nazi doctors. The significance of the Code is that it addressed the necessity to require the voluntary consent of the human subject and that any individual “who initiates, directs, or engages in the experiment” must bear personal responsibility for the quality of consent.

B. The Declaration of Helsinki. Similar principles have been articulated and expanded in later codes, such as the World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects (1964, revised 1975, 1983, 1989, 1996, 2000, which calls for prior approval and ongoing monitoring of research by independent ethical review committees).

C. The Belmont Report. Revelations about the 40-year United States Public Health Service Syphilis Study at Tuskegee and other ethically questionable research resulted in legislation in 1974 calling for regulations to protect human subjects and for a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to examine ethical issues related to human subject research.

The Commission’s final and most influential report, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, defines the ethical principles and guidelines for the protection of human subjects. Perhaps the most important contribution of The Belmont Report is its elucidation of three basic ethical principles:

(i.) respect for persons (operationalized by obtaining informed consent);

(ii.) beneficence (operationalized by weighing risks and benefits); and

(iii.) justice (operationalized by the fair selection of subjects).

Respect for Persons

Voluntary Participation and Informed Consent. One of the most important elements in any research involving human research participants is the assurance of voluntary informed consent. Any person who is to be a research participant, whether that research is designed for his/her own direct benefit or for the advancement of scientific knowledge in general, must understand as completely as possible what is to be done and the associated potential risks and benefits. The person must give his/her consent freely, without pressure or inappropriate inducement. The IRB at ND strives to ensure voluntary informed consent of research participants through careful review of the recruitment and consent processes, and of the consent form or information sheet to be used with participants.

The informed consent concept is extended to those studies in which participants are not able to give personal consent for themselves. In such cases, the consent document is addressed to those who have been designated as responsible for the research participants’ well being (e.g. parents of children). The IRB’s concern is to verify that the consent process and document are likely to assist these persons in making informed decisions which are in the best interest of the research participants.

The capacity for truly informed and voluntary participation in research varies widely among study populations. At one extreme, there may be ample understanding and manifest freedom from coercion; at the other, there may be degrees of understanding and freedom that affect the consent of potential participants. The IRB must exercise special care when considering participants whose ability to give free and informed consent may be compromised in any way.

Beneficence:

The Risk-Benefit Ratio. The IRB is charged with deciding, for any proposed activity which falls under its jurisdiction, whether: “The risks to the participant are so outweighed by the sum of the benefit to the participant and the importance of the knowledge to be gained as to warrant a decision to allow the subject to accept (those) risks” (Federal Register, May 30, 1974).

Assessment of the risk/benefit relation is a complex task. Risks of injury or discomfort to the individual can be physical, psychological, and/or social. There can be potential benefits to the individual, to a group to which the individual belongs, and/or to society. When reviewing applications, the IRB must carefully assess the types and degrees of both risks and benefits for a given participant population, as well as the investigator’s communication of these risks and benefits in the consent process and form. While the IRB is not charged with reviewing scientific design per se, it must sometimes do so in order to assess the risk/benefit ratio. If a study design does not seem adequate to attain the stated aim of the investigation, then no benefit can be anticipated from conducting the study, and there is no justification for placing any research participant at risk, however minimal. Thus the design of the study must be sound, and the nature and likelihood of all risks and benefits must be made clear in any application to the IRB.

Justice:

The Fair Selection of Research Participants. Both the risks and the potential benefits of research should be spread fairly among potential individual research participants and groups of individuals participating in research. Study design and selection of participants should avoid bias for or against particular social, racial, sexual, or ethnic groups.

Sharing Research Risks. The guiding principle in the ethical selection of research participant groups is that any risks of the research should fall upon the groups that might benefit from the research. If the results of a risky protocol might benefit the general population, it would be unethical to focus participant recruitment on vulnerable or disadvantaged groups (e.g. institutionalized people or prisoners, patients at free clinics primarily patronized by people unable to afford other medical care) simply because they are easily accessible or can be persuaded to participate. An undue share of research risks should not also burden groups already burdened by other factors. Rather, attempts should be made to include a fair sampling of the groups that might benefit from the study. When research involves persons whose autonomy is compromised, it is expected that the research bear some direct relationship to the conditions or circumstances of the research participant population. In addition, groups fully able to consider research risks and informed consent should be asked to face research risks before more vulnerable populations.

Sharing Research Benefits. In recent years, increasing attention has been paid to the rights of various groups to be included in research. In addition, researchers, ethicists, and public officials have recognized that because many clinical trials focus primarily on White middle-class research participant groups, the results of some trials have been of questionable value for members of other social, racial, sexual, and ethnic groups. As a result, both the National Institutes of Health and the Food and Drug Administration now require that study design include as broad a range of research participants as feasible and data be analyzed to uncover responses that differ between groups. Whereas women of child-bearing potential and pregnant and nursing women previously were routinely excluded from new drug trials, it is now required that whenever possible these women be asked to make their own choices after being fully informed of the risks of the research.

Chapter 2. The Regulatory Mandate to Protect Human Subjects

The University of Notre Dame and Federal regulations require specific protections for human subjects.

A. Department of Health and Human Services (DHHS). DHHS regulations at 45 CFR Part 46, Subpart A constitute the Federal Policy (Common Rule) for the protection of human subjects. The DHHS regulations also include additional protections for pregnant women, human fetuses and neonates (Subpart B), prisoners (Subpart C), and children (Subpart D). All human subject research at the University of Notre Dame must comply with all four Subparts of the DHHS regulations. These regulations are enforced by the DHHS, Office for Human Research Protections (OHRP).

B. Food and Drug Administration (FDA) Regulations. FDA has codified informed consent (21 CFR Part 50), IRB (21 CFR Part 56), and child protection (61 FR 20589 and 21 CFR Part 50, Subpart D) regulations that are almost identical to the DHHS regulations. Additional FDA regulations relevant to the protection of human subjects address Investigational New Drug Applications (21 CFR Part 312), Biological Products (21 CFR Part 600), and Investigational Device Exemptions (21 CFR Part 812).

In general, FDA human subject regulations apply to clinical investigations and other research involving products regulated by FDA, including food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products. IRB review and approval is required for clinical investigations and other research involving products regulated by FDA for human use, even where an Investigational New Drug Application (IND) or Investigational Device Exemption (IDE) is not required.

C. The Assurance and IRB Registration Process. Every institution that receives funds from DHHS for human subject research must have an “Assurance” of protection for human subjects (45 CFR 46.103).

The University of Notre Dame currently conducts human subject research under a DHHS, OHRP- approved Federalwide Assurance (FWA) with Federal wide application. The University of Notre Dame Office of Vice President for Research coordinates IRB registration and Assurance filings.

Chapter 3. Types of Human Subject Research

All research involving human subjects conducted at the University of Notre Dame or by its faculty, staff, and students must be reviewed by the University of Notre Dame’s Institutional Review Board (IRB).

A. Definition of Human Subject and Research. Federal regulations (45 CFR 46.102(d)) define research as “a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.”

For the purposes of this policy, a systematic investigation is an activity that involves a prospective research plan, which incorporates data collection, either quantitative or qualitative, and data analysis to answer a research question. Investigations designed to develop or contribute to generalizable knowledge are those designed to draw general conclusions (i.e., knowledge gained from a study may be applied to populations outside of the specific study sample), inform policy, or generalize findings.

Federal regulations (45 CFR 46.102(f)) define human subject as “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual or (2) identifiable private information.” Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may readily be ascertained by the investigator or associated with the information.

B. Types of Human Subject Research. The following examples illustrate common types of human subject research. These are examples only, and are not exhaustive of all human subject research.

1. Biomedical Research. Biomedical research involves research (i) to increase scientific understanding about normal or abnormal physiology, disease states, or development; and (ii) to evaluate the safety, effectiveness or usefulness of a medical product, procedure, or intervention. Vaccine trials, medical device research trials, and cancer research trials are all types of biomedical research.

2. Social and Behavioral Research. The goal of social and behavioral research is similar to that of biomedical research — to establish a body of knowledge and to evaluate interventions — but the content and procedures often differ. Social and behavioral research involving human subjects focuses on individual and group behavior, mental processes, or social constructs and usually generates data by means of surveys, interviews, observations, studies of existing records, and experimental designs involving exposure to some type of stimulus or environmental intervention.

3. Clinical Research. Clinical research involves the evaluation of biomedical or behavioral interventions related to disease processes or normal physiological functioning.

4. Epidemiology Research. Epidemiology research investigates specific health outcomes, interventions, or disease states and attempts to reach conclusions about cost-effectiveness, efficacy, interventions, or delivery of services to affected populations. Some epidemiology research is conducted through surveillance, monitoring, and reporting programs— such as those employed by the Centers for Disease Control and Prevention (CDC)—whereas other epidemiology research may employ retrospective review of medical, public health, and/or other records. Because epidemiology research often involves aggregate examination of data, it may not always be necessary to obtain individually identifiable information. When this is the case, the research may qualify for exemption or expedited review. In all cases, the IRB (not the individual investigator) will determine when IRB review of the activity is required.

5. Repository Research. Research utilizing stored data or materials from individually identifiable living persons qualifies as human subject research, and requires IRB review. When data or materials are stored in a bank or repository for use in future research, the IRB should review a protocol detailing the repository’s policies and procedures for obtaining, storing, and sharing its resources, for verifying informed consent provisions, and for protecting subjects’ privacy and maintaining the confidentiality of data. The IRB may then determine the parameters under which the repository may share its data or materials with, or without, IRB review of individual research protocols.

6. Quality Assurance Activities. Quality assurance activities attempt to measure the effectiveness of programs or services. Such activities may constitute human subject research, and require IRB review, if they are designed or intended to contribute to generalizable knowledge. Quality assurance activities that are designed solely for internal program evaluation purposes with no external application or generalization may not require IRB review. Where any question arises about whether a quality assurance activity constitutes human subject research, the IRB (not the individual investigator) will determine when IRB review of such activities is required.

7. Pilot Studies. Pilot studies involving human subjects are considered human subject research and require IRB review.

Chapter 4. Shared Responsibilities for Protecting Human Subjects

The ethical conduct of research is a shared responsibility. It requires cooperation, collaboration, and trust among the institution, investigators and their research staff, the subjects who enroll in research, and the IRB. A clear delineation of the responsibilities of each of these parties can help protect the participants who volunteer for research.

A. The Institution. It is the responsibility of the institution to assure Federal Agencies in writing that it will comply with regulations governing the protection of human subjects. As part of this Assurance, the institution must develop policies and procedures for conducting human subject research in a responsible and ethical fashion, including how research will be reviewed by the IRB, the reporting of unanticipated problems to the IRB and appropriate regulatory bodies, and other issues.

Furthermore, the responsibilities of the University of Notre Dame flow from its research mission as a Catholic institution committed to compassionate care for the whole person. Thus, in all of its activities, the University of Notre Dame will promote the physical, psychological, spiritual, and social wellbeing of those we serve. The University of Notre Dame is dedicated to defending and promoting human dignity, health, and well-being.

The Vice President for Research serves as the Institutional Signatory Official for the University of Notre Dame’s Assurance and is ultimately responsible for overseeing the protection of human subjects within the institution. The Institutional Signatory Official must also maintain open channels of communication between the IRB, research investigators and staff, and administration, and provide the IRB with sufficient meeting space and staff to support its substantial review and record keeping responsibilities.

B. The Institutional Review Board (IRB). An IRB is an appropriately constituted group that has been formally designated to review and monitor research involving human subjects. In accordance with the Common Rule and FDA regulations, the IRB has responsibility for approving, requiring modification in (to secure approval), or disapproving research protocols. The IRB at the University of Notre Dame also has the authority to suspend or terminate research, if such action is believed to be in the best interest of research subjects. Reasons for this action may include, but are not limited to, hazard to subjects, continued noncompliance with the Common Rule, FDA regulations, or its own findings, determinations, and initial and continuing review procedures.

C. The Principal Investigator. As the individual responsible for the implementation of research, the principal investigator bears direct responsibility for protecting every research subject. This responsibility starts with protocol design, which must minimize risks to subjects while maximizing research benefits. In addition, the principal investigator and all members of the research team must comply with the findings, determinations, and requirements of the IRB. The principal investigator must also be responsible for the adequacy of both the informed consent document and the informed consent process, regardless of which members of the research team actually obtain and document consent.

Principal investigators have the following responsibilities: (i) that all human subject research which they conduct at this institution or as employees or agents of this institution has received prospective review and approval by an IRB designated by this institution; (ii) that continuing review and approval of the research has been secured in a timely fashion; and (iii) that the research is conducted at all times in compliance with all applicable regulatory requirements and the determinations of the IRB. No changes in approved research may be initiated without prior IRB approval, except where necessary to eliminate apparent immediate hazards to subjects; and no research may be continued beyond the IRB-designated approval period. Investigators must notify the IRB promptly of (i) any unanticipated problems or serious adverse events involving risks to subjects or others, and (ii) any serious or continuing noncompliance with applicable regulatory requirements or determinations of the IRB.

D. Other Members of the Research Team. Every member of the research team is responsible for certification in the protection of human subjects. Co-investigators, study coordinators, research assistants, and all other research staff have a strict obligation to comply with all IRB determinations and procedures, adhere rigorously to all protocol requirements, inform investigators of all adverse subject reactions and/or unanticipated problems, oversee the adequacy of the informed consent process, and take whatever measures are necessary to protect the safety and welfare of subjects. Researchers at every level are responsible for notifying the IRB promptly of any serious or continuing noncompliance with applicable regulatory requirements or determinations of the IRB, whether or not they themselves are involved in the research.

E. Research Subjects. Subjects have responsibilities as well. They can be expected to make every effort to comprehend the information researchers present to them so that they can make an informed decision about their participation in good faith. They should also be willing to comply with protocol requirements (unless they decide to discontinue participation) and inform the investigators of unanticipated problems.

Chapter 5. IRB Roles and Authorities

A. Human Subject Protections under Federal Regulations. Federal regulations at 45 CFR Part 46 require that institutions engaging in human subject research funded by the Department of Health and Human Services (DHHS) devise mechanisms for the protection of human subjects. The regulations require that each institution conducting human subject research file a written “Assurance” of protection for human subjects and designate one or more Institutional Review Boards (IRBs) to review its human subject research.

B. Institutional Authority of the IRB. The Office of the Vice President for Research is responsible for the oversight of all research activities conducted under the auspices of this institution.

C. Purpose of the IRB. The IRB’s primary responsibility is to protect the rights and welfare of participants involved in human subject research. In doing so, the IRB monitors human subject research to determine that it is conducted ethically, and in compliance with the University of Notre Dame and Federal regulations, the requirements of applicable law, this institution’s Assurance, and this institution’s policies and procedures. The IRB fulfills these responsibilities by conducting prospective and continuing review of human subject research, including review of the protocol and grant applications or proposals, the informed consent process, procedures used to enroll subjects, as well as any adverse events or unanticipated problems reported to the IRB.

D. Scope of the IRB’s Authority. All human subject research conducted at the University of Notre Dame or by its employees or agents must be prospectively reviewed and approved by the IRB. No human subject research may be initiated or continued at the University of Notre Dame or by Notre Dame’s employees or agents without prospective approval of the IRB.

The IRB has the authority to approve, require modifications, or disapprove any human subject research conducted at the University of Notre Dame or by its employees or agents. The IRB may suspend or terminate the enrollment and/or ongoing involvement of human subjects in this institution’s research as it determines necessary for the protection of those subjects. The IRB has the authority to observe and/or monitor this institution’s human subject research to whatever extent it considers necessary to protect human subjects.

E. Additional Institutional Review of IRB­Approved Research. Although research approved by the IRB may be disapproved by other Notre Dame committees or officials, no human subject research may be conducted at Notre Dame or its employees or agents without the initial and continuing approval of the IRB. No University of Notre Dame committee or official may approve or authorize to any human subject research that has not been reviewed and approved by the IRB.

F. Appeal of IRB Determinations. The IRB will provide the investigator with a written statement of its reasons for disapproving or requiring modifications in proposed research and will give the investigator an opportunity to respond in person or in writing. The IRB will carefully and fairly evaluate the investigator’s response in reaching its final determination. There is no limit to the number of times a research project can be revised and re-submitted to the IRB for consideration.

G. Relationship of University of Notre Dame’s IRB to Other Institutions. The University of Notre Dame’s IRB must review all human subject research conducted by faculty, students, or staff, including when research takes place in a foreign country. When international research is conducted, the University of Notre Dame’s IRB and the foreign site’s IRB/Ethics Committee, if one exists, must approve the research before the study begins. Research or data collected without IRB approval cannot be approved retroactively, which also means that such research or data may not be used for publication or professional presentations. Researchers should consult the OHRP 2010 edition of the International Compilation of Human Subject Protections (http://www.hhs.gov/ohrp/international/), which lists approximately 1,100 laws, regulations, and guidelines on human subject protections from 96 countries. Many of the listings include web addresses, allowing researchers to link directly to the law, regulation, and guideline of interest.