Brief History of Research Ethics

Institutional Review Board (IRB)

Brief History of Research Ethics

Prior to 1906, when the Pure Food and Drug Act was passed, there were no regulations regarding the ethical use of human subjects in research. There were no consumer regulations, no Food and Drug Administration (FDA), no Common Rule, and no Institutional Review Board (IRB). What follows is a brief discussion of why federal rules and regulations were established and why the IRB became a necessity.

Nuremberg Code. The most dramatic and well-known chapter in the history of research with human subjects opened on December 9, 1946, when an American military tribunal opened criminal proceedings against 23 leading German physicians and administrators for their willing participation in war crimes and crimes against humanity. Among the charges were that German physicians conducted medical experiments on thousands of concentration camp prisoners without their consent. Most of the subjects of these experiments died or were permanently crippled as a result.

As a direct result of the trial, the Nuremberg Code was established in 1948, stating that “The voluntary consent of the human subject is absolutely essential,” making it clear that subjects should give consent and that the benefits of research must outweigh the risks.

Although it did not carry the force of law, the Nuremberg Code was the first international document which advocated voluntary participation and informed consent.

Thalidomide. In the late 1950s, thalidomide was approved as a sedative in Europe; it was not approved in the United States by the FDA. The drug was prescribed to control sleep and nausea throughout pregnancy, but it was soon found that taking this drug during pregnancy caused severe deformities in the fetus. Many patients did not know they were taking a drug that was not approved for use by the FDA, nor did they give informed consent. Some 12,000 babies were born with severe deformities due to thalidomide.

U.S. Senate hearings followed and in 1962 the so-called "Kefauver Amendments" to the Food, Drug and Cosmetic Act were passed into law to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers were required to prove to FDA the effectiveness of their products before marketing them.

Declaration of Helsinki. In 1964, the World Medical Association established recommendations guiding medical doctors in biomedical research involving human subjects. The Declaration governs international research ethics and defines rules for “research combined with clinical care” and “non-therapeutic research.” The Declaration of Helsinki was revised in 1975, 1983, 1989 and 1996 and is the basis for Good Clinical Practices used today.

Issues addressed in the Declaration of Helsinki include:

Research with humans should be based on the results from laboratory and animal experimentation
Research protocols should be reviewed by an independent committee prior to initiation
Informed consent from research participants is necessary
Research should be conducted by medically/scientifically qualified individuals
Risks should not exceed benefits

Tuskegee Syphilis Study (1932-1972). During a research project conducted by the U.S. Public Health Service, 600 low-income African-American males, 400 of whom were infected with syphilis, were monitored for 40 years. Free medical examinations were given; however, subjects were not told about their disease. Even though a proven cure (penicillin) became available in the 1950s, the study continued until 1972 with participants being denied treatment. In some cases, when subjects were diagnosed as having syphilis by other physicians, researchers intervened to prevent treatment. Many subjects died of syphilis during the study. The study was stopped in 1973 by the U.S. Department of Health, Education, and Welfare only after its existence was publicized and it became a political embarrassment. In 1997, under mounting pressure, President Clinton apologized to the study subjects and their families.

National Research Act (1974). Due to the publicity from the Tuskegee Syphilis Study, the National Research Act of 1974 was passed. The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which was charged to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles.

The Commission drafted the Belmont Report, a foundational document in for the ethics of human subjects research in the United States.

Take Home Points:

Nazi atrocities in World War II drew attention to the lack of international standards on research with human subjects and led to the formulation of the Nuremberg Code.
The thalidomide disaster led to the adoption of the “Kefauver Amendments” to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the effectiveness of their products before marketing them.
The Declaration of Helsinki is the basis for Good Clinical Practices used today.
The Tuskegee Syphilis Study is probably the worst case of unethical human subjects research in the history of the United States.
The National Research Act codified the requirement that human subjects in research must be protected and set the stage for the issuance of the Belmont Report.

THE BELMONT REPORT

Carrying out its charge, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research prepared the Belmont Report in 1979. The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. The Report is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. The three basic ethical principles and their corresponding applications are:

Principle

Application

Respect for persons

Individuals should be treated as autonomous agents
Persons with diminished autonomy are entitled to protection.

Informed consent

Subjects, to the degree that they are capable, must be given the opportunity to choose what shall or shall not happen to them
The consent process must include three elements:

information,
comprehension, and
voluntary participation

Beneficence

Human subjects should not be harmed
Research should maximize possible benefits and minimize possible harms.

Assessment of risks and benefits

The nature and scope of risks and benefits must be assessed in a systematic manner

Justice

The benefits and risks of research must be distributed fairly.

Selection of subjects

There must be fair procedures and outcomes in the selection of research subjects

Take Home Point:

The Belmont Report established three basic ethical principles – autonomy/respect for persons, beneficence and justice – which are the cornerstone for regulations involving human subjects. It is these basic ethical principles that Indiana University and Clarian Health Partners follow to govern the conduct of human research.

Related Internet Link:

The Belmont Report

CURRENT REGULATIONS

In 1981, the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) issued regulations based on the Belmont Report. DHHS issued Code of Federal Regulations (CFR) Title 45 (public welfare), Part 46 (protection of human subjects). The FDA issued CFR Title 21 (food and drugs), Parts 50 (protection of human subjects) and 56 (Institutional Review Boards).

In 1991, the core DHHS regulations (45 CFR Part 46, Subpart A) were formally adopted by more than a dozen other Departments and Agencies that conduct or fund research involving human subjects as the Federal Policy for the Protection of Human Subjects. This widely accepted policy if now referred to as the "Common Rule." Today, the 1991 Federal Policy is shared by 17 Departments and Agencies, representing most, but not all, of the federal Departments and Agencies sponsoring human-subjects research.

The main elements of the Common Rule include:

requirements for assuring compliance by research institutions;
requirements for researchers obtaining and documenting informed consent;
requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping.
additional protections for certain vulnerable research subjects-- pregnant women, prisoners, and children

In addition, certain federally sponsored and much privately sponsored research is subject to the regulations of the Food and Drug Administration (FDA) at 21 CFR Parts 50 and 56. FDA regulations confer protections on human subjects in research when a drug, device, biologic, food additive, color additive, electronic product, or other test article subject to FDA regulation is involved. FDA regulations and the provisions of the Common Rule are largely congruent, although some significant differences exist.

Take Home Point:

Both the Common Rule and the FDA regulations provide protections for human subjects in research and mandate IRB oversight of such research. When DHHS regulations (or the regulations of any other federal agency that follows the Common Rule) apply to the organization, the activities subject to the Human Research Protection Program include research involving humans as participants, as defined by the DHHS regulations. When FDA regulations apply to the organization, the activities subject to the Human Research Protection Program include clinical investigations, as defined by FDA regulations.

Related Internet Links:

           Common Rule: Code of Federal Regulations Title 45, Part 46 #46.102
           U.S. Food & Drug Administration Title 21 Food & Drugs, 50.01
           U.S. Food & Drug Administration Title 21 Food & Drugs, 56.101

FEDERALWIDE ASSURANCE

Under the Department of Health and Human Services (DHHS) human subjects protection regulations at 45 CFR 46.103, every institution engaged in human subjects research supported or conducted by DHHS must obtain an assurance of compliance approved by the Office for Human Research Protections (OHRP). Indiana University, Clarian Health Partners, and their affiliates hold such an assurance (hereafter known as a federalwide assurance, or FWA).

This assurance identifies our responsibilities and explains the steps that we will take to meet the federal regulations for research on human subjects. The FWA requires that all research projects involving human subjects, regardless of funding source, conducted by an employee of Indiana University, Clarian Health Partners, or their affiliates be reviewed and approved by an Institutional Review Board (IRB) prior to initiating any research. Failure by any investigator to adhere to the provisions of the FWA may cause the institution to have an FWA suspended or revoked. Therefore, it is important that all investigators be knowledgeable about the contents of the FWA.

Take Home Point:
Indiana University, Clarian Health Partners, and their affiliates, through FWAs, have pledged to protect human subjects and comply with all relevant federal regulations with respect to all research, whether funded or unfunded.

Related Internet Links:

Office for Human Research Protections - Assurances

Definitions:

Research is defined by the Department of Health and Human Services as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge” (45 CFR 46). The FDA includes “clinical investigation” in its definition of a research activity.

Clinical Investigation is defined by the Food and Drug Administration as “any experiment that involves a test article and one or more human participants and that is one of the following:

Subject to requirements for prior submission to the Food and Drug Administration under §505(i) or §520(g) of the act
Not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit
The term does not include experiments that are subject to the provisions of 21 CFR §58, regarding non-clinical laboratory studies

Systematic Investigation typically involves a predetermined method for studying a specific topic, answering a specific question(s), testing a specific hypothesis(es), or developing theory.

Examples: observational studies, interview or survey studies, group comparison studies, program evaluation, test development, interventional research.

Develop or contribute to generalizable knowledge typically requires that results (or conclusions) of the activity are intended to be extended beyond a single individual or an internal program.

Examples: activities where there is an intent to publish the results in a peer-reviewed journal or to present at a regional or national meeting, as well as, theses or dissertation projects conducted to meet the requirements of a graduate degree.

When in doubt, contact the IRB Staff to help determine whether a particular project is “research” as defined by the institution and federal regulations.

TAKE HOME POINT:

If you are planning to publish the results of a project, it is almost always regarded as “research.” Research can involve a variety of methods and materials. If you are unsure about your project, check with IRB Staff.

Related Internet Links:

Common Rule: Code of Federal Regulations Title 45, Part 46 #46.102
U.S. Food & Drug Administration Title 21 Food & Drugs, 50.01

WHAT IS A HUMAN SUBJECT?

Definition:

A Human Subject is defined by DHHS as a living individual about whom an investigator (whether professional or student) conducting research obtains:

data through intervention or interaction with the individual

identifiable private information.

A Human Participant is defined by the FDA as an individual who is or becomes a participant in research, either as a recipient of an investigational drug, as an individual on whom or on whose specimen an investigational device is used, or as a control. A “human subject” may either be a healthy human or a patient and is synonymous with “subject,” “participant,” and “volunteer.”.

Interventions include both:

physical procedures by which data are gathered (e.g., venipuncture)

manipulations of the subject or the subject’s environment that are performed for research purposes.

Interaction includes communication or interpersonal contact between investigator and participant.

Private information may be:

information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place

information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public

AND

individually identifiable in order for obtaining the information to constitute research involving human subjects.

Test article means any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the act or under sections 351 or 354-360F of the Public Health Service Act.

Act means the Federal Food, Drug, and Cosmetic Act

IRBs review research that involves human subjects or participants.