• Am I proposing Human Subjects Research?
• Am I proposing human subjects research if my studies will use only cadaver specimens?
• Am I proposing human subjects research if my studies will use only cell lines?
• Am I proposing human subjects research if I obtain specimens/data from a repository or database?
• What is the difference between a “research repository” and a “non-research repository“?
• Is the use of a “focus group” human subjects research?
• What do I check in Item 4 if my application describes many subprojects but not all of the subprojects include human subjects research?
• How can I determine whether research proposed in my application involves human subjects if I will only use human specimens (and/or cell lines, and/or data) for part of the project?
• What do I check in Item 4 if I do not have definite plans to conduct human subjects research?
• What do I check in Item 4 if my application describes research that meets the criteria for an exemption in Item 4a?
• Is research that meets the criteria for Exemption 4 considered human subjects research?

Am I proposing Human Subjects Research?

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, check “Yes” in Item 4 and complete the Human Subjects section of your application as per the PHS 398 Instructions.

Am I proposing human subjects research if my studies will use ONLY cadaver samples?

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, check “No” in Item 4. 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.

Am I proposing human subjects research if my studies will use ONLY cell lines?

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.

Am I proposing human subjects research if I obtain specimens/data from a repository or database?

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 check “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 check “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.

What is the difference between a “research repository” and a “non-research repository“?

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”.

Is the use of a “focus group” human subjects research?

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.

What do I check in Item 4 if my application describes many subprojects but not all of the subprojects include human subjects research?

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, check “Yes” in Item 4 and complete the Human Subjects section of your application as per the PHS 398 Instructions.

How can I determine whether research proposed in my application involves human subjects if I will only use human specimens (and/or cell lines, and/or data) for part of the project?

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, 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.

What do I check in Item 4 if I do not have definite plans to conduct human subjects research?

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, check “Yes” in Item 4. 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 PHS 398 Instructions) to your Program Official for approval.

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

What do I check in Item 4 if my application describes research that meets the criteria for an exemption in Item 4a?

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 check “Yes” in Item 4, and complete the Human Subjects section of your application as per the PHS 398 Instructions, describing the involvement of human subjects in the research and why you believe the research meets the criteria for an exemption.

Is research that meets the criteria for Exemption 4 considered human subjects research?

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.