Protecting Human Research Participants

Definitions

Research: A systematic investigation designed to develop or contribute to generalizable knowledge. Activities that meet this definition include research development, testing, and evaluation.

Human Subject: A living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information, or (3) identifiable biospecimens.

Minimal Risk: The probability and magnitude of harm or discomfort anticipated in the research are not greater, in and of themselves, than those ordinarily encountered in daily life of the general population or during the performance of routine physical or psychological examinations or tests.

Privacy: Free from unsanctioned intrusion.

Confidentiality: Holding secret all information relating to an individual, unless the individual gives consent permitting disclosure.

Equitable: To treat fairly.

Equal: To treat in exactly the same way.

Debrief: Provide research participants with additional pertinent information after they have participated in a study.

Children: Persons who have not attained the legal age of consent to procedures or treatments involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. For purposes of inclusion in NIH-funded research, children are defined as individuals under the age of 18.

Introduction

The relationship between investigators and human subjects should be based on honesty, trust, and respect.

All investigators involved in human subjects research should be knowledgeable about basic research ethics and associated federal regulations and policies.

This tutorial provides an introduction to the Health and Human Services (HHS) Regulations for the Protection of Human Subjects, 45 CFR Part 46. It is not intended to be exhaustive and investigators are encouraged to click on the links within the tutorial for fuller explanations.

History

The Nuremberg Code (PDF) of 1947, which was a response to Nazi Medical War Crimes (1939-1945) was the first international code of research ethics.

The Syphilis Study at Tuskegee, initiated by the U.S. Public Health Service in the 1930s and continued until 1972, is the U.S.’s most notorious example of the violation of the rights and welfare of human subjects, and eventually resulted in the drafting of the Belmont Report by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

The Belmont Report of 1979 sets forth the basic ethical principles governing the conduction of human subjects research.

In 1991, as an outgrowth of the Belmont Report, the Federal Policy for the Protection of Human Subjects or the “Common Rule” was published.

The Office for Human Research Protections (OHRP) was created in June 2000 to lead HHS and other federal agencies’ efforts to protect human subjects in biomedical and behavioral research under the Common Rule.

The 2018 Revised Common Rule includes the requirement that subjects be informed about the possibility of future commercial profit from research materials.

The Belmont Report

The Belmont Report sets forth three basic ethical principles for the conduct of human subjects research:

Respect for persons

  • Individuals should be treated as autonomous agents
  • Persons with diminished autonomy are entitled to additional protections

Beneficence

  • Do no harm
  • Maximize possible benefits and minimize possible harms

Justice

  • Equitable distribution of research burdens and benefits

Application of these ethical principles to the conduct of human subjects research leads to the following requirements:

Respect for persons

  • Informed consent
  • Protecting privacy and maintaining confidentiality
  • Additional safeguards for protection of subjects likely to be vulnerable to coercion (e.g. threats of harm) or undue influence (e.g. excessive compensation)

Beneficence

  • IRB assessment of risk/benefit analysis, including study design
  • Ensure that risks to subjects are minimized
  • Risk justified by benefits of the research

Justice

  • Ensure that selection of subjects is equitable

IRB Review of Research

An IRB (Institutional Review Board) must review all human subjects research activities covered by the HHS regulations.

Non-exempt research undergoes either Expedited (subcommittee) review or Full Board review. Protocols cannot be expedited if the research involves more than minimal risk.

Investigators should understand that while Expedited review is conducted by fewer individuals, it is no less stringent and not necessarily faster than a Full Board review.

Research approved by Full Board review undergoes continuing review by the IRB at least once a year. The following categories of research do not require continuing review:

  1. Research initially approved by Expedited review
  2. Research that has progressed to the data analysis stage

Exempt Research

Certain research is exempt from the requirements of the HHS regulations.

A determination that research is exempt does not imply that investigators have no ethical responsibilities to subjects in such research; it means only that the regulatory requirements related to IRB review, informed consent, and assurance of compliance do not apply to the research.

Exemption categories include:

  1. Study takes place in an educational setting with normal educational practices.
  2. Educational testing which does not include intervention or interaction. This exemption does not apply to intervention studies.
  3. Benign, behavioral intervention studies. This exemption does not apply to studies with children.
  4. Secondary use of data.

Respect for Persons

The Belmont principle of respect for persons is primarily applied by requiring that all human subjects research participants provide voluntary informed consent to participate in research.

Informed consent is not a single event or just a form to be signed. Rather, it is an ongoing process that takes place between the investigator and the potential subjects.

Informed Consent

The three fundamental aspects of informed consent are:

  • Voluntariness
  • Comprehension
  • Disclosure

Subjects must be informed that participation is voluntary, participation may be discontinued at any time, and there is no penalty or loss of benefits for refusing to participate or discontinuing participation.

In order for participation to be voluntary, the potential for coercion and undue influence must be minimized. Compensation should never be presented as a benefit of the research. To avoid undue influence, investigators should carefully consider compensation and other inducements with respect to potential participants’ characteristics such as:

  • Financial and employment status
  • Emotional state
  • Legal standing

To ensure comprehension, information must be conveyed in language that is understandable to the subject or the subject’s legally authorized representative.

The consent process must include full disclosure of the nature of the research and the subject’s participation.

The consent form must start with a brief presentation of key information most likely to help prospective subjects understand why someone would or would not want to participate and should consist of a concise explanation covering the following:

  • Consent is being sought for research
  • Participation is voluntary
  • The duration of the participation
  • The research procedures to be used
  • Reasonable foreseeable risks/discomforts
  • Possible benefits to subjects or others

HHS regulations require that informed consent be documented using:

  1. A written form signed by the participant that contains the following required elements:
    • The purpose of the study
    • Foreseeable risks/discomforts to the individual
    • Potential benefits to the individual or others
    • Confidentiality protections for the individual
    • Compensation plan
    • Contact information for questions regarding the study, participants’ rights, and in case of injury
    • The conditions of participation, including the right to refuse or withdraw without penalty
    • Whether samples obtained can be used for future research
  2. A short form signed by the investigator that states that all of the required elements have been presented verbally (oral consent).

Beneficence

The Belmont principle of beneficence requires that benefits to participants are maximized and risks are minimized.

Categories of risks encountered by participants in research include: physical (e.g. fatigue), psychological (e.g. anxiety), social (e.g. stigma), legal (e.g. disclosure of illegal drug use) and economic (e.g. loss of job or advancement).

After minimizing risks to the extent possible, HHS regulations require that investigators consider:

  • Protections against risks (e.g. added safeguards for sensitive or identifiable data)
  • Potential benefits to individual participants in light of risks
  • Importance of the knowledge to be gained and potential for public good

Vulnerable populations require additional safeguards:

  • Pregnant women because of the unique physiological connections between the woman and her fetus
  • Children due to their lesser ability to make autonomous decisions
  • Persons with impaired decision-making capacity
  • Economically and/or educationally disadvantaged persons
  • Prisoners due to their diminished ability to make autonomous decisions

Protecting Research Data

Data can be de-identified by coding and anonymizing.

Confidentiality can be maintained by:

  • Properly disposing of data sheets and other paper records
  • Limiting access to identifiable data
  • Storing research records in locked cabinets or secured databases

Certificates of Confidentiality (CoCs) provide additional protection against legal demands for sensitive, identifiable research information.

NOTE: Publishing demographic information is only acceptable in situations where the population is large enough, or the condition is common enough, that research participants cannot be identified using the demographic data provided.

Justice

The choice of participants in research needs to be considered carefully to ensure that groups are not selected for inclusion mainly because of easy availability, compromised position, or manipulability.

Selection should always depend on reasons directly related to the research questions.

The Belmont principle of justice requires that investigators strive for equitable distribution of the risks and potential benefits of the research.

NIH inclusion policies require that:

  • Inclusion be generalizable to the population of the United States
  • Women and minorities be included as participants in human subjects research
  • Children and older adults be in all NIH-supported human subjects research

International Research

When HHS-supported research takes place outside of the United States, careful consideration must be given to justice, as well as beneficence, and respect for persons, particularly in resource-poor settings, to avoid exploiting participants.

IRB review for research in international settings must be informed by a sufficient knowledge of the local context, which may be provided by:

  • Inviting specialists with personal, direct knowledge of the local research context
  • An IRB within the local research context