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NIH Investigator Manual for Human Subjects Research

Chapter 1 - Types of Research: Human Subjects Research Vs. Not Human Subjects Research

Overview

Key points

  • NIH investigators should be knowledgeable as to whether research activities meet the definition of human subjects research.

  • Proposed human subjects research must be submitted in the electronic IRB system for IRB review or consideration of an exemption from IRB review prior to commencing research activities.
What does the term research mean?

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.


FDA uses the term clinical investigation to be synonymous with research and defines clinical investigation as any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the FDA . . . [or] the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit.

What does the term human subject mean?

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 (FDA) 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.

What does the term human subjects research mean given the explanations for research and human subjects above?

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

  1. Meets the US Department of Health and Human Services (HHS) definition of research and involves human subjects as defined in the HHS regulations; and/or

  2. Meets the Food and Drug Administration (FDA) definition of research and involves human subjects as defined in FDA regulations.

Note that FDA uses the term clinical investigation which means any experiment that involves a test article and one or more human subjects, as well as the term clinical investigation (involving drugs) which is defined as any experiment in which a drug is administered or dispensed to, or used involving, 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.

How do I know if my research is human subjects research?

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 definition of research. Some activities such as QA/QI projects or types of scholarly and journalistic activities may not be research under the 2018 Common Rule. Please see the definition of research in the regulations (2018 requirements) for an expanded list of activities that are deemed not to be research under these regulations.

  • Next, determine if the research is being conducted with living human subjects. If not, no IRB review is required because research with identifiable specimens and/or data from deceased individuals falls under the category of not human subjects research.  1 There is an exception to this statement when the safety and/or efficacy of Invitro Diagnostic Devices are being studied. In such cases, the FDA does not differentiate whether the specimens are from living or deceased individuals.

  • Research that includes living human subjects as described above, or that meets the definition of clinical trial or clinical investigation above, 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.

  • See the following flow diagram:

  • If the research is "not human subjects research," a formal determination by OHSRP is not mandatory for research activities involving only use (including secondary use study or analysis) of coded or de-identified (not individually identifiable) human specimens and/or data.

  • Investigators should assess whether their research meets the regulatory definition of human subjects research. If an investigator is not certain, a request for a formal determination may be made through the NIH electronic IRB system.

  • If a formal determination that an activity is not human subjects research is needed or desired, only OHSRP or the Office of IRB Operations (IRBO) can make a formal determination that an NIH IRP activity is not human subjects research.

  • There may be other special research considerations per NIH policies or additional requirements for the review of research that apply, e.g., those involving human fetal tissue or human stem cells.

  • If the protocol involves conducting research with data or biospecimens, consider whether these are individually identifiable under federal regulations for the protection of human subjects.

  • 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 if they are unsure whether data or biospecimens being used in a specific research project would be considered individually identifiable. 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)
Does secondary research with specimens and/or data need IRB review?

Secondary research is research use of existing biospecimens and/or data for a purpose other than the original purpose(s) for which they were initially collected through interaction or intervention with living individuals, including those collected for clinical purposes.

Secondary research requiring IRB approval:

  • Includes research with identifiable specimens and/or data or with coded specimens and/or data for which the investigator has the code key. When identifiable biospecimens or data are used to address new aims or to conduct new research analyses (not explicitly described in the current IRB approved protocol), the PI should write and submit a new protocol to the IRB.

  • When an investigator conducts secondary research with coded and linked biospecimens or data and will generate individual subject level results that he or she can link back to the research subjects, this is considered human subjects research requiring prospective IRB review and approval.

  • When there are collaborations with external researchers in which the NIH investigator shares coded and linked biospecimens or data for secondary research and receives coded and linked results that link back to individual subjects, IRB review and approval is needed.

Consent related issues for secondary research with identifiable materials

  • All non-exempt secondary research requires either that consent be obtained from the prospective participants or that the IRB grant a waiver of informed consent.
    • Note: If the proposed research is within the scope of the aims and objectives described in the open and IRB approved research protocol, it is not considered secondary research and new consent or a waiver of consent is not necessary.

  • For the IRB to grant a waiver of consent; the following considerations apply:
    • The research must meet the regulatory requirements for a waiver at 45 CFR 46.116(f)(3).
    • The proposed research must be consistent with the terms of the initial consent (if any) under which the specimens and/or data were collected.
      • For example, the initial consent states that the samples/data may be used in the future for any biomedical or health related research.

  • If the proposed research is not consistent with the terms of the initial consent, the IRB may require reconsent of participants in order for their specimens and/or data to be used
    • Examples of terms that would not be consistent include:
      • If the initial consent said the samples would not be used for any future research;
      • If the consent stated that the samples would only be used for specific types of research and those differ from the proposed research; or
      • If it stated the samples would be destroyed after the initial research was completed.

  • If the original consent form was silent with regard to future research, or informed consent was not obtained at the time of the original collection (e.g., biospecimens were collected for clinical diagnostic purposes/pathological waste from surgery), the PI can either obtain new consent from the participants or describe to the IRB why the conditions for a waiver of consent are met and why it is needed to conduct the research (See the section of this manual that describes criteria that need to be met for the IRB to approve waiver of consent.)

  • If the secondary research will involve genetic testing or sequencing or other types of genetic research, or use for drug development, subjects must have explicitly consented to this.

  • If the biospecimens and/or data may be used for commercial profit, the consent must address this as well as whether the subject will or will not share in the profit.

The OHSRP website has a document titled When is IRB Approval Needed to Use or Share Data or Biospecimens? This document provides additional information and examples and can be found on the Sharing Data and Specimens webpage of the OHSRP website.

The decision tree below for sharing specimens and/or data from an NIH IRB-approved protocol for secondary research provides additional information.

Can I Share Specimens or Data from My IRB-Approved Protocol for Secondary Research?*
Review the consent form associated with the protocol to determine which scenario below is true. There is…

Flowchart diagram

*  Secondary research: research use of biospecimens or data for other than the original purpose(s) for which the biospecimens or data were initially collected through interaction or intervention with living individuals

1 If you will receive research results that you can link back to identifiers after sharing specimens or data, the project is considered to be human subjects research. You must submit a secondary research protocol to address the planned research and seek IRB approval prior to initiation of the activities. The protocol must include new consent or a justification of a waiver of consent for the planned research.

2 In some circumstances, it may be appropriate to re-consent the subject to allow their specimens and data to be shared. Consult the IRB if you wish to proceed with sharing.


IRB approval is not needed for secondary research when:

  • The biospecimens and/or data are fully de-identified/anonymized by removing all identifiers and re-coding or disposing of the code key AND no one collaborating will have any way to re-identify the materials:
    1. If materials were collected with research consent, investigators must consider what subjects originally consented to with regard to future research.
    2. If biospecimens and/or data were collected as part of a protocol subject to the revised (2018) Common Rule, the consent form language must specifically address and allow for this possibility.
  • An investigator shares coded and linked biospecimens and/or data with a collaborator for secondary research and will only receive summary level results (not results which can be linked back to individual subjects).

However, the sharing investigator still must:

  1. Ensure that the original consent form addresses sharing for future research; and

  2. Ensure that the consent language is consistent with the planned research or allows for broad future research.

  3. If the original consent form does not contain language about sharing for future research ("is silent"), the investigator should reach out to the IRB Chair who will determine whether sharing is permissible or not.
Where can I find additional information about secondary research and repositories?

The following OHSRP Education Series sessions (slides and videocast) can be accessed as follows:


Additionally, the OHSRP website has protocol templates for both secondary research projects and repository protocols in the Observational Research Protocol Templates section of the Protocol Templates and Forms page.

Human subjects research that is exempt from IRB review

Key points

  • Some research which involves human subjects may be exempt from IRB review if it falls into one of the specific categories of exempt research.

  • Investigators who wish to conduct exempt human subjects research must submit the project in the NIH IRB electronic IRB system and receive a formal determination of an exemption before commencing any research activities. At NIH, only designated staff in IRBO can make a determination that research is exempt.

  • In order to be exempt, certain human subjects research subject to the 2018 Common Rule may require limited IRB review.
Can my human subjects research study be considered exempt from IRB review?

Human subjects research requires review by the IRB or, alternatively, it may be eligible for determination that the research is exempt from such review. Some exemption categories may require limited IRB review based on which exemption criteria are met, and this review is conducted by a designated limited IRB reviewer using expedited procedures. Charts 2-8 at this OHRP link describe the exemption categories. (NIH is not implementing broad consent at this time, so the exemptions noted in Charts 9 and 10 are not currently relevant to NIH investigators.) The list of potential exemptions in the HHS regulations for the protection of human subjects can be found here (in § 46.104 Exempt research in section (d)) and includes research involving the following:

  • Specific types of research conducted in educational settings that involves certain normal educational practices, such as research on instructional techniques already in use or classroom management. (This type of research is not regularly conducted at NIH.)

  • Interactions involving educational tests, surveys, interviews, or observation of public behavior if specific criteria are met. This exemption does not apply to survey or interview research with children or research involving public observation of children, when the researcher participates in the activities being observed.

  • Benign behavioral interventions that meet specific criteria and that are brief in duration, harmless, painless, and not physically invasive, and not likely to have a significant adverse lasting impact on subjects or be offensive or embarrassing to subjects. This exemption is not applicable to research involving children.

  • Secondary research of identifiable private information or identifiable biospecimens, if at least one of the following criteria is met: when the identifiable materials are publicly available, or when the data is recorded by the investigator in a de-identified manner, i.e., no identifiers are accessible to the researcher once the analysis begins. Additional provisions apply.

  • Public benefit or service programs. 



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  • Taste and food quality evaluation and consumer acceptance.

Investigators who wish to conduct exempt human subjects research must submit the project and receive a formal determination of an exemption before commencing any research activities. All requests for exemptions must be submitted in the NIH electronic IRB system and will be reviewed by a designated staff member in the NIH IRBO. These submissions require a protocol for which templates are available on the OHSRP website.

In order to be exempt, certain human subjects research subject to the 2018 Common Rule may require limited IRB review. Limited IRB review may be conducted by a designated limited IRB reviewer using expedited procedures.

Does my QA/QI project require IRB review?
  • The answer is "it depends."

  • Many quality improvement efforts are not research subject to the HHS protection of human subjects regulations and would not require IRB review. However, in some cases quality improvement activities are designed to accomplish a research purpose as well as the purpose of improving the quality of care, and in these cases, the regulations for the protection of subjects in research (45 CFR part 46) may apply.

  • QA/QI activities such as implementing a practice to improve patient care or collecting patient or provider data for non-research clinical or administrative purposes, do not meet the definition of research under the Common Rule. Nor would QI activities that are limited to delivering health care, or measuring and reporting provider performance data for clinical, practical, or administrative purposes.

  • In other cases, QI projects may constitute nonexempt human subject research such as when a project involves using an untested intervention which includes collection of information about patient outcomes to establish scientific evidence to determine how well the intervention achieved its intended results.

  • Planning to publish an account of a quality improvement project does not necessarily mean that the project fits the definition of research. Conversely, a quality improvement project may involve research even if there is no intent to publish the results.

  • See OHRP Quality Improvement Activities FAQs for more information.

  • Also see OHSRP guidance document, QA/QI vs. Research: Do I Need to Submit for an Exemption or IRB Approval? on the OHSRP webpage Step 1: Do you need to submit to the IRB?
If I am planning a program evaluation, do I need to submit for an exemption or IRB approval?
  • The answer is (again) "it depends."

  • The Centers for Disease Control and Prevention define program evaluation as the systematic collection of information about the activities, characteristics, and outcomes of programs to make judgments about the program (or processes, products, systems, organizations, personnel, or policies), improve program effectiveness, and/or inform decisions about future program development.

  • Key concepts in considering program evaluations as they relate to IRB review:
    • Program evaluations may be considered research when there is a hypothesis or question being answered, and the information being collected is designed to contribute to generalizable knowledge (i.e., beyond the context of the specific institution(s) conducting the evaluation).
    • Whether these projects are research is determined by the IRBO on a case-by case-basis.
    • The IRBO makes this determination by evaluating a group of factors including the purpose and intention of the project, level of risk, and methodology.
    • Publishing or presenting program evaluation findings does not automatically mean the project is research.

  • For additional information and a helpful table that differentiates characteristics that may make such projects research activities requiring submission for an exemption or IRB approval see the document labeled Program Evaluation vs. Research found on the OHSRP webpage Step 1: Do you need to submit to the IRB?.
How do I submit a request for exemption if I believe my research should be considered exempt human subjects research?
  • All requests for exemptions must submitted via the electronic IRB system.

  • Requests for exemption are broken into two different categories based on the type of research being performed. Each category has its own template and set of instruction on the IRBO Protocol Templates and Forms webpage. The two categories are:
    • Retrospective Data or Biospecimen Review
    • Collecting Prospective Data from Humans

  • After determining which type of exempt research applies, download both the applicable instructions and protocol template here. Please review the instructions and the template carefully. Use the provided template to create a complete protocol to ensure that you have included all the required elements.

  • Requests for exemptions are submitted in the electronic IRB system. The instructions from the IRBO website walk you through the process.

  • If your project is Determined to be Exempt from IRB Review, you will receive an outcome letter informing you that your research has been confirmed as Exempt Human Subjects Research. The letter will provide you the applicable exemption category and further instructions on possible future responsibilities.
Where can I find resources about exempt research or information to help me submit a request for an exemption determination to the NIH IRB?

See the OHSRP Education Series session Exemptions from IRB Review and the Revised Common Rule: What Has Changed and What Has Stayed the Same? (Slides and videocast)

Information to help with submission of requests for exemptions can be found on the OHSRP Website on the Protocol Templates and Forms webpage and include:

  • Instructions and Protocol Template for Retrospective Data or Biospecimen Review

  • Instructions and Protocol Template for Prospective Data Collection from Humans

Types of IRB review of Non-exempt Human Subjects Research

Key points

  • Non-exempt human subjects research may be approved by the NIH IRB only when all required regulatory and policy criteria are met.

  • NIH investigators may not begin research activities until all required approvals have been obtained (e.g., institutional approvals, as applicable, and approvals from IRB, and ancillary committees).
If my human subjects research is not eligible for an exemption, is it eligible for expedited IRB review?

Expedited review means review of research that falls within specific categories and that is reviewed by an IRB Chair or an expedited reviewer designated by the Chair, in consultation with the IRBO as needed.

  • Some human subjects research may possibly be eligible for expedited review if it does not involve research with prisoners.

  • Most minimal risk studies are reviewed by an expedited reviewer. The categories that allow for Expedited Review of Research are further described in this complete list from OHRP. The following is a summary of the categories:
    • Category 1: Clinical studies of drugs and medical devices only when either of the two conditions below is met.
      1. Research on drugs for which an investigational new drug (IND) application (21 CFR Part 312) is not required.
      2. Clinical studies of medical devices for which an investigational device exemption application (21 CFR Part 812) is not required, or the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.

    • Category 2: Collection of blood specimens by finger stick, heel stick, ear stick, or venipuncture as follows:
      1. From healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 mL in an 8-week period and collection may not occur more frequently than 2 times per week.
        or
      2. From other adults and children, considering the age, weight and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8-week period and collection may not occur more frequently than 2 times per week.

    • Category 3: Prospective collection of biological specimens for research purposes by noninvasive means. See this category in OHRP document for more details: Expedited Review: Categories of Research that may be Reviewed Through an Expedited Review Procedure

    • Category 4: Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing.

    • Category 5: Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis)

    • Category 6: Collection of data from voice, video, digital, or image recordings made for research purposes

    • Category 7: Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. 

      3

    • Category 8: All greater than minimal risk studies will be reviewed by a fully convened IRB unless it falls under one of these Expedited Continuing Review Categories:
      1. Continuing review of research previously approved by the convened IRB where the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects.
      2. Continuing review of research previously approved by the convened IRB where no subjects have been enrolled and no additional risks have been identified. (An example would be if there was a new risk added to the Investigational Brochure.)
      3. Continuing review of research previously approved by the convened IRB where the remaining research activities are limited to data analysis.

    • Category 9: Continuing review of research, not conducted under an IND or IDE where categories 2-8 above do not apply, but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified. (This means that this category applies if the protocol does not fit in one of the above categories and is minimal risk but was initially be reviewed by the Full Board to allow Category 9 to be used.)
When does my human subjects research require review by the convened IRB?

If the protocol constitutes human subjects research and is not eligible for exemption from IRB review and it is not eligible for expedited review, it will be reviewed by the convened IRB. Convened IRB means committee review of human subjects research by an IRB that meets the membership requirements specified in federal regulations. Review by the convened IRB is sometimes referred to as full board review.

What criteria must my non-exempt human subjects research meet to be approved by the IRB?

In order to approve non-exempt human subjects research that is subject to HHS regulation, whether reviewed by expedited review or by the full board, the IRB must determine that all of the following requirements are satisfied in order to approve the research. These requirements are known as the, "criteria for approval" and are found at 45 CFR 46.111, and, when applicable, found at 21 CFR 56.111 for FDA regulated research.

The criteria below are further described at 45 CFR 46.111.

  1. Risks to subjects are minimized: By using procedures that are consistent with sound research design and that do not unnecessarily expose subjects to risk; and whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
  2. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.
  3. Selection of subjects is equitable.
  4. Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by federal regulations (§46.116).
  5. Informed consent will be appropriately documented or appropriately waived by the IRB in accordance with federal regulations (§46.117).
  6. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
  7. When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
  8. When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects.
What options does the IRB have when deciding whether to approve my research when it is reviewed by the full Board?

The IRB will make one of the following determinations:

  • Approve as submitted: The convened IRB, the expedited reviewer, or the limited IRB reviewer approves the research study.

  • Modifications Required to Secure Approval: The convened IRB, or the expedited reviewer, or the limited IRB reviewer approves the research study contingent on stipulated changes to the research.

  • Defer: The convened IRB determines that a research study requires resolution of one or more criteria for IRB approval of research at § 46.111, or other substantive issues have been identified (e.g., risks have not been identified, risks are significant and have not been adequately minimized, or the safety monitoring plan is not adequate). When such an action is taken, the IRB may stipulate substantive changes to the research study. Deferred actions must be reviewed by the convened IRB in order to be approved.

  • Disapprove: The convened IRB determines that a research study cannot be approved in its present form or is inappropriate based on its present design (e.g., for reasons such as subject safety or scientific validity).


  1. There is an exception to this statement when the safety and/or efficacy of Invitro Diagnostic Devices are being studied.  In such cases, the FDA does not differentiate whether the specimens are from living or deceased individuals.     
  2. This type of research is not commonly conducted by NIH investigators and includes the following: Research and demonstration projects that are conducted or supported by a Federal department or agency, or approved by the relevant department/agency head and that are designed to study, evaluate, improve, or otherwise examine public benefit or service programs, including procedures for obtaining benefits or services under those programs, possible changes in or alternatives to those programs or procedure OR possible changes in methods or levels of payment for benefits or services under those programs.     
  3. NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. See 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.     

Chapter 2 - Roles and Responsibilities of the Principal Investigator