Ethical Guidelines and the Institutional Review Board – An Introduction

More than 130 countries and international organizations have developed independent committees to approve or deny research that involves human subjects. These entities are often called institutional review boards (IRB), ethical review boards (ERB), independent ethics committees (IEC), or research ethics boards (REC) (USAID, 2018). The institutional review board (IRB) is a research ethics committee that reviews and approves human subjects’ research. The IRB’s primary responsibility is to protect research participants’ rights, safety, and welfare, especially society’s most vulnerable groups (i.e., prisoners, children, educationally/economically deprived, critically/terminally ill, and individuals with mental disabilities) (Gallin, 2018). This paper will briefly overview the IRB history and its role in the research process.

History of Ethics Guidelines

The Nuremberg Code is a vital document in the history of medical research ethics. The document was developed in August 1947 by American judges in response to the deadly and torturous human experiments conducted in the Auschwitz concentration camps during World War II by Nazi doctors. The Nuremberg Code is the first set of international ethical guidelines for human research, based on the Guidelines for Human Experimentation of 1931 (Ghooi, 2011). Moreover, it serves as a foundation for the principles that ensure the rights of study participants in medical research (Shuster, 1997). However, in the early years, the Nuremberg Code was ignored due to the connection with the prisoners in concentration camps. In addition, there was debate as to the applicability of the Code to medical research (Shuster, 1997).

The principles of the Nuremberg Codes are: (“The Nuremberg Code (1947),” 1996)

1. The voluntary consent of the study participant is essential.

2. The experiment should aim to yield results that benefit society and cannot be obtained in another way.

3. The research should be based on previous knowledge (animal experiments, etc.).

4. The risks involved in the investigation should be proportional to (that is, not exceed) the anticipated benefits and conducted to avoid unwarranted physical and mental afflictions and injury.

5. The research should not be conducted if there is reason to believe that death or a disabling injury could occur.

6. The amount of risk should not surpass the significance of the problem solved by the study.

7. The setting and environment must be adequate to protect the study participant from any possibility of harm, injury, or death.

8. Scientifically qualified individuals must conduct the research.

9. At any time during the study, a study participant can leave or drop out of the study.

10. The lead scientist of a study must be prepared to end the research at any stage if there is probable reason to believe that the continuation of the study could result in injury, disability, or death.

Examples of how some researchers continued to exploit patients even after the publication of the Nuremberg Code are as follows. In the Willowbrook State School for Children Hepatitis Study (from 1956–1971), children with mental disabilities were deliberately infected with hepatitis to develop a vaccine (Das & Sil, 2017; Dubois, 2019). Parents provided consent to join the study but were not informed about the hazards. Children that entered the study were guaranteed admission to Willowbrook, which was cost-prohibited by many parents. While the 1963 Brooklyn Jewish Chronic Disease Hospital Study injected cancer cells into elderly patients with dementia who could not adequately provide informed consent and were not informed that they were injected with cancer cells (Das & Sil, 2017; Lerner, 2004). This study, along with others like it, targeted vulnerable groups of people who could not make sound decisions for themselves. An article by Beecher (Beecher, 1966) brought to light 22 different examples of research that had ethical controversies, all conducted by researchers with good reputations and published in legitimate journals.

The Declaration of Helsinki

As more ethical issues emerged with medical research, additional guidelines were formulated in 1964 by the World Medical Association (WMA) General Assembly to create safeguards for people participating in clinical research called the Declaration of Helsinki (DoH) (Carlson, Boyd, & Webb, 2004). The 1964 WMA General Assembly was in Helsinki, Finland, hence the document’s name. It was founded on September 1947 when representatives from 27 countries met in Paris. This organization aims to ensure independence, high ethical standards, and excellent care performed by physicians. After World War II, this was crucial for physicians to maintain public trust in the general population (World Medical Association (WMA), 2022).

The DoH is a set of ethical principles regarding biomedical research involving human participants. The DoH stresses physician-researchers responsibilities to their study participants (Carlson et al., 2004). As such, the DoH sets out principles for the requirements for informed consent, assessment of risks and benefits, and protecting vulnerable populations. These principles are intended to ensure that medical research is conducted ethically and respects the dignity and rights of all individuals involved (Shuster, 1997). The DoH was adopted in 1964 and has been revised several times. The most recent revision was in October 2013. See Table 1 for additional information.

Table 1.

Weblinks for Additional Information

Declaration of Helenski https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/#:~:text=The%20World%20Medical%20Association%20(WMA,identifiable%20human%20material%20and%20data. Belmont Report https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/index.html Tuskegee History https://www.tuskegee.edu/about-us/centers-of-excellence/bioethics-center/about-the-usphs-syphilis-study Frequently Asked Questions about the IRB: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/institutional-review-boards-frequently-asked-questions IRB Exempt Classifications: https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/common-rule-subpart-a-46104/index.html IRB Minimal Risk and Expediated Classifications: https://www.hhs.gov/ohrp/sites/default/files/ohrp/sachrp/mtgings/2013%20March%20Mtg/expeditedreviewcategories.pdf Revised Common Rules https://www.hhs.gov/ohrp/education-and-outreach/revised-common-rule/revised-common-rule-q-and-a/index.html

History of Institutional Review Boards

The origin of the IRB in the United States (U.S.) stems from the National Institutes of Health (NIH), the federal agency that funds biomedical research. In 1954, the NIH’s research hospital, the Clinical Center, opened. The administrators from the Clinical Center were concerned with potential lawsuits when enrolling healthy study participants into research studies who might incur injury or harm (Stark & Greene, 2016). As a result, an internal committee was developed to review two types of studies conducted at the Clinical Center. The first involved “unusual hazards” to study participants (sick or normal study participants), and the second, research that included healthy research controls (volunteers) (Stark & Greene, 2016).

Initially, the internal committee was to govern clinical research within the NIH. However, NIH administrators were concerned that they could also be held liable for extramural studies funded by grants from the agency. For example, in the mid-1960s, prosecutors approached the agency about their possible liability for a study conducted by Chester Southam, an NIH-funded researcher. He injected patients with live cancer cells without their consent. To avoid potential lawsuits associated with extramural research, the NIH’s parent agency (the Public Health Service) required all institutions it funded to adopt a review committee similar to the one used by the Clinical Center. The goal was to make those institutes liable for ethical violations instead of the U.S. government (Stark & Greene, 2016).

The National Research Act and the Belmont Report

The National Research Act (NRA) was passed in 1974 in response to public outcry over the Tuskegee Syphilis Study (see Table 1 for additional information). Hundreds of African-American men were left untreated for syphilis, despite available effective antibiotics (Tuskegee University, 2022). The NRA developed the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (Department of Health,Education, and Welfare, 1979). The Belmont Report was generated from the National Commission and summarized the three ethical principles required for human-subjects research. The Belmont Report continues to provide a framework for ethically thinking about these issues. The principles are (Moon, 2009):

• Respect for persons - refers to respecting autonomous decisions made by individuals in making choices about their involvement in research and protecting vulnerable persons in research.

• Beneficence - obliges researchers to promote the well-being of individuals and groups involved in research by maximizing benefits and minimizing foreseeable risks.

• Justice - requires that people be treated equitably and that the burden and benefits of research are distributed fairly.

Additionally, the Belmont Report has influenced federal regulations governing human subjects research. In particular, the report’s ethical principles are reflected in the Common Rule (Federal Policy for the Protection of Human Subjects), now called the IRB, a set of regulations governing federally-funded research in the United States (Stark & Greene, 2016). IRBs are mandatory by federal law for all clinical research involving human subjects and are also required by law in many countries (Grady, 2015).

Functions of the IRB

The IRB is vital to the research process and benefits both the researchers and the participants. It is a scientific committee that reviews research protocols. The main purpose of IRBs is to protect the rights and welfare of study participants by ensuring that research is ethical and those study procedures are conducted in a way that is respectful of participants. IRBs review proposed research studies to assess whether the risks to participants are minimized and reasonable in relation to the anticipated benefits. In addition, IRBs ensure that adequate informed consent is obtained from all participants (Gallin, 2018).

IRB approval is typically required before research can begin. A study protocol must meet specific criteria to be approved by the IRB. First, the protocol must have a clear scientific purpose. Second, the protocol must be designed to minimize the risks to participants. Third, the protocol must include procedures for protecting the confidentiality of participant information. Confidentiality is when a study participant discloses information in a trusting relationship with the expectation that the data is not shared without their permission. In comparison, privacy refers to the study participants’ control over when and how they share information about themselves with others (Gallin, 2018). Finally, an IRB-approved research ethics committee must review and approve the protocol (Das & Sil, 2017; Gallin, 2018).

The IRB can approve, modify, or reject research protocols that do not meet scientific or ethical standards to protect participants’ rights and welfare. The IRB can also require changes to the study design or informed consent process to protect participants. If, for example, an investigator is studying dementia in adults, they will need a scientific justification to support the inclusion of such individuals. Therefore, the protocol should describe how they will get ‘adequate’ informed consent from participants, which could include: 1) methods of determining if someone has the capacity to provide consent, 2) ways of identifying a legal representative who can give permission on behalf of the participant, and 3) describe other procedures for protecting such individuals (Gallin, 2018).

IRB Composition

The composition of the IRB is set by Federal regulations and composed of at least five members, including at least one scientist and one layperson (Gallin, 2018). In addition, the five members include a chair, a vice-chair, and at least one member not affiliated with the research institution (USAID, 2018). The IRB must have members who are experts in the specific type of research conducted. These persons should be knowledgeable about regulations related to the institution funding (i.e., NIH, National Science Foundation) the study and follow laws and standards set by professional organizations (USAID, 2018). IRBs often strive for a mix of disciplines represented among their members.

Additionally, IRBs can invite others to review a protocol if the research area is beyond its members’ expertise but is not considered a member of the IRB. Moreover, the goal of the membership requirements is founded on the belief that an objective review best occurs when a group of individuals not involved with the investigation review the protocol to best promote the protection of human subjects (Gallin, 2018). See Table 2 for an overview of the IRB process

Table 2.

^*IRB Process

The investigator obtains IRB forms (either from the institution’s online IRB portal or from the local IRB office) The investigator completes the forms and submits the IRB packet to the IRB office. The IRB packet generally includes the study protocol, study materials (i.e., questionnaires), recruitment materials (i.e., study flyers, brochures), consent forms, roles and responsibilities of study team members, curriculum vita of investigators, conflict of interest disclosures) The IRB office conducts a pre-review of the submitted documents (any questions or areas that need clarification will prompt the IRB to contact the investigator). The investigator is notified regarding the review requirements of the protocol (exempt, expedited, or full-board review) The IRB reviews the documents. The IRB notifies the investigator of the outcome of the review process. If the research is approved, the study may begin, and the consent form and recruitment materials will get an IRB approval stamp. If the IRB gives a ‘conditional’ approval, the research can not start until the conditions of approval are met. Other reviews. Studies generally need at least an annual IRB review. In addition, study modifications (i.e., changes to recruitment plans), wherein the investigator changes an aspect of an already approved IRB protocol, require another review by the IRB. Finally, adverse events and unanticipated issues require another IRB review. Report to the IRB when the study is completed.

^*Please note: Each IRB will have its procedures. The outline is a general overview of the process.

Reference: USAID, 2018

IRB and Classifications: Exempt, Minimal Risk, Expedited, and Continuing Reviews

Exempt Classification

The IRB evaluates the risk of research by considering the study type, the population, the expected benefits, and the risks associated with participating in the investigation. The IRB also considers other factors, such as whether the research is conducted according to federal regulations and whether the participants will be adequately protected from harm. However, several categories are considered ‘exempt’ from IRB approval (Office of Protection of Human Subjects Research (OFPHSR), 2018). To be considered ‘exempt,’ the study does not expose participants to risks beyond those encountered daily (Gallin, 2018; OFPHSR, 2018). An example of exempt research is using an existing data set, such as the Framingham Heart Study or other publicly available data set wherein study participants’ identifying information is not linked. Please see Table 1 for a list of additional resources. Each institution has procedures to determine whether a study is exempt. Investigators do not make the ‘exempt’ determination; the IRB makes the decision.

Examples of Exempt Research

• Educational and classroom research (testing a new curriculum)

• Public observations (children are not involved; i.e., watching what shoppers buy at the local grocery store)

• Analysis of existing data sets

• Taste and food evaluation studies

• Use of a database or biobank.

  (Parker, 2020)

Minimal Risk and Expedited Review

Minimal risk is research in which the “probability and magnitude of physical or psychological harm does not exceed that which is ordinarily encountered in daily life or routine medical, psychological, or educational examinations, tests, or procedures of the general population” (OFPHSR, 2018). Examples of minimal risk studies include:

• Blood collection via venipuncture, fingerstick, etc

  • From nonpregnant healthy adults who weigh at least 110 pounds. The amount of blood can not exceed 550ml in an 8-week time frame or occur more frequently than twice a week

• Noninvasive collection of biological samples for research, such as hair, fingernails

• Noninvasive data collection, not using general anesthesia or sedation, and part of routine clinical care (X-rays are excluded).

• Data collected for research purposes involving voice, video, or images

• Research involving individual or group behaviors or attributes, such as social and cultural beliefs, using surveys, interviews, or focus groups

The expedited review process is only used when the proposed research study involves little to no risk to study participants. Otherwise, the IRB chairperson conducts the review by one or more designated members of the IRB. Generally, studies that don’t meet this requirement need a meeting with the entire board (Parker, 2020).

Continuing IRB Reviews

At least annually, approved research is reviewed by the IRB, or sooner if the research could potentially result in physical, social, or psychological harm to study participants (Gallin, 2018). The annual review is often called a ‘continuing review’ and assures those involved in the study that assessments are done regularly to help protect against any risks.

The information that investigators submit to the IRB during a continuing review varies depending on the institution’s requirements and whether any participants are still enrolled or followed up. Usually, investigators submit required documents such as a current copy of the approved consent form; an overview of the protocol’s progress; scientific developments that have occurred since the last IRB submission, and updates related to risks, benefits, or difficulties for study participants. By contrast, if none of the original participants are still in the study, a more expedited process is possible (Gallin, 2018).

It is important to emphasize that the IRB can suspend, modify, or terminate approval of research during the continuing review. If the associated research causes serious harm to participants or the study is not conducted following Federal regulations, ethical guidelines, and/or institutional policies. Furthermore, the Final Rule (updated Common Rule) permits any study approved via the expedited review process, exempt from the continuing review process (Gallin, 2018).

Summary

The institutional review board (IRB) is a research ethics committee that reviews and approves research involving human subjects. The IRB’s primary responsibility is to protect the rights and welfare of research participants. IRBs have origins in the Nuremberg Code, a set of principles governing research with human subjects developed in the aftermath of World War II. Over the years, the IRB system has evolved to become a vital part of ensuring the ethical conduct of research. Today, IRBs are required by law in many countries, and their approval is typically required before research can begin.