Glossary: Research Involving Human Subjects
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Glossary

Agent, as it pertains to “engagement” in research involving human subjects

defined in the OHRP memo Engagement of Institutions in Research all individuals performing institutionally designated activities or exercising institutionally delegated authority or responsibility

Assent, as it pertains to the protection of children as subjects in research

defined in 46.402, Subpart D – a child’s affirmative agreement to participate in research.  Mere failure to object should not, absent affirmative agreement, be construed as assent.

Children

There are separate definitions for the protection of children in the HHS regulations and for the inclusion of children in the NIH policy, as follows:

1.  From the HHS regulations (46.402, Subpart D) – persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted

2.  From NIH Policy (NIH Policy and Guidelines on the Inclusion of Children as Participants in Research) – an individual under the age of 21 years

Clinical Research

defined in the PHS 398 Definitions and the Grants Policy Statement Glossary

  1. Patient-oriented research.  Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects.  Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual.  Patient-oriented research includes:

  2. a.  Mechanisms of human disease,
    b.  Therapeutic interventions,
    c.  Clinical trials, or
    d.  Development of new technologies.
  3.   Epidemiologic and behavioral studies
  4.   Outcomes research and health services research
NOTE:  Studies that meet the criteria for Exemption 4 are not considered clinical research for purposes of this definition
Clinical Trial, as pertains to the review of applications submitted to the NIH

defined in the PHS 398 Definitions – a prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices)

Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious and effective. Clinical trials of experimental drug, treatment, device or behavioral intervention may proceed through four phases: 

Phase I clinical trials are done to test a new biomedical intervention in a small group of people (e.g., 20-80) for the first time to evaluate safety (e.g. determine a safe dosage range, and identify side effects).

Phase II clinical trials are done to study the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and to further evaluate its safety. 

Phase III studies are done to study the efficacy of the biomedical or behavioral intervention in large groups of human subjects (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions as well as to monitor adverse effects, and to collect information that will allow the intervention to be used safely.

Phase IV studies are done after the intervention has been marketed. These studies are designed to monitor effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use.

Coded, as it pertains to private information or human biological specimens
  1. having identifying information (such as name or social security number) that would enable the investigator to readily ascertain the identity of the individual to whom the private information or specimens pertain, and includes replacing identifying information with a number, letter, symbol, or combination thereof (i.e., the code); and
  2. a key to decipher the code exists, enabling linkage of the identifying information to the private information or specimens

(defined in the OHRP Guidance on Research Involving Coded Private Information or Biological Specimens )

NIH-Defined Phase III Clinical Trials

defined in the PHS 398 Definitions – broadly based prospective Phase III clinical investigations, usually involving several hundred or more human subjects, for the purpose of evaluating or comparing two or more existing treatments with the aim of providing evidence leading to a scientific basis for a consideration of a change in health policy or standard of care (applicable to the NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research)

Delivery, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – complete separation of the fetus from the woman by expulsion or extraction or any other means

Engagement, as it pertains to institutions conducting research involving human subjects

defined in the OHRP memo Engagement of Institutions in Research an institution is automatically considered to be “engaged” in human subjects research whenever it receives a direct HHS award to support human subjects research. 

The awardee institution bears ultimate responsibility for protecting human subjects under the award.

An institution becomes “engaged” in human subjects research when its employees or agents:

  1. Intervene or interact with living  individuals for research purposes; or
  2. Obtain individually identifiable private information for research purposes.

Pharmaceutical companies may also become “engaged” in human subjects research without receiving a direct HHS award if they:

  1. Provide test articles regulated by the FDA for use in HHS-supported research;
  2. Supply other materials or support for HHS-supported research; or
  3. Otherwise collaborate in HHS-supported research
Exemption 1, as it pertains to research involving human subjects

defined in 46.101(b) – in order for proposed research to be exempt from the requirement for continuing IRB review and approval, investigators must propose research in educational settings involving normal educational practices, such as:

  1. (i) Research on regular and special education instructional strategies, or
  2. (ii) Research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods
Exemption 2, as it pertains to research involving human subjects

defined in 46.101(b) – in order for proposed research to be exempt from the requirement of continuing IRB review and approval under exemption 2, researchers must propose the use of educational tests, survey or interview procedures, or observations of public behavior involving human subjects who:

cannot be identified, either directly or indirectly;

OR

may be identified, but would not be put at risk if information is disclosed

Exemption 3, as it pertains to research involving human subjects

defined in 46.101(b) – in order for proposed research to be exempt from the requirement of continuing IRB review and approval, investigators must propose the use of educational tests, survey or interview procedures, or observations of public behavior that does not meet the requirements for Exemption 2 if:

  1. the human subjects are elected or appointed public officials; or
  2. the human subjects are candidates for public office; or
  3. Federal statutes require without exception that the confidentiality of the personally identifiable information will be maintained during and after the proposed research
Exemption 4, as it pertains to research involving human subjects

defined in 46.101(b) – in order for proposed research to be exempt from the requirement of continuing IRB review and approval under Exemption 4, investigators must propose the use of data or samples that are either :

existing and publicly available;

OR

existing and unidentifiable to the research team

Exemption 5, as it pertains to research involving human subjects

defined in 46.101(b) – in order for proposed research to be exempt from the requirement of continuing IRB review and approval under Exemption 5, investigators must propose research and demonstration projects conducted by or subject to the approval of Department or Agency heads, and which are designed to study, evaluate, or otherwise examine:

  1. public benefit or service programs;
  2. procedures for obtaining benefits or services under those programs;
  3. possible changes in or alternatives to those programs or procedures;

    OR

  4. possible changes in the methods or levels of payment for benefits or services under those programs
Exemption 6, as it pertains to research involving human subjects

defined in 46.101(b) – in order for proposed research to be exempt from the requirement of continuing IRB review and approval under Exemption 6, investigators must propose research involving taste and food quality evaluation and consumer acceptance studies if:

  1. wholesome foods without additives are consumed;
  2. a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture; or

  3. a food is consumed that contains an agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture

Fetus, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – the product of conception from implantation until delivery

Dead Fetus, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – a fetus that exhibits neither heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, nor pulsation of the umbilical cord

Guardian, as it pertains to the protection of children as subjects in research

defined in 46.402, Subpart D – an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care

Human Subject, as it pertains to research involving human subjects in the HHS regulations

defined in 46.102, Subpart A – a living individual about whom an investigator conducting research obtains

  1. data through intervention or interaction with the individual, or
  2. Identifiable private information
Individually Identifiable, as it pertains to research involving human subjects

defined in 46.102 within the Human Subject definition – the identity of the subject is or may be readily ascertained by the investigator or readily associated with the information

*In addition, OHRP generally considers private information or specimens to be individually identifiable when they can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems (according to the Guidance on Research Involving Coded Private Information or Biological Specimens).

Institution, as it pertains to research involving human subjects

defined in 46.102, Subpart A – any public or private entity or Agency (including Federal, State and other agencies)

Interaction, as it pertains to research involving human subjects

defined in 46.102 within the Human Subject definition – includes communication or interpersonal contact between investigator and subject

Intervention, as it pertains to research involving human subjects

defined in 46.102 within the Human Subject definition – includes both:

  • physical procedures by which data are gathered (for example, venipuncture) and
  • manipulations of the subject or the subject’s environment that are performed for research purposes
Institutional Review Board (IRB), as it pertains to the protection of human subjects in research

defined in 46.102, Subpart A – a board established in accord with and for the purposes expressed in 45 CFR part 46

Investigator, as it pertains to research involving human subjects

Anyone involved in conducting the research. Individuals who provide coded information or specimens and collaborate on other activities related to the conduct of the research with the investigators who receive such information or specimens, are considered to be involved in the research.

(defined in the OHRP Guidance on Research Involving Coded Private Information or Biological Specimens)

Key Personnel

There are two definitions of key personnel, as follows:

1.  As listed in grant applications/contract proposals with respect to conducting human subjects research and meeting the human subjects education requirement – individuals who contribute to the scientific development or execution of the project in a substantive way, whether or not salaries are requested; defined in the PHS 398 Definitions

2.  In the NIH Grants Policy Statement for the purposes of budgetary considerations – The PI and other individuals who contribute to the scientific development or execution of a project in a substantive, measurable way, whether or not they receive salaries or compensation under the grant. Typically these individuals have doctoral or other professional degrees, although individuals at the masters or baccalaureate level may be considered key personnel if their involvement meets this definition. Consultants also may be considered key personnel if they meet this definition. “Zero percent” effort or “as needed” is not an acceptable level of involvement for key personnel; defined in the Grants Policy Statement Glossary

Legally Authorized Representative, as it pertains to decisionally incapacitated individuals

defined in 46.102, Subpart A – an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research

Minimal Risk

The HHS regulations contain two definitions for minimal risk, as follows:

1.  A general definition found in Subpart A (46.102) – 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 or during the performance of routine physical or psychological examinations or tests

2.  A specific definition for research involving prisoners found in Subpart C (46.303) – the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons

Neonate, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – a newborn

Nonviable Neonate, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – a neonate after delivery that, although living, is not viable

Viable Neonate, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – being able, after delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heartbeat and respiration.  The Secretary, HHS, may from time to time, taking into account medical advances, publish in the Federal Register guidelines to assist in determining whether a neonate is viable for the purposes of Subpart B.  If a neonate is viable then it may be included in research only to the extent permitted and in accordance with the requirements of Subpart A and Subpart D

Obtain, as it pertains to research involving human subjects

To receive or access identifiable private information or identifiable specimens for research purposes and includes an investigator’s use, study, or analysis for research purposes of identifiable private information or identifiable specimens already in the possession of the investigator.

(defined in the OHRP Guidance on Research Involving Coded Private Information or Biological Specimens)

Parent, as it pertains to the protection of children as subjects in research

defined in 46.402, Subpart D – a child’s biological or adoptive parent

Permission, as it pertains to the protection of children as subjects in research

defined in 46.402, Subpart D – the agreement of parent(s) or guardian for (“to” in the regulations) the participation of their child or ward in research

Pregnancy, as it pertains to research involving pregnant women, human fetuses and neonates

defined in 46.202, Subpart B – the period of time from implantation until delivery.  A woman shall be assumed to be pregnant if she exhibits any of the pertinent presumptive signs of pregnancy, such as missed menses, until the results of a pregnancy test are negative or until delivery:

Prisoner, as it pertains to protections for prisoner subjects in research

defined in 46.303, Subpart C – any individual involuntarily confined or detained in a penal institution.  The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial or sentencing:

Private Information, as it pertains to research involving human subjects

defined in 46.102 within the Human Subject definition – includes:

  • information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and
  • information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record)
Research, as it pertains to protections for human subjects in research

defined in 46.102, Subpart A – a systematic investigation designed to develop or contribute to generalizable knowledge

Systematic Investigation, as it pertains to research involving human subjects

defined in 46.102, Subpart A – includes research development, testing and evaluation

Ward, as it pertains to the protection of children as subjects in research

defined within 46.409, Subpart B – a child whose welfare is the responsibility of the State or any other agency, institution, or entity


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