|Policy & Guidance|
|Compliance & Oversight|
|Research Involving Human Subjects|
|Regulations, Policies & Guidance|
|Research w/Vulnerable Populations|
|Research Using Human Specimens, Cell Lines or Data|
|Human Subjects Protections Training|
|NIH Inclusion Policies and Procedures|
|Frequently Asked Questions|
|Office of Laboratory Animal Welfare (OLAW)|
|Animals in Research|
|Peer Review Policies & Practices|
|Guidance for Reviewers|
|Intellectual Property Policy|
|Acknowledging NIH Funding|
|Invention Reporting (iEdison)|
|NIH Public Access|
defined in the OHRP memo Engagement of Institutions in Research all individuals performing institutionally designated activities or exercising institutionally delegated authority or responsibility
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.
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
A research study1 in which one or more human subjects2 are prospectively assigned3 to one or more interventions4 (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes5.
Biomedical clinical trials of an experimental drug, treatment, device, or behavioral intervention may proceed through four phases:
Phase I Tests a new biomedical intervention in a small group of people (e.g. 20-80) for the first time to determine efficacy and evaluate safety (e.g., determine a safe dosage range and identify side effects).
Phase II Study the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and further evaluate safety.
Phase III Study to determine efficacy of the biomedical or behavioral intervention in large groups of people (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 interventions to be used safely.
Phase IV Studies conducted after the intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use..
NIH-Defined Phase III Clinical Trial. An NIH-defined Phase III clinical trial is a broadly based prospective Phase III clinical investigation, usually involving several hundred or more human subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or controlled intervention or comparing two or more existing treatments. Often the aim of such investigation is to provide evidence leading to a scientific basis for consideration of a change in health policy or standard of care. The definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based intervention trials are also included.
1 See Common Rule definition of research at 45 CFR 46.102(d).
2 See Common Rule definition of human subject at 45 CFR 46.102(f).
3 The term "prospectively assigned" refers to a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial.
4 An intervention is defined as a manipulation of the subject or subject's environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. Examples include: drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies.
5 Health-related biomedical or behavioral outcome is defined as the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects' biomedical or behavioral status or quality of life. Examples include: positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression); positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers; reading comprehension and /or information retention); positive or negative changes to disease processes; positive or negative changes to health-related behaviors; and, positive or negative changes to quality of life.
(defined in the OHRP Guidance on Research Involving Coded Private Information or Biological Specimens )
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)
defined in 46.202, Subpart B – complete separation of the fetus from the woman by expulsion or extraction or any other means
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:
Pharmaceutical companies may also become “engaged” in human subjects research without receiving a direct HHS award if they:
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:
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;
may be identified, but would not be put at risk if information is disclosed
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:
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;
existing and unidentifiable to the research team
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:
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:
defined in 46.202, Subpart B – the product of conception from implantation until delivery
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
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
defined in 46.102, Subpart A – a living individual about whom an investigator conducting research obtains
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).
defined in 46.102, Subpart A – any public or private entity or Agency (including Federal, State and other agencies)
defined in 46.102 within the Human Subject definition – includes communication or interpersonal contact between investigator and subject
defined in 46.102 within the Human Subject definition – includes both:
defined in 46.102, Subpart A – a board established in accord with and for the purposes expressed in 45 CFR part 46
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)
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
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
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
defined in 46.202, Subpart B – a newborn
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
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)
defined in 46.402, Subpart D – a child’s biological or adoptive parent
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
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:
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:
defined in 46.102 within the Human Subject definition – includes:
defined in 46.102, Subpart A – includes research development, testing and evaluation
defined within 46.409, Subpart B – a child whose welfare is the responsibility of the State or any other agency, institution, or entity