• When does research with human specimens, cells, cell lines, or data involve human subjects?
• What are examples of research involving human specimens, cells, cell lines, or data that would not be considered human subjects research under HHS regulations at 45 CFR Part 46?
• What are examples of research involving coded human specimens, cell, cell lines, or data that is not human subjects research?
• 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 are the requirements for Exemption 4 (E4)?
• Is research that meets the criteria for Exemption 4 considered human subjects research?
• How can I determine whether my research meets the criteria for Exemption 4?
• What is meant by “existing” data or specimens?
• What is meant by “publicly available sources”?
• What is meant by “identifiers linked to the subjects”?

1. The specimens, cells, or data:

• Must be or must have been obtained from individuals who are alive; AND
• Must be or must have been obtained by an investigator conducting research

AND

2. The investigator EITHER:

• Must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals; OR
• Must be obtaining or have obtained individually identifiable private information.

IF providers of coded human specimen, cells, cell lines or data:

1. Obtained or will obtain the specimens or data, AND
2. Can link the specimens or data to living individuals, AND
3. Will also collaborate on other activities related to the conduct of a proposed research project with the investigators who obtain the specimens or data;

THEN both the providers and recipients will be considered to be involved in the conduct of the research and are conducting human subjects research.

Research that proposes the use of only cadaver specimens is not human subjects research, because, by definition, human subjects must be “living individuals.” Research involving cadaver specimens, therefore, is not regulated by 45 CFR Part 46, but may be governed by other Federal, state and local laws.

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 IRB-approved policies and procedures prohibiting release of identifiers or an agreement specifying that identifying information will not be shared with the investigator.

Research that involves only coded human biological specimens or coded private information/data from living individuals is not human subjects research under the HHS human subjects regulations (45 CFR Part 46) if:

(1) the specimens, cells, cell lines or private information/data were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals;
and
(2) 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 (note that the HHS regulations do not require the IRB to review and approve this agreement);
(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.

Refer to following guidance from the Office for Human Research Protections (OHRP) for additional information and examples: http://www.hhs.gov/ohrp/humansubjects/guidance/cdebiol.pdf.

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.

IF the repository/database obtains the specimens/data without identifiers, OR

IF 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,

THEN studies using the specimens/data from the repository/database are not human subjects research.

If your proposed studies meet these criteria, you should check “No” in Item 4, and you should consider including an explanation of why your research does not involve human subjects in the Human Subjects section of your application

If your proposed studies do not meet these criteria, you are proposing human subjects research. You should check “Yes” in Item 4 and complete the Human Subjects section of your application.

*Because NIH is not a covered entity, NIH cannot comment on the adequacy with which institutions address HIPAA requirements. NIH, therefore, cannot recognize the HIPAA Privacy Act as the law preventing the release of identifiers.

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.

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.