Definitions for Research with Human Subjects

The definitions of "research" and "human subject" were revised to provide greater clarity.

Defining Research

• Revised Definition of 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.

  For purposes of this part, the following activities are deemed not to be research:

  (1) Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research, and historical scholarship), including the collection and use of information, that focus directly on the specific individuals about whom the information is collected.

  (2) Public health surveillance activities, including the collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority. Such activities are limited to those necessary to allow a public health authority to identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products). Such activities include those associated with providing timely situational awareness and priority setting during the course of an event or crisis that threatens public health (including natural or man-made disasters).

  (3) Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for activities authorized by law or court order solely for criminal justice or criminal investigative purposes.

  (4) Authorized operational activities (as determined by each agency) in support of intelligence, homeland security, defense, or other national security missions." 45 CFR 46.102(l)(2018 requirements)

• Summary of Changes

  The definition of research now includes activities that are deemed NOT to be research.

  These include, when specific criteria are met:

  • Scholarly and journalistic activities
  • Public health surveillance activities
  • Criminal justice activities
  • National security activities

   

  See the description of the changes below for specific criteria and more information.

• More Information About Scholarly and Journalistic Activities

  Regulatory Text

  "For purposes of this part, the following activities are deemed not to be research:

  Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research, and historical scholarship), including the collection and use of information, that focus directly on the specific individuals about whom the information is collected." 45 CFR 46.102(l)(1)(2018 requirements)

  More Information

  • Scholarly and journalistic activities concern specific activities in various fields that focus directly on the specific individuals about whom information are collected.
  • The definition explicitly cites fields as examples (e.g. oral history, journalism, biography, literary criticism, legal research, and historical scholarship) to clarify that the focus is on the specific activities that collect and use information about specific individuals themselves, and not generalizing to other individuals, and that such activities occur in various fields of inquiry and methodological traditions.
  • It is not the particular field that removes the activity from the definition, but rather the particular activity's focus on specific individuals. 
  • Studies using methods such as participant observation and ethnographic studies, in which investigators gather information from individuals in order to understand their beliefs, customs, and practices, and the findings apply to the studied community or group, and not just the individuals from whom the information was obtained, fall within the scope of the definition of research of the final rule.
• More Information About Public Health Surveillance Activities

  Regulatory Text

  "For purposes of this part, the following activities are deemed not to be research:

  "Public health surveillance activities, including the collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority. Such activities are limited to those necessary to allow a public health authority to identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products). Such activities include those associated with providing timely situational awareness and priority setting during the course of an event or crisis that threatens public health (including natural or man-made disasters)." 45 CFR 46.102(l)(2)(2018 requirements)

  "Public health authority means an agency or authority of the United States, a state, a territory, a political subdivision of a state or territory, an Indian tribe, or a foreign government, or a person or entity acting under a grant of authority from or contract with such public agency, including the employees or agents of such public agency or its contractors or persons or entities to whom it has granted authority, that is responsible for public health matters as part of its official mandate." 45 CFR 46.102(k)(2018 requirements)

  More Information

  • Provides the current interpretation that the definition of research does not include a category of activities that solely involve public health surveillance.
  • This codification of public health surveillance activities as outside the definition of research is designed to remove uncertainty, but is not intended to change the scope of activities subject to or not subject to the Common Rule.
  • Public health surveillance refers to collecting, analyzing, and using data to target public health and disease prevention. Surveillance uses data from a variety of sources, including mandatory reporting of certain conditions, routine monitoring, vital records, medical billing records, and public health investigations. The line between public health surveillance and epidemiological research can be difficult to draw, as the same epidemiological techniques may be used in both. Generally, the difference between the activities is the purpose or context in which the investigation is being conducted and the role of the public health authority.
  • The following are examples of public health surveillance activities being codified as outside of the definition of research in this regulation:
    • Safety and injury surveillance activities designed to enable a public health authority to identify, monitor, assess, and investigate potential safety signals for a specific product or class of products (for example, the surveillance activities of the FDA’s Adverse Event Reporting System,26 the Vaccine Adverse Event Reporting System,27 Manufacturer and User Facility Device Experience database,28 the Medical Product Safety Network, and the Sentinel Initiative);
    • Surveillance activities designed to enable a public health authority to identify unexpected changes in the incidence or prevalence of a certain disease in a defined geographic region where specific public health concerns have been raised (e.g., the U.S. influenza surveillance system, which allows CDC to find out when and where influenza activity is occurring, track influenza related illness, determine what strains of influenza virus are circulating, detect changes in influenza viruses, and measure the impact influenza is having on hospitalizations and deaths in the United States);
    • Surveillance activities designed to enable a public health authority to identify the prevalence of known risk factors associated with a health problem in the context of a domestic or international public health emergency;
    • Surveillance activities designed to enable a public health authority to locate the range and source of a disease outbreak or to identify cases of a disease outbreak;
    • Surveillance activities designed to enable a public health authority to detect the onset of disease outbreaks or provide timely situational awareness during the course of an event or crisis that threatens the public health, such as a natural or man-made disaster; and,
    • Surveillance activities designed to enable a public health authority to identify the prevalence of a condition of public health importance, known risk factors associated with a condition of public health importance, or behaviors or medical practices related to prevalence of a known condition of public health importance (e.g., surveillance of the prevalence of: tobacco use, exposure to secondhand smoke, lung cancer, or use of smoking cessation treatments).
  • Subsequent research using information collected during a public health surveillance activity, for instance, genetic analysis of biospecimens, would be research.
  • The following activities would be ‘‘research’’:
    • Exploratory studies designed to better understand risk factors for chronic diseases, including genetic predisposition, for chronic diseases;
    • Exploratory studies designed to elucidate the relationships between biomarkers of exposure and biomarkers of disease; and
    • Exploratory studies of potential relationships between behavioral factors (e.g., diet) and indicators of environmental exposures.
  • These types of activities would be considered research because they would not be conducted solely for the purposes described in the definition of research, and thus would be covered by the Common Rule if they involved human subjects, even if conducted by a federal agency with a public health mandate.
  • For more information, see the U.S. Office for Human Research Protections draft guidance document, https://www.hhs.gov/ohrp/draft-guidance-public-health-surveillance-activities.html 
• More Information About Criminal Justice Activities

  Regulatory Text

  "For purposes of this part, the following activities are deemed not to be research:

  Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for activities authorized by law or court order solely for criminal justice or criminal investigative purposes." 45 CFR 46.102(l)(3)(2018 requirements)

  More Information

  • Clarifies that, consistent with current practice and interpretation of the pre-2018 rule, data collection and analysis that enables the conduct of certain activities carried out as part of the criminal justice system is not research.
  • This category is also not intended to include social and behavioral studies of the causes of criminal behavior. Such studies would be considered research.
• More Information About National Security Activities

  Regulatory Text

  "For purposes of this part, the following activities are deemed not to be research:

  Authorized operational activities (as determined by each agency) in support of intelligence, homeland security, defense, or other national security missions." 45 CFR 46.102(l)(4)(2018 requirements)

  More Information

  • Clarifies current federal practice and the interpretation of the pre-2018 rule that the definition of research does not include authorized operational activities (as determined by each agency) in support of intelligence, homeland security, defense, or other national security missions.

Defining Human Subject

• Revised Definition of Human Subject

  "(1) Human subject means a living individual about whom an investigator (whether professional or student) conducting research:

  (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or

  (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

  (2) Intervention includes both physical procedures by which information or biospecimens are gathered (e.g., venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

  (3) Interaction includes communication or interpersonal contact between investigator and subject.

  (4) 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).

  (5) 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.

  (6) An identifiable biospecimen is a biospecimen for which the identity of the subject is or may readily be ascertained by the investigator or associated with the biospecimen." 45 CFR 46.102(e)(2018 requirements)

• Summary of Changes
  Definitions
  

  • The final rule does NOT implement the proposed expansion of the definition of ‘‘human subject’’ to include all biospecimens regardless of identifiability.
  • The definition of human subject in the final rule replaces the reference to data with a reference to information or biospecimens (this is also reflected in the definition for intervention) and adds language relating to using, studying, or analyzing the information or biospecimens.
  • The definition for identifiable biospecimen is new.
  • The definitions for interactions, private information, and identifiable private information have not been substantively changed.

   

  Assessments

  • The revised rule also requires that federal departments and agencies subject to the Common Rule perform several assessments:
    • Reexamine the meaning of identifiable private information and identifiable biospecimens with consultation with appropriate experts (including experts in data matching and re-identification), within 1 year and regularly thereafter (at least every 4 years). If appropriate and permitted by law, such Federal departments and agencies may alter the interpretation of these terms, including through the use of guidance.
    • Whether there are analytic technologies or techniques that should be considered by investigators to generate identifiable private information or identifiable biospecimen, with consultation with appropriate experts, within 1 year and regularly thereafter (at least every 4 years). Any such technologies or techniques will be included on a list of technologies or techniques that produce identifiable private information or identifiable biospecimens that will be published in the Federal Register after notice and an opportunity for public comment. 
• More Information About Identifiable Biospecimens

  Regulatory Text

  "An identifiable biospecimen is a biospecimen for which the identity of the subject is or may readily be ascertained by the investigator or associated with the biospecimen." 45 CFR 46.102(e)(6)(2018 requirements)

  More Information

  • The pre-2018 rule’s concept of identifiable private information had encompassed the concept of an identifiable biospecimen, whereas under the final rule that concept has been given its own definition.
  • A biospecimen is deemed to include private information (consistent with the understanding of this concept under the pre-2018 rule), so there is no need to make any additional determination about the ‘‘private’’ aspects of what is taking place.
  • Once a biospecimen becomes identifiable (for example, by being tagged with the name or other information that indicates the person from whom the biospecimen was obtained), then an investigator using that biospecimen is already using something to which definition of human subject would apply (i.e. obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens).
• More Information About Use of Newborn Dried Blood Spots
  • Newborn Screening Saves Lives Reauthorization Act states that research on newborn dried blood spots shall be considered research carried out on human subjects meeting the definition of section 46.102(f)(2) of title 45, Code of Federal Regulations, for purposes of Federally funded research conducted pursuant to the Public Health Service Act until such time as updates to the Federal Policy for the Protection of Human Subjects (the Common Rule) are promulgated pursuant to subsection (c).
  • The Newborn Screening Saves Lives Reauthorization Act of 2014 (Pub. L. 113–240) will no longer be effective following the effective date of this final rule, given that its changes applied only until changes to the Common Rule were promulgated.
  • As a result, under the final rule, secondary research with nonidentified newborn dried blood spots would be treated in the same way as secondary research with any other type of nonidentified biospecimen.
  • Such research would not be considered research with human subjects under the final rule, and thus would not be subject to the rule, unless a change is made to the law.