IRB Regulation and Ethical Guidance | Quorum Review IRB

IRB Regulation and Ethical Guidance

While laws and regulations cannot always guarantee ethical decisions in research, they do provide a structure for those decisions. Decades of attention to the ethics of conducting research on human participants have contributed to the framework that now guides researchers and research ethics committees (known as institutional review boards, or IRBs, in the United States). We can trace the development of key ethical concepts from the Nuremberg Code all the way through the most recent changes in our regulations.

The Nuremberg Code

The current framework for ethically conducting research on human subjects starts with the Nuremberg Code (1947). The Code came from the post-World War II trials of Nazi personnel who conducted appalling experiments on concentration camp prisoners. By the end of the trials, 23 physicians received sentences for their crimes. The Nuremberg Code defined fundamental ethical requirements in an effort to prevent such atrocities from occurring again. Originally titled “Permissible Medical Experiments,” the Code expressed essential principles that continue to guide study design.

The Nuremberg Code presented ten requirements for conducting research on humans (Read the complete text here):

  1. The voluntary consent of the human subject is absolutely essential. . . .The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
  2. The experiment should . . . yield fruitful results for the good of society, unprocurable by other methods or means of study, and not [be] random and unnecessary in nature.
  3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.
  4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
  5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
  6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
  7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
  8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
  9. During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seems to him to be impossible.
  10. During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage, if he has probably cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Declaration of Helsinki

The World Medical Association published the Declaration of Helsinki in 1964. The Declaration sought to expand the principles of the Code, with a focus on the responsibilities of the physician/researcher. Although the Declaration has no legal authority, it has influenced the world’s standards of ethical research on human subjects. The Declaration has been through seven revisions, most recently in 2013. Recent versions of the Declaration have faced some controversy over statements about the role of placebo in clinical trials. After changes to the Declaration in 1989, the Food and Drug Administration (FDA) decided that the Declaration was not a satisfactory overseas alternative to the FDA’s protections in the United States. To accept data from foreign studies that operate outside an Investigational New Drug (IND) application, the FDA now requires that foreign clinical studies follow good clinical practice (GCP, see below) instead of the Declaration of Helsinki.

The Belmont Report

In the United States, the 1974 National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and from this committee came the Belmont Report. Inspired by the research wrongs that occurred during the Tuskegee syphilis and Willowbrook hepatitis studies, the Belmont Report defined key ethical principles for research in human subjects. The National Research Act also mandated IRB review for federally funded research. While government authorities started requiring ethical review as a condition of research grants in 1966, the National Research Act codified that requirement into law.

The Belmont Report emphasized the distinction between research and care; set down the three foundational concepts of respect for persons, beneficence, and justice; and applied those ideas to elements of research such as informed consent, risk and benefits in research, and the selection of subjects. The Belmont Report principles continue as cornerstone concepts in the ethics of clinical research. When federal agencies proposed changes to the Common Rule in 2016 (see below), the justifications for those changes relied on interpretations of the Belmont Report principles.

The Common Rule

The “Common Rule” is shorthand for a collection of regulations formally titled “The Federal Policy for the Protection of Human Subjects.” The source language of the Common Rule is in the Code of Federal Regulations (CFR) for the Department of Health and Human Services (HHS), Title 45 CFR 46. HHS human subjects research regulations have four sections, Subparts A through D. Subpart A contains the language of the Common Rule, and Subparts B through D set guidelines for particular vulnerable populations (Subpart B applies to pregnant women, unborn fetuses, and neonates; Subpart C to prisoners; and Subpart D to children). HHS introduced those regulations in 1981, and Subpart A became known as the Common Rule when other agencies agreed to follow the same requirements ten years later. The Common Rule remained unchanged until the government announced revisions in 2017, which  were scheduled to become effective starting in 2018.

A total of 18 government agencies follow the Common Rule; 14 agencies have imported HHS’s Subpart A language formally into their own regulations, while three others treat all of HHS’s subparts as their own. The Common Rule describes the requirements for IRB review, informed consent, and other essential elements of human subjects research protections. Research institutions must adhere to Common Rule requirements for any research funded by a Common Rule signatory. This includes research funded by the National Institutes of Health (NIH), part of HHS. Agencies such as the NIH may treat Common Rule regulations as a minimum and introduce more restrictive requirements, such as requiring single IRB review for certain studies before the Common Rule does.

FDA-Regulated Research

When HHS introduced its rules for federally funded research in 1981, the FDA formed a corresponding set of regulations for research in the private sector (CFR Title 21, Part 50, 56, and 312). FDA requirements apply to research used to support INDs, which are applications for new treatments involving drugs, devices, or biological products. Research for approval of treatments must follow CFR Title 21. (As mentioned earlier, if research overseas happens outside of a formal IND, it must follow the human subject protection requirements of the country where the research takes place and follow GCP.) While the Common Rule and FDA regulations have substantial overlap, notable differences have complicated research requirements.

Tri-Council Policy Statement (TCPS)

The full title of Canada’s seminal policy document on human subjects research is the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Its most recent version—issued in 2014—is known as TCPS 2, and as The Policy. The three agencies that make up Tri-Council are the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada, and the Social Sciences and Humanities Research Council of Canada (SSHRC). These agencies fund and oversee federal research involving human subjects in Canada. Health Canada has its standards of human subjects protection in research, similar to the FDA and HHS, and the TCPS sets down three essential principles for ethical research involving human subjects that are similar to the Belmont Report’s:

  • Respect for Persons
  • Concern for Welfare
  • Justice

Clinical Trial Guidance Documents:

The FDA and the Office of Human Research Protections (OHRP) regularly clarify their regulations with guidance documents and information sheets. These updates can be issued faster than formal changes to regulations or law, and so respond better to new developments. The guidance documents also indicate how an office intends to enforce provisions of a law or regulation, but the comments often are presented as recommendations and not necessarily enforceable.

 FDA Guidance Documents and information sheets

The FDA states that its guidance documents and information sheets “represent the agency’s current thinking” on good clinical practice (GCP) and conducting safe, effective clinical trials. These guidance documents can clarify FDA policies, guide implementation of regulations, or update requirements because of changes in technology. One example is the FDA’s perspective on medical device regulations and mobile health apps. The FDA also maintains a section on guidance documents specific to IRBs.

OHRP Policies and Guidance:

Like the FDA, OHRP periodically issues guidance to clarify new or existing policies. In recent years, FDA and OHRP have been issuing guidance together as part of efforts to harmonize their requirements.

ICH GCP Guidelines

The International Council of Harmonisation (ICH, originally the International Conference on Harmonisation) first formed in 1990. The ICH seeks to establish consistent research guidelines across a number of countries – notably the United States, Japan, and much of Europe. The ICH has a wide range of guidelines organized under four topics: Efficacy, Joint Safety, Quality, and Safety. The requirements for human subjects protection appear in a section of guidelines called Good Clinical Practices (GCP). GCP, which was released in 1995 and revised in 2016, sets international standards for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials. This includes defining the responsibilities of IRB/ethics reviews committees. The FDA has adopted GCP as guidance, and requires that overseas studies follow it.

 21st Century Cures Act

Signed into law in 2016, the 21st Century Cures Act represents an ambitious goal of modernizing the U.S. health system’s regulatory framework. In the area of medical research, the Cures Act mandated many changes aimed at making research more efficient and taking advantage of developing technologies. Regarding human subjects protection, the Cures Act directed the FDA and HHS to continue harmonization of their regulations, and endorsed other policies intended to improve research’s effectiveness. Two examples were an endorsement of single IRB review in studies with multiple investigators and a directive to explore using real-world evidence for approving new uses of medicines or treatment.

 Conclusion

From the 1947 Nuremberg Code to the 21st Century Cures Act and the 2017 changes to the Common Rule, the guidance and regulations governing research with human subjects has evolved in sophistication and complexity. Still, the core ethical values of the Nuremberg Code persist and the Belmont principles—respect for persons, beneficence, and justice—guide ethical research. The guidance and regulations discussed here form a structure to accommodate the expansion of scientific knowledge while showing compassion for – and protection of – the people who join clinical trials. The regulations governing human subjects research do not on their own guarantee that every study will be ethical, but direct us also to rely on human judgment. The principles that come to us from Nuremberg and Belmont form a context within which research sponsors design their trials, IRBs and other ethics committees make decisions, and investigators interact with their human subjects to advance our knowledge. Together, those members of the scientific community drive research forward.