Not Human Subjects Research

Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities.

Human subject (2018 HHS Common Rule) means a living individual about whom an investigator (whether professional or student) conducting research:

• Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or
• Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

Human subject (as defined in the Food and Drug Administration (FDA) regulations) means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient.

Subject (as defined in the FDA regulations that relate to investigational medical devices) means a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease.

Interaction includes communication or interpersonal contact between the investigator and subject.

Intervention 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.

Private information 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 that has been provided for specific purposes by an individual and that the individual can reasonably expect will not be made public (e.g., a medical record).

Identifiable private information is private information for which the identity of the subject is or may readily be ascertained by the investigator or associated with the information.

An identifiable specimen is a specimen for which the identity of the subject is or may readily be ascertained by the investigator or associated with the biospecimen.

Human Subjects Research (HSR) is any activity that either:

• Meets the HHS definition of research and involves human subjects as defined in the HHS regulations; and/or
• Meets the FDA definition of research and involves human subjects as defined in FDA regulations.

For examples of when an institution might or might not be considered engaged in non-exempt human subjects research, please review the HHS Office of Human Research Protections’ (OHRP) Engagement of Institutions in Human Subjects Research.

Note that FDA uses the term clinical investigation which means any experiment that involves a test article and one or more human subjects. More specifically, a clinical investigation involving drugs is any experiment in which a drug is administered, dispensed, or used, and involves one or more human subjects. For the purposes of this part of the FDA regulations, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. A clinical investigation involving devices is any experiment in which a medical device is tested to evaluate its safety or effectiveness and involves one or more human subjects.

First, consider the following process for deciding if the NIH Investigator will be conducting “Human Subjects Research” or “Not Human Subjects Research”:

• Determine if the activity meets the regulatory definition of research. Some activities may not be research under the 2018 Common Rule. Please see the definition of research in the HHS regulations (2018 Common Rule) for an expanded list of activities that are deemed not to be research under these regulations.
• Other examples of activities which may not be considered research under the HHS regulations include Quality Assurance/Quality Improvement projects, program evaluations, clinical consulting, evidence-based practice projects, case reports involving clinical data only from three or less patients.
• Please review QA/QI vs. Research document on this page for detailed guidance about how to determine if the planned QA/QI activity falls within the category of research and may require IRB approval or an exemption.  
• Please review Program Evaluation vs. Research document on this page for detailed guidance about how to determine if the planned program evaluation falls within the category of research and may require IRB approval or an exemption.
• Next, determine if the research is being conducted with living human subjects, including secondary research that uses biospecimens or data from living subjects. If not, generally no IRB review is required because research with biospecimens and/or data from deceased individuals, even if identifiable, falls under the category of not human subjects research.
• The exception to this rule is when the study meets the definition of an FDA-regulated clinical investigation, e.g. testing the safety and/or efficacy of a medical device, like an in vitro diagnostic device, above. In such cases, the FDA does not differentiate whether the biospecimens or data are from living or deceased individuals. The FDA requires IRB review of the research in these cases.
• Research that includes living human subjects as described above, including secondary research with identifiable biospecimens or data, or that meets the definition of an FDA-regulated clinical investigation, is considered human subjects research that requires that a protocol be submitted in the electronic IRB management system for IRB review or consideration of an exemption from IRB review.
• Investigators should assess whether their research meets the regulatory definition of “human subjects research”. For additional information and education on how to make this assessment, we recommend completing OHRP’s online training, What is Human Subjects Research?
• If the protocol involves conducting research with biospecimens or data, consider whether these are individually identifiable under the federal regulations for the protection of human subjects.
• Coded data and/or biospecimens should be considered identifiable if any member of the research team has access to the code key. Please review HHS OHRP 's “Coded Private Information or Specimens Use in Research, Guidance (2018) for additional information.
• When an investigator is conducting research with coded and linked biospecimens or data and will generate results that he or she can link back to the identifiers of the research subjects, this is considered human subjects research requiring prospective IRB review and approval.
• The same is true when an investigator plans to share coded and linked biospecimens or data with a collaborator and will receive individual level results generated by the collaborator, which he or she can link back to identifiers.

As a general rule, if gaining access to identifiable information is more involved than either using a key that links coded information to identifiers or combining information that is either already in the possession of the investigator or easily accessible to the investigator, the investigator may not be considered to be in possession of individually identifiable information. Certain demographic or clinical characteristics of the subjects may impact whether their data or biospecimens are individually identifiable to an investigator, e.g., the sample size; the location of the original collection (i.e., small town or the zip code); the disease or condition being studied, particularly if a rare disease; and membership in a unique cultural group. If an investigator has a prior relationship with the subjects and is able to re-identify the data based on past experience with the subjects or the data set, NIH considers the data to be identifiable to them.

Investigators should consult with OHSRP or the Office of IRB Operations (IRBO), if they are unsure whether data or biospecimens being used in a specific research project would be considered individually identifiable under 45 CFR 46. The following elements (either individually or in combination) may constitute an identifier (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information). The list below is not intended to be exhaustive:

• Names (or initials)
• Street address or geocode data
• Date of birth
• Telephone numbers
• Fax numbers
• Electronic mail addresses
• Social security numbers
• Medical record numbers
• Health plan beneficiary numbers
• Account numbers
• Certificate/license numbers
• Vehicle identifiers and serial numbers, including license plate numbers
• Device identifiers and serial numbers
• Internet protocol (IP) address numbers
• Biometric identifiers, including finger and voice prints
• Full face photographic images and any comparable images
• Any other unique identifying number, characteristic, or code (when a key to the identifier/characteristic/code is readily accessible to the investigator or given the context or circumstance could make a participant identifiable to the researcher)