NOTE: THIS GUIDANCE REPLACES OHRP’S AUGUST 10, 2004 GUIDANCE ENTITLED “GUIDANCE ON RESEARCH INVOLVING CODED PRIVATE INFORMATION OR BIOLOGICAL SPECIMENS.” CLICK HERE FOR THE AUGUST 10, 2004 GUIDANCE. THIS GUIDANCE HAS BEEN UPDATED TO BE CONSISTENT WITH THE CONTENT OF OHRP’S OCTOBER 16, 2008 “GUIDANCE ON ENGAGEMENT OF INSTITUTIONS IN HUMAN SUBJECTS RESEARCH.”

This guidance represents OHRP’s current thinking on this topic and should be viewed as recommendations unless specific regulatory requirements are cited. The use of the word must in OHRP guidance means that something is required under HHS regulations at 45 CFR part 46. The use of the word should in OHRP guidance means that something is recommended or suggested, but not required. An institution may use an alternative approach if the approach satisfies the requirements of the HHS regulations at 45 CFR part 46. OHRP is available to discuss alternative approaches at 240-453-6900 or 866-447-4777.

Date: October 16, 2008

Scope:This document applies to research involving coded private information or human biological specimens (hereafter referred to as “specimens”) that is conducted or supported by HHS. This document does the following:

Provides guidance as to when research involving coded private information or specimens is or is not research involving human subjects, as defined under HHS regulations for the protection of human research subjects (45 CFR part 46). Reaffirms OHRP policy (see OHRP guidance on repository activities http://www.hhs.gov/ohrp/regulations-and-policy/guidance/issues-to-consider-in-use-of-stored-data-or-tissues/index.html and research on human embryonic stem cells http://www.hhs.gov/ohrp/sites/default/files/ohrp/archive/references/HESCGuidance.pdf) that, under certain limited conditions, research involving only coded private information or specimens is not human subjects research. Clarifies the distinction between (a) research involving coded private information or specimens that does not involve human subjects and (b) human subjects research that is exempt from the requirements of the HHS regulations. (4) References pertinent requirements of the HIPAA Privacy Rule that may be applicable to research involving coded private information or specimens.

NOTE: Some HHS conducted or supported research involving coded private information or specimens may be subject to Food and Drug Administration (FDA) regulations. The FDA regulatory definitions of human subject (21 CFR 50.3(g), 21 CFR 56.102(e)) and subject (21 CFR 312.3(b), 21 CFR 812.3(p)) differ from the definition of human subject under HHS regulations at 45 CFR 46.102(f). This guidance document does not apply to research regulated by FDA that involves coded private information or specimens. Anyone needing guidance on such FDA-regulated research should contact the FDA.

Target Audience: Institutional review boards (IRBs), investigators, and funding agencies that may be responsible for review or oversight of human subjects research conducted or supported by HHS.

Background:

HHS regulations define research at 45 CFR 46.102(d) as follows:

Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.

HHS regulations define human subject at 45 CFR 46.102(f) as follows:

Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains data through intervention or interaction with the individual, or identifiable private information. Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject. 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 which has been provided for specific purposes by an individual and which 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 (bolding added for emphasis).

For purposes of this document, coded means that:

identifying information (such as name or social security number) that would enable the investigator to readily ascertain the identity of the individual to whom the private information or specimens pertain has been replaced with a number, letter, symbol, or combination thereof (i.e., the code); and a key to decipher the code exists, enabling linkage of the identifying information to the private information or specimens.

OHRP considers the term investigator to include anyone involved in conducting the research. OHRP does not consider the act of solely providing coded private information or specimens (for example, by a tissue repository) to constitute involvement in the conduct of the research. Note that if the individuals who provide coded information or specimens collaborate on other activities related to the conduct of this research with the investigators who receive such information or specimens, then OHRP would consider such additional activities to constitute involvement in the conduct of the research. Examples of such additional activities include, but are not limited to: (1) the study, interpretation, or analysis of the data resulting from the coded information or specimens; and (2) authorship of presentations or manuscripts related to the research.

Guidance:

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. Obtaining identifiable private information or identifiable specimens includes, but is not limited to:

using, studying, or analyzing for research purposes identifiable private information or identifiable specimens that have been provided to investigators from any source; and using, studying, or analyzing for research purposes identifiable private information or identifiable specimens that were already in the possession of the investigator.

In general, OHRP 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. For example, OHRP does not consider research involving only coded private information or specimens to involve human subjects as defined under 45 CFR 46.102(f) if the following conditions are both met:

the private information 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: 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); 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 there are other legal requirements prohibiting the release of the key to the investigators, until the individuals are deceased.

This guidance applies to existing private information and specimens, as well as to private information and specimens to be collected in the future for purposes other than the currently proposed research. The following are examples of private information or specimens that will be collected in the future for purposes other than the currently proposed research: (1) medical records; and (2) ongoing collection of specimens for a tissue repository.

In some cases an investigator who obtains coded private information or specimens about living individuals under one of the conditions cited in 2(a)-(c) above may (1) unexpectedly learn the identity of one or more living individuals, or (2) for previously unforseen reasons now believe that it is important to identify the individual(s). If, as a result, the investigator knows, or may be able to readily ascertain, the identity of the individuals to whom the previously obtained private information or specimens pertain, then the research activity now would involve human subjects under the HHS regulations. Unless this human subjects research is determined to be exempt under HHS regulations at 45 CFR 46.101(b), IRB review of the research would be required. Informed consent of the subjects also would be required unless the IRB approved a waiver of informed consent under HHS regulations at 45 CFR part 46.116(c) or (d).

Who Should Determine Whether Human Subjects are Involved in Research

OHRP recommends that institutions have policies in place that designate the individual or entity authorized to determine whether research involving coded private information or specimens constitutes human subjects research. The person(s) authorized to make the determination should be knowledgeable about the human subject protection regulations. In addition, the institution should ensure the appropriate communication of such a policy to all investigators. OHRP recommends that investigators not be given the authority to make an independent determination that research involving coded private information or specimens does not involve human subjects.

Research not Involving Human Subjects Versus Exempt Human Subjects Research

OHRP is aware that questions often are raised regarding the distinction between research involving private information or specimens that does not involve human subjects (as above) and human subjects research that is exempt from the requirements of HHS regulations at 45 CFR part 46. This distinction can be made easier by always using the following sequential assessment when evaluating a particular activity conducted or supported by HHS:

Does the activity involve research? If yes, proceed to question (2). If no, 45 CFR part 46 does not apply to the activity. Does the activity involve human subjects? If yes, proceed to question (3). If no, 45 CFR part 46 does not apply to the activity.



In analyzing a particular activity under the second question, it is important to focus on what is being obtained by the investigators. If the investigators are not obtaining either data through intervention or interaction with living individuals, or identifiable private information, then the research activity does not involve human subjects. Therefore, no assessment of the research activity using the third question below regarding exemptions is required because the exemptions provided for under 45 CFR 46.101(b) apply only to research involving human subjects. Is the activity exempt under HHS regulations at 45 CFR 46.101(b)? If yes, 45 CFR part 46 does not apply. If no, 45 CFR part 46 does apply.



With respect to research involving private information and specimens, the exemption that is most frequently relevant is the exemption under HHS regulations at 45 CFR 46.101(b)(4):



"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."



Having determined under the second question above that a research activity involves human subjects because the investigators are obtaining identifiable private information or specimens, assessment under the exemption at 45 CFR 46.101(b)(4) focuses, in part, on: (1) whether the data or specimens are existing at the time the research is proposed to an institutional official or IRB for a determination of whether the research is exempt, and (2) how the data or information is recorded by the investigators. This exemption would not apply if the investigators, having obtained identifiable private information or specimens from existing records or specimens, record the data or information in a coded manner, since the code would enable subjects to be identified through identifiers linked to the subjects.

To demonstrate how the determination of whether a research study is human subjects research differs from the determination of whether a human subjects research study is exempt under 45 CFR 46.101(b)(4), consider the following examples, in which an investigator obtains health information of living patients who were treated for arthritis with either Drug A or Drug B. The investigator obtains this information in order to evaluate and compare the treatment outcomes associated with these two drugs:

An investigator obtains only coded information on the treatment outcomes of patients treated for arthritis with Drug A versus Drug B from the patients’ treating physician. The only involvement of the treating physician is to provide coded information to the investigator. The investigator and the treating physician enter into an agreement prohibiting the release of the key to decipher the code to the investigator under any circumstances, until the individuals are deceased. In this example, the investigator is not conducting human subjects research because the investigator cannot readily ascertain the patients’ identity. An investigator obtains individually identifiable information on the treatment outcomes of patients treated for arthritis with either Drug A or Drug B by viewing patients’ existing individually identifiable medical records at the clinics where the patients were treated. The investigator records the patients’ treatment outcomes in a coded manner that could permit the identification of the patients. In this example, the investigator is conducting human subjects research because the investigator is obtaining identifiable private information from patients’ (and now subjects’) medical records. The study would not be exempt under 45 CFR 46.101(b)(4) since the investigator is recording the information in a coded manner, thus allowing the subjects to be identified indirectly through identifiers linked to the subjects. An investigator obtains individually identifiable information on the treatment outcomes of patients treated for arthritis with either Drug A or Drug B by viewing patients’ existing individually identifiable medical records at the clinics where the patients were treated. The investigator records only patient age, sex, diagnosis, treatment, and health status at the end of 6 months of treatment so that the investigator cannot link the recorded information back to the patients. In this example, the investigator is conducting human subjects research because the investigator is obtaining identifiable private information from patients’ (and now subjects’) medical records. However, the study would be exempt under 45 CFR 46.101(b)(4) since the investigator records the information in such a manner that subjects cannot be identified either directly or indirectly through identifiers linked to the subjects.

Comparison to the HIPAA Privacy Rule

The Privacy Rule is a Federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 (see 45 CFR part 160 and subparts A and E of part 164). The Privacy Rule permits covered entities under the Rule 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; the code could not be translated to identify the individual; and the covered entity under the Privacy Rule does not use or disclose the code for other purposes or disclose the mechanism for re-identification (see HHS guidance entitled, Institutional Review Boards and the HIPAA Privacy Rule, page 6, Q and A #3, at http://privacyruleandresearch.nih.gov/pdf/IRB_Factsheet.pdf).

Regarding condition (1) above, in contrast to the Privacy Rule, information that is linked with a code derived from identifying information or related to information about the individual is not considered to be individually identifiable under the HHS regulations for the protection of human subjects at 45 CFR 46.102(f), if the investigators cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimen pertains. Therefore, some coded information, in which the code has been derived from identifying information linked to or related to the individual, would be individually identifiable under the Privacy Rule, but might not be individually identifiable under 45 CFR part 46.

If you have specific questions about how to apply this guidance, please contact OHRP by phone at (866) 447-4777 (toll-free within the U.S.), (240) 453-6900, or by e-mail at ohrp@hhs.gov.

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