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Frequently Asked Questions from Applicants

Assurances

An “Assurance” is a documented commitment by an institution to comply with the requirements in 45 CFR 46. All institutions “engaged” in research covered by the HHS regulations (45 CFR 46) that is conducted or supported by a Federal Department or Agency must either apply to OHRP for an Assurance or provide their Assurance number to NIH. 

The HHS regulations state the requirement for an Assurance and define what it must contain at 46.103. The OHRP Federalwide Assurance page describes Assurances in greater detail and provides the documents and instructions necessary for obtaining an Assurance.

An institution needs an Institutional Assurance whenever that institution is engaged in non-exempt human subjects research. OHRP provides Guidance on Engagement of Institutions in Human Subjects Research.
http://www.hhs.gov/ohrp/policy/engage08.html

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 an HHS award.

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

Intervene or interact with living individuals for research purposes; or

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:

Provide test articles regulated by the FDA for use in HHS-supported research;

Supply other materials or support for HHS-supported research; or

Otherwise collaborate in HHS-supported research

Engagement is defined on OHRP Guidance on Engagement of Institutions in Human Subjects Research
http://www.hhs.gov/ohrp/policy/engage08.html

Institutions can apply for a Federalwide Assurance (FWA) from OHRP (not from NIH). Applying for an FWA involves filling out an electronic application and registering an Institutional Review Board that has agreed to review the human subjects research of that institution or for that research study.

Instructions, including application forms, can be found at the OHRP Federalwide Assurance page.

Institutions can apply for a Federalwide Assurance (FWA) from OHRP (not from NIH). Applying for an FWA involves filling out an electronic application and registering an Institutional Review Board that has agreed to review the human subjects research of that institution or for that research study.

Instructions, including application forms, can be found at the OHRP Federalwide Assurance page.

Data and Safety Monitoring

45 CFR 46.111(a)(6) states the following requirement for IRB approval of human subjects research:

"When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects."

The NIH Policy for Data and Safety Monitoring states that all NIH funded clinical trials require a Data and Safety Monitoring Plan and that monitoring should be commensurate with risk.

Most NIH Institutes/Centers have individual Data and Safety Monitoring policies. Click here for the links to I/C-specific policies.

Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials

  • Data and Safety Monitoring Boards (DSMBs) are specifically required for multi-site clinical trials with interventions that entail risk(s) to participants
  • DSMBs are generally required for Phase III clinical trials
  • A DSMB may be required for Phase I, Phase II or Phase III clinical trials if:
    • The clinical trial is blinded
    • The clinical trial involves high risk intervention(s), or
    • The clinical trial includes vulnerable population(s)

Definitions

“Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains
 

  1. data through intervention or interaction with the individual, or
  2. identifiable private information.” (45 CFR 46.102(f))

Obtaining means receiving or accessing identifiable private information or identifiable specimens for research purposes, including observing or recording private behavior. OHRP interprets obtaining to include an investigator's use, study, or analysis for research purposes of identifiable private information or identifiable specimens already in the possession of the investigator or provided to the investigators from any source. http://www.hhs.gov/ohrp/policy/cdebiol.pdf

Under the definition of human subject at 45 CFR 46.102(f), obtaining identifiable private information or identifiable specimens for research purposes constitutes human subjects research.

 

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 (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects. 45 CFR 46.102(f).

According to the “Guidance on Research Involving Coded Private Information or Biological Specimens”(http://www.hhs.gov/ohrp/policy/cdebiol.pdf) OHRP generally considers private information or specimens to be individually identifiable as defined at 45 CFR 46.102(f) when they can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems.

Conversely, OHRP considers private information or specimens not to be individually identifiable when they cannot be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems.

The Privacy Rule permits a covered entity to determine that health information is de-identified even if the health information has been assigned, and retains, a code or other means of record identification, provided that the code is not derived from or related to the information about the individual and could not be translated to identify the individual and the covered entity does not use or disclose the code for other purposes or disclose the mechanism for re-identification. Under the HHS Protection of Human Subjects Regulations, if an investigator obtains private information about living individuals for research purposes and that private information retains a link to individually identifying information, such private information ordinarily would be considered by OHRP to be individually identifiable to the investigator. However, OHRP does not ordinarily consider such information to be individually identifiable to the investigator if (1) the investigator and the holder of the individually identifying information sign an agreement prohibiting the release of individually identifying information to the investigator under any circumstances, or (2) there are other legal requirements prohibiting the release of the link to the investigator.

An example of a legal requirement prohibiting the release of the key is the HIPAA Privacy Rule, which permits a covered entity to assign a code to de-identified health information for re-identification under specific conditions. One such condition prohibits a covered entity from disclosing the mechanism for re-identification (e.g., releasing the key or the mechanism for breaking the code).

The OHRP considers the term investigator to include anyone involved in conducting a proposed research project.

Exemption 4 applies to retrospective studies of specimens and/or data that have already been collected. The materials must be “on the shelf” (or in the freezer) at the time the protocol is submitted to the IRB or other designated officials at your institution to determine whether the research is indeed exempt. Research that involves the ongoing collection of specimens and/or data does not meet the criteria for Exemption 4, even if they were destined to be discarded.

This language in the regulation was intended to apply to public sources of data, such as census data. Its meaning with respect to human tissue specimens is widely debated. Although there are organizations that make human cells and tissues broadly accessible to the research community, these materials are not usually available to the public at large and are not generally considered to be publicly available.

Examples of identifiers, would include names, social security numbers, medical record numbers, or pathology accession numbers, or any other “code” that permits specimens or data to be linked to individually identifiable living individuals and perhaps also to associated medical information.

Exemptions

The six exemptions to the regulatory requirements are described in section 46.101(b) of 45 CFR 46.

Subpart B: YES, all exemptions may be applied to research involving pregnant women, neonates and fetuses.

Subpart C: NO, the exemptions at 46.101(b) do not apply to research involving prisoners.

Subpart D: YES, all exemptions may be applied to research involving children except some parts of exemption 2. Exemption 2 regarding educational tests is applicable to this subpart. However, the components for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed.

OHRP recommends that institutions adopt clear procedures under which the IRB (or some authority other than the investigator) determines whether proposed research is exempt from the human subjects regulations [see 45 CFR 46.101(b)]. Documentation should include the specific category justifying the exemption. (http://www.hhs.gov/ohrp/polciy/irbgd107.html).

Because NIH does not require IRB approval at time of application, claimed exemptions often represent the opinion of the PI, and justification provided for the exemption(s) by the Principal Investigator is evaluated during the peer review process.

HHS regulations state:
Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:
 

  • information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and
  • any disclosure of the human subjects' responses outside of the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation 46.101(b)(2)

NIH Interpretation:
In order to be exempt from the requirement of IRB review and approval under exemption 2, researchers must propose the use of tests or procedures 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

HHS regulations state: Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects 46.101(b)(2).

If you receive or have access to existing individually identifiable private information or identifiable specimens from living individuals (e.g., pathology or medical records), you are conducting human subjects research. If you as the investigator or your collaborator record the information in such a manner that you cannot subsequently access or obtain direct or indirect identifiers that are linked to the subjects, research activities that involve data recorded in this manner meets the requirements of Exemption 4. If you will retain or can access any identifiers, the research project is not exempt under Exemption 4.

Yes. Research that meets the criteria for Exemption 4 is Human Subjects Research.

Exemption 4 includes research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

Please note: human subjects research that meets the criteria for Exemption 4 is not considered “clinical research” as defined by NIH; therefore, the NIH policies for addressing inclusion of women, minorities and children do not apply to research that is determined to meet the criteria for Exemption 4.

The humans subjects regulations decision charts from the Office of Human Research Protection (OHRP) will help you to see whether your research falls under the human subjects regulations and if so, whether it meets the criteria for Exemption 4.

Please note: OHRP advises that investigators should not have the authority to make an independent determination that research involving human subjects is exempt. OHRP guidance states that Exemptions should be independently determined. Institutions often designate their IRB to make this determination. Because NIH does not require IRB approval at time of application, the exemptions designated in Item 4a often represent the opinion of the Principal Investigator, and the justification(s) provided by the Principal Investigator for the exemption(s) is/are evaluated during peer review.

It depends: Specimens that would have otherwise been discarded do not automatically meet the requirements for E4. In order for the research to meet E4, such samples MUST either be BOTH existing AND publicly available or BOTH existing AND unidentifiable to all members of the research team.

Provide any and all information you have about the sample, but there is no need to obtain additional, potentially identifiable, information for the NIH population sample information requirement that is not needed for your proposed studies.

Exemption 4 applies to retrospective studies of specimens and/or data that have already been collected. The materials must be “on the shelf” (or in the freezer) at the time the protocol is submitted to the IRB or other designated officials at your institution to determine whether the research is indeed exempt. Research that involves the ongoing collection of specimens and/or data does not meet the criteria for Exemption 4, even if they were destined to be discarded.

This language in the regulation was intended to apply to public sources of data, such as census data. Its meaning with respect to human tissue specimens is widely debated. Although there are organizations that make human cells and tissues broadly accessible to the research community, these materials are not usually available to the public at large and are not generally considered to be publicly available.

Examples of identifiers, would include names, social security numbers, medical record numbers, pathology accession numbers, or any other “codes” that permits specimens or data to be linked to individually identifiable living individuals and perhaps also to associated medical information.

Exemption 6 (E6) states that research is exempt from the Regulatory requirements if the only involvement of human subjects is:
“(6) Taste and food quality evaluation and consumer acceptance studies,

  1. if wholesome foods without additives are consumed or
  2. if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or 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.”

To determine whether your proposed research meets the Regulatory requirements for E6, you must determine:

  1. Will participants be consuming “food”?

    The FDA regulations define “food” as follows:

    The term "food" means (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.

    If the answer to this question is “no,” the proposed research does not meet the regulatory requirements for E6.

    If the answer to this question is “yes,” the proposed research may meet the regulatory requirements for E6; see question 2.

  2. Does the food that participants will be consuming contain “additives”?

    The FDA regulations define “food additives” and “color additives.”

    If the answer to this question is “no,” the proposed research does meet the regulatory requirements for E6(i).

    If the answer to this question is “yes,” the proposed research does not meet the regulatory requirements for E6(i) but may meet the requirements for E6(ii); see question 3.

  3. Does the food that participants will be consuming contain:
     
    • a “food ingredient” at or below the level and for a use found to be safe by FDA,
    • an “agricultural chemical” at or below the level found to be safe by USDA, or
    • an “environmental contaminant” at or below the level found to be safe by EPA?

    If the answer to this question (all options) is “no,” the proposed research does not meet the regulatory requirements for E6(ii).

    If the answer to this question (one or more options) is “yes,” the proposed research does meet the regulatory requirements for E6(ii).

     

General

Research is considered to involve human subjects when an investigator conducting research obtains (1) data through intervention or interaction with a living individual, or (2) identifiable private information about a living individual. (45 CFR 46) If your research meets this definition, indicate “Yes” for involvement of human subjects and include a protection of human subjects section in your application as per the supplemental instructions for preparing the human subjects section of the research plan.

NO. According to the definition of "human subject," research is only considered to involve human subjects if the data/samples are from living individuals. If the data or samples you propose to use in your research are not from living individuals, indicate “No” for the involvement of human subjects in your application. You may wish to make it clear in the Human Subjects section of your application that none of your data/samples are from living individuals and your research, therefore, does not involve human subjects.

Research that proposes the use of human cell lines available from the American Type Culture Collection or a similar repository is not considered human subjects research because the cells are publicly available and all of the information known about the cell lines (perhaps, including the donor) is also publicly available. Research that proposes the use of established cells from a donor whose identity cannot be readily ascertained by the investigator is not considered to be human subjects research, either for example, because there are written policies and procedures prohibiting release of identifiers and/or an agreement specifying that identifying information will not be shared with the investigator. Research with Primary cells: If you are taking blood or other cells from living individuals for research purposes in order to create a cell line, the research involves human subjects.

Studies using specimens/data from a repository/database are not human subjects research if a study meets one or more of these criteria:

  • the repository/database obtains the specimens/data without identifiers, OR
  • the repository/database obtains the specimens/data with identifiers but is prevented, by law*, from providing identifiers that link to living individuals and the repository/database plays no collaborative role in the proposed research, OR
  • the investigators and the repository that holds the key that links coded specimens/data to living, identifiable, individuals enter into an agreement prohibiting the release of the key to the investigators under any circumstances, until the specimen/data donors are deceased, OR
  • there are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of the key to the investigators under any circumstances, until the specimen/data donors are deceased.

If your proposed studies using specimens/data from a repository/database meet one or more of the above criteria, you should indicate “No” for Human Subjects, and you should provide the appropriate justification in the Human Subjects section of your application for your claim that no human subjects are involved.

However, if your proposed studies do not meet any of these criteria, you are proposing human subjects research. You should indicate “Yes” for Human Subjects and complete the Human Subjects section of your application.

* “It is important to note that the Privacy Rule does not replace or act in lieu of existing regulations for the protection of human subjects found in 45 CFR 46. Therefore, instructions in the Human Subjects section of the PHS398 (or other NIH applications) remain the same. Researchers should continue to consider issues of privacy and confidentiality as they affect the adequacy of protections of human subjects from research risks, and when appropriate, address these issues in the Human Subjects section of the research plan.” See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

Non-Research Repositories & Databases:
If specimens or data were originally collected for non-research purposes AND were submitted to the repository/database without any links to identifiable private data or information, it is a non-research repository/database.

Studies using specimens/data from non-research repositories or databases are not human subjects research.

Research Repositories & Databases:
If specimens or data were collected for research purposes it is a research repository. Collection of specimens/data, repository storage or data management and use of specimens or disclosure of data are all considered “research activities”.

Please also see the OHRP guidance document, “Issues to Consider in the Research Use of Stored Data or Tissues”.

We have found that investigators tend to use three separate definitions for “focus group:”

  1. If the proposed studies involve a group of individuals who are consultants and have been chosen for their expertise to improve the research design, the research IS NOT considered human subjects research.
  2. If the studies involve a group of individuals who are brought in to test a new product (e.g. software, equipment, surveys) to identify “bugs” or problems, the research IS NOT considered human subjects research because the data collected is about the product and not about the individuals. This is a Beta -Test of the product.
  3. If the studies involve a group of the eventual target population who is brought in to “pilot test” a new product or intervention before researchers finalize the design of the product or intervention, the research MAY BE considered human subjects research. Pilot tests involve living individuals if the PI conducting research obtains data or individually identifiable private information. These studies may or may not meet the criteria for E2, depending on the age of participants and whether there are potential risks associated with disclosure of identifiable data.

One Human Subjects code is assigned each application, for the entirety of the project period. The code assigned will be the most protective code appropriate. If one of the proposed subprojects involves human subjects, indicate “Yes” for human subjects and complete the Human Subjects section in your application as per the supplemental instructions for preparing human subjects section of the research plan.

The research described in your application may include more than one research activity. Each research activity should be assessed independently to determine whether it meets the requirements for human subjects research, exempt human subjects research, or research that does not involve human subjects. The involvement of human subjects in your application is determined by the greatest involvement of human subjects in any single research activity. Examples are provided below to help you determine whether your proposed research involves human subjects.

Human Subjects Research
 

  • If the specimens and/or data were obtained specifically for the currently proposed research project through intervention or interaction with a living individual, then your research is human subjects research.
  • If you receive or have access to individually identifiable specimens or data from living individuals (e.g., pathology or medical records), your proposed research is human subjects research.

Exempt Human Subjects Research
 

  • If you receive or have access to existing individually identifiable private information or identifiable specimens from living individuals (e.g., pathology or medical records), you are conducting human subjects research. If you as the investigator or your collaborator record the information in such a manner that you cannot subsequently access or obtain direct or indirect identifiers that are linked to the subjects, research activities that involve data recorded in this manner meets the requirements of Exemption 4.

Not Human Subjects Research
 

  • If you are using specimens and/or data and neither you nor your collaborators can identify the subjects from whom the specimens and/or data were obtained, either directly or indirectly through coding systems, this is not considered human subjects research and the HHS human subjects regulations (45 CFR Part 46) do not apply at all.
  • If your research involves only coded private information/data or coded specimens, OHRP does not consider this research to involve human subjects as defined under the HHS Protection of Human Subjects Regulations (45 CFR Part 46.102(f)) if the following conditions are both met: the private information/data or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example:

(a) the key to decipher the code is destroyed before the research begins;
(b) the investigators and the holder of the key enter into an agreement prohibiting the release of the key to the investigators under any circumstances, until the individuals are deceased;
(c) there are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of the key to the investigators under any circumstances, until the individuals are deceased; or
(d) there are other legal requirements prohibiting the release of the key to the investigators, until the individuals are deceased.

See the OHRP Guidance on Research Involving Coded Private Information or Biological Specimens (PDF)

If you are not sure whether human subjects will be involved, or if the eventual research design is dependent on preliminary studies described in your application, indicate “Yes” for human subjects. In the Human Subjects section of your application, provide a description of possible planned human subjects research. After you have enough information to more completely describe the human subjects research, submit both a protocol and a revised Human Subjects section (as per the supplemental instructions for preparing the human subjects section of the research plan) to your Program Official for approval.

This situation is specifically covered in sections 46.118 and 46.119 of the HHS regulations.

Research described by the six exemption categories in section 46.101(b) of 45 CFR 46 is considered human subjects research but is exempt from the requirement for IRB oversight of the research as described in 45 CFR 46. If you believe that the research described in your application is exempt, you should indicate “Yes” in Item 4, and include a Human Subjects section in your application as per the supplemental instructions for preparing the human subjects section of the research plan, describing the involvement of human subjects in the research and why you believe the research meets the criteria for an exemption.

Yes. Research that meets the criteria for Exemption 4 is Human Subjects Research.

Exemption 4 includes research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

Please note: human subjects research that meets the criteria for Exemption 4 is not considered “clinical research” as defined by NIH; therefore, the NIH policies for addressing inclusion of women, minorities and children do not apply to research that is determined to meet the criteria for Exemption 4.

Other Requirements - Inclusion, Human Subjects Education

All individuals involved in the design or conduct of the research must meet the human subjects education requirement. The Frequently Asked Questions specific to the Required Education in the Protection of Human Research Participants policy may also be helpful.

The Required Education in the Protection of Human Research Participants policy does not state how often human subjects education must be completed. It is up to each institution to determine how often investigators must complete human subjects education. Documentation of human subjects education for all investigators involved in the design and conduct of the proposed research must be submitted prior to each new award for research that will involve human subjects.

Provide any and all information you have about the sample, but there is no need to obtain additional, potentially identifiable, information for the NIH population sample information requirement that is not needed for your proposed studies.

The OHRP Guidance: Applicability of 45 CFR part 46 to Clinical Investigations Conducted Under FDA's Interim Final Rule at 21 CFR 50.23(e)


  • Clarifies that institutions whose employees or agents use an investigational device only to (1) identify a potentially life-threatening chemical, biological, radiological, or nuclear agent, (2) facilitate the treatment of individuals exposed to such an agent, and/or (3) report test results to a public health authority would not be engaged in human subjects research under 45 CFR part 46.

  • Clarifies that institutions whose employees or agents obtain or analyze identifiable private information derived from an investigational in vitro diagnostic device in order to evaluate the safety and effectiveness of the in vitro diagnostic device would be engaged in human subjects research under 45 CFR part 46.
This should not impact research funded by NIH because these statements are consistent with the OHRP Guidance on Engagement of Institutions in Human Subjects Research
http://www.hhs.gov/ohrp/policy/engage08.html

(B) Institutions would not be considered "engaged" in human subjects research (and would not need an Assurance) if their involvement is limited to the following:

Institutions whose employees or agents release identifiable private information or specimens to a State or Local Health Department or its agent for legitimate public health purposes within the recognized authority of that Department. However, utilization of such information or specimens by Department investigators for research purposes would constitute engagement in research, and would require an Assurance from the Department.

 

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