Todd W. Rice, MD, MSc
Division of Allergy, Pulmonary, and Critical Care Medicine
Chair, Health Sciences Committee #2, Institutional Review Board
Vanderbilt University School of Medicine, Nashville, TN

Gordon R. Bernard, MD
Melinda Owen Bass Professor of Medicine
Director, Division of Allergy, Pulmonary, and Critical Care Medicine
Assistant Vice-Chancellor for Research
Medical Director, Institutional Review Board Vanderbilt University School of Medicine, Nashville, TN

Introduction

The Institutional Review Boards (IRB), or Institutional Ethics Committees (IEC), represent American configurations designed to evaluate the ethical aspects of research involving human subjects. Other countries have similar organizations, termed Research Ethic Committees or Ethical Review Boards. The following description will detail the history behind the legislation establishing IRBs followed by a discussion of the role of the IRB in human research protection, the composition of IRBs, and the oversight of research involving human subjects.

Brief History of Research Ethics and Regulation

In the last half century, the level of oversight for research using human subjects has exploded from almost none to what is now an exhaustive system of protections. At the end of World War II, the Nuremberg trials were conducted to bring justice to Nazi leaders for crimes against humanity. A significant portion of the trials undertook the case of Nazi physicians who forced prisoners to undergo appalling, and often inhumane, procedures in the name of clinical research. At that time, there were no laws, regulations, codes or formal documents describing the ethical standards for conducting research in human subjects. The Nuremberg proceedings resulted in the development of a document articulating the basic requirements for conducting research in a manner that respects the fundamental rights of research subjects, called the Nuremberg Code (available at http://www.hhs.gov/ohrp/references/nurcode.htm). The three basic elements of the Code, namely the requirement for voluntary and informed consent, a favorable benefit to risk analysis, and the right of the participant to withdraw voluntarily without repercussions have become the foundation for subsequent ethical codes and federal research regulations. Thus, every person involved in conducting human subjects research should read and familiarize themselves with this Code.

Despite the creation of the Nuremberg code, the United States federal government still had only a very minor role in regulating research conduct as recently as 1950. At that time, federal regulations requiring Institutional Review Board (IRB) approval were lacking for most research settings. Between 1950 and 1974, however, numerous controversies in human research became highly publicized, especially involving perceived abuses in the rights of vulnerable human populations. In 1955, unbeknownst to jurors, researchers audiotaped jury deliberations of criminal trials in Wichita, Kansas in an attempt to better understand the decision making process undertaken by such groups. Post-publication discussions focused on the unethical nature of deceiving people in a setting where privacy and confidentiality were important for research purposes. Shortly thereafter, Congress marked the beginning of legislation regulating human subject research by passing a federal law prohibiting the recording of jury deliberations.

In 1962, the use of Thalidomide, an investigational drug, prompted the first instance of a federal agency establishing and enforcing specific ethical standards for the conduct of research in human subjects. Prior to this, it was not standard practice to inform patients of the investigational nature of pharmaceuticals still being tested. Once it became clear that this drug led to birth deformities, public outrage led to an amendment in the Food, Drug and Cosmetic Act that required investigators to obtain informed consent from subjects before administering investigational medications.

During the 1960's, three events heralded a change in the ethical oversight of human subject research. In 1964, James Shannon, Director of the National Institutes of Health, established a policy that required an ethics committee review of all research funded by the Public Health Service. That same year, the World Medical Association met in Helsinki, Finland to draft a document describing the standards of ethical research involving human subjects. In addition to the three central ethical principles outlined in the Nuremberg Code, the Declaration of Helsinki (available at http://www.fda.gov/oc/health/helsinki89.html) added two novel elements: 1) the interests of the subject should always be placed above the interests of society; and 2) every person in clinical research should get the best known treatment [1]. In 1966, researchers began using these guidelines to police their own conduct in human research and focus attention on the need to improve the ethical standards for conducting such research. Dr. Henry Beecher, a senior member of the anesthesiology faculty at Harvard Medical School, published an article entitled "Ethics of Clinical Research." In this New England Journal of Medicine publication, Dr. Beecher detailed unethical practices in twenty-two studies conducted by respected investigators and published in prestigious medical journals [2].

Although none individually resulted in new federal regulation, the conduct of four infamous studies during this time period received unheralded national media attention and resulted in public outrage. In the 1950s, studies investigating issues in the transmission of the hepatitis virus were performed in the Willowbrook State School, an extended care facility for mentally-challenged children in New York State. These studies generated intense debate in professional journals and the national media over their design, which involved intentionally infecting children with hepatitis by feeding them a solution made from the feces of those with active hepatitis. The Jewish Chronic Disease Hospital study generated similar debate in the 1960s. In this study, live cancer cells were injected into the bloodstream of chronically ill, mostly demented, elderly patients residing in this New York City hospital to determine the influence of a weakened immune system on the spread of cancer. In the early 1970s, a contraception clinic serving mostly indigent patients in San Antonio, Texas, evaluated the efficacy of different types of oral contraceptive pills using a randomized, blinded, placebo-controlled design. Unfortunately, none of the participants were informed that they were participating in this type of research or that they might be receiving inactive medication. Not unexpectedly, many of those receiving placebo had unplanned pregnancies.

The most infamous study also occurred during this time period. The details of the Tuskegee Syphilis Study are well known to most investigators. The purpose of this study, funded by the U.S. Public Health Service, was to investigate the natural history of untreated syphilis in humans. To accomplish this, participants with known syphilis, were observed without treatment and subjected to tests and procedures, including spinal taps, to follow the course of their illness. When this study was developed in 1932, it was considered ethically sound because effective treatment for syphilis did not exist. However, the subjects continued to be followed for several years without treatment so as to not interrupt the study, even after the antibiotic penicillin, known to be highly effective in the treatment of syphilis, became widely available. The study was finally halted in 1972 after national media attention generated public outrage over the exploitation of this vulnerable population of indigent, uneducated, African-American sharecroppers from Tuskegee, Alabama who believed they were receiving beneficial medical care for their disease.

The National Research Act of 1974 and The National Commission

All of this national debate culminated in Congressional hearings about research in human subjects, directed by Senator Edward Kennedy, in 1973. From these hearings, a consensus was reached that federal oversight was required to protect the rights and welfare of research subjects. This consensus led to the development and passage of the National Research Act in 1974, which initiated the process of developing ethical standards and oversight for the conduct of human research. Although Congress did set forth some early regulations in this legislation, the highly contested debate and hearings forced many to realize that establishing ethical standards for the conduct of research in human subjects was riddled with complexity. Consequently, the legislation also called for the establishment of the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, commonly known simply as the National Commission. This commission, composed of experts in ethics, religion, law, industry, and medicine, met numerous times over the next few years and issued recommendations on the conduct of research in human subjects. The National Commission published numerous population-specific reports for classes of subjects they considered vulnerable, including children, pregnant women, prisoners, and cognitively-impaired persons.

The Belmont Report

In 1978, the National Commission detailed the fundamental ethical principles that should guide the conduct of research involving human subjects [3]. This Belmont Report (available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm), named for the Belmont Conference Center at the Smithsonian Institution where the meetings took place, is an eight-page document describing the three fundamental principles for conducting research involving human subjects. These principles, namely respect for persons, beneficence, and justice are now accepted as the requirement for the ethical conduct of such research.

The principle of respect for persons incorporates two components related to individual autonomy, namely that each individual has the right to self-determination and persons with diminished autonomy, who thus lack the capability of self-determination, are entitled to additional protection to prevent exploitation. The term "vulnerable" has been used in describing those populations with diminished autonomy. Four requirements for ethical conduct of research follow directly from this principle of respect for persons: 1) Participants must voluntarily consent to participate in research; 2) The voluntary consent obtained from participants must be informed consent; 3) Protection of privacy and confidentiality must be incorporated into the research; and 4) Participants must maintain the right to withdraw from research participation without penalty or repercussions.

The principle of beneficence requires that research be designed to maximize benefit and minimize harm. In other words, the risks of research must be justified by the potential benefits to the individual and/or society. The founders of the Belmont Report acknowledged that comparing the risk of research to an individual with the benefit derived by society will often be difficult and recommended determinations be made on a case-by-case basis.

The third principle is that of justice. The concept of justice relates to the distribution of risk across society. The Belmont Report directs that members of society who are likely to benefit from the research bear the potential risks of such research equally. In other words, the research should not systematically select specific classes of individuals simply because they are readily available where research is conducted, or because they are "easy to manipulate as a result of their illness or socioeconomic condition." Instead, enrollment should focus on individuals for reasons directly related to the research. Recent years has seen debate over whether the principle for justice also extends to protect persons from systematic exclusion from research that may apply to them. The implication of such is that research should not systematically exclude a specific type of person (i.e. children or pregnant women) who is likely to benefit from participation or in whom the results of the research are likely to be applied.

The Institutional Review Board (IRB)

In addition to establishing the National Commission, legislation in the National Research Act of 1974 also paved the way for the modern IRB system for regulating human subject research. Federal regulations in the act required IRB approval for most research involving human subjects, defined the policies and procedures that the IRB must follow when reviewing such research, and established criteria to be utilized by the IRBs to approve the research. After the National Commission disbanded, responsibility for implementing its recommendations was delegated to The Office of Human Research Protections (OHRP), a division of the Department of Health and Human Services (DHHS). IRBs function under the power of the OHRP, whose job is to develop regulations for the protection of human subjects and oversee compliance with these regulations. In 1981, the Secretary of the DHHS signed a revised Code of Federal Regulations for the Protection of Human Subjects, as put forth by the OHRP in Title 45, Part 46 of the Code of Federal Regulations (45 CFR 46) (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm). In 1991, these regulations were adopted by the 16 federal agencies that conduct, support, or otherwise regulate human subjects research, including the National Institutes of Health. This has resulted in the regulations becoming better known as the "Common Rule," which despite modification over time, still serves as the guideline for IRB decisions and approvals, today. Of note, the Food and Drug Administration also adopted certain provisions of the Common Rule, but has its own set of regulations for the protection of human subjects, codified at Title 21 Parts 50 and 56 of the Code of Federal Regulations.

Membership of an Institutional Review Board

Although many IRBs have more, federal law mandates each IRB must have at least five members, with varying backgrounds and expertise to promote complete and adequate review of research activities commonly conducted by their institution. The members should represent a diversity of backgrounds to promote respect for its advice and counsel in protecting the rights and welfare of human research subjects. This diversity should include considerations of their sensitivity to community attitudes, in addition to racial and cultural heritage. An IRB may chose to invite individuals with competence in certain areas to review issues which require expertise beyond that available to the IRB, but these expert ad hoc reviewers may not vote at the committee meeting.

At least one member of each IRB must possess primary concerns in a non-scientific area, and at least one other member must possess primary concerns in a scientific area. Investigators can be members of the IRB, but as such, cannot participate in the review and approval process for any project in which he or she has a present or potential conflict of interest. In addition, at least one member must not be affiliated with the institution nor be part of the immediate family of a person who is affiliated with the institution. This non-affiliated member of the IRB, often called the community member, should be drawn from the community-at-large. This member should possess extensive knowledge about the type of community from which the institution will draw its research subjects and be willing to evaluate and discuss the research proposals from that unique perspective. Ministers, attorneys, teachers, business persons, or homemakers make ideal community members. If an IRB regularly reviews research involving vulnerable populations, (such as children, pregnant women, cognitively impaired persons, or prisoners), at least one member should be knowledgeable about and experienced in working with these subjects. Furthermore, when the IRB reviews research which proposes targeted inclusion of either handicapped children or mentally disabled persons, the roster must include at least one person primarily concerned with the welfare of these vulnerable subjects.

What is the Purpose of an Institutional Review Board?

Institutional Review Boards are charged with protecting the rights and welfare of human subjects recruited to participate in research activities conducted under the auspices of the institution to which the IRB is affiliated. The IRB reviews proposed research activities and has the authority, granted by the federal regulations and local institutional policy, to approve, disapprove, or require modifications to all research activities involving human subjects. In this role, the IRB assumes numerous duties and often must collaborate closely with other institutional bodies, including scientific review committees, human subject radiation committees, biosafety experts, conflict of interest committees, and requested ad hoc expert reviewers. To accomplish this, IRBs must first determine whether the proposed activity involves research and if so, whether the research involves human subjects. Research is defined as "a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." The regulations define human subjects as "living individuals 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."

Determining whether an activity qualifies as human subjects research represents only the beginning. What follows is an extensive review process by the IRB, assessing the risk to benefit ratio. In protecting human subjects, the IRB is commissioned with the task of evaluating whether the risks to participants are minimized for accomplishing the research objectives. This requires a detailed analysis of the study design, level of expertise of the investigators, and characteristics of the research participants. In addition, IRBs must rigorously assess the proposed process of informed consent, including any written forms, to ensure that participants are able to voluntarily provide informed consent without coercion.

IRBs also bear the responsibility of reviewing ongoing research at least annually in order to re-evaluate the risk to benefit assessment and ensure that the research continues to be conducted according to the regulations. In order to abide by the regulations governing the conduct of human subject research, investigators and other research personnel require education and training. This education and training also rests within the domain of the IRB.

Conclusion

In conclusion, Institutional Review Boards were established as part of federal legislation in response to growing concerns over the ethical conduct of research involving human subjects. The main role of the IRB is to protect the rights and welfare of human research subjects. The complexity of providing such protection has rendered the make-up and functioning of these configurations equally as complex. The ultimate goal of the IRB, however parallels that of the researcher; both are charged with ensuring that research on human subjects is conducted ethically, with sound scientific rationale, maximized benefits, and minimized risks. Furthermore, IRBs must ensure adequate protection of vulnerable populations serving as participants in human subjects research.

References: