This directive establishes policies and procedures for ensuring appropriate implementation of Department of Health and Human Services (HHS) regulations for the protection of human subjects (45 CFR part 46) for research programs conducted or supported by the Health Resources and Services Administration (HRSA).
It gives guidance for compliance with HHS regulations for the protection of human research subjects. It states HRSA policy for various levels of protection applicable to HRSA programs, and explains how to determine the protection level appropriate to each program. It provides guidance on the exemption for certain research from the coverage of 45 CFR Part 46 for certain research on "public benefit or service" programs, requiring evaluation of such claims by program staff and approval by a HRSA Committee for Human Research Protections.
This policy applies to all research activities involving human subjects conducted or supported by any HRSA Bureau, Office, or program (see Section III A, for definitions of research and human subject). Support includes all HRSA grants, cooperative agreements, and contracts.
HHS regulations at 45 CFR 46.102(d) defines "research" as 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." Some kinds of surveys or service utilization studies that HRSA conducts or supports may fit this definition of research. For the purposes of HRSA policy, "research" should include all HRSA-conducted or supported epidemiological and service utilization studies, surveys, and evaluations involving a systematized collection and analysis of information about living individuals for the purpose of developing or contributing to generalizable knowledge, whether or not these activities are conducted or supported under a program which is considered "research" for other purposes. "Research" would not ordinarily include public or personal health service programs that collect information solely to establish eligibility for public health services or benefits, or solely to record or evaluate the delivery of such services for internal program purposes.
B. Human subject
HHS regulations at 45 CFR 46.102(f) define a "human subject" as a living individual about whom an investigator conducting research (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered, (for example venipuncture) and manipulation 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. Human subjects in HRSA conducted or supported research may include patients, clients, or beneficiaries who receive services.
On September 30, 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research submitted to the President its report entitled "The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The Belmont Report sets forth the following three basic ethical principles underlying the acceptable conduct of research involving human subjects:
A. Respect for persons
Involves a recognition of the personal dignity and autonomy of individuals, and special protections for those persons with diminished autonomy. The principle of respect for persons underlies the need to obtain informed consent. Potential subjects should be treated as individuals capable of deliberate judgment; they must be given the opportunity to be fully informed about, and to choose voluntarily and without coercion, what will or will not happen to them. At the same time, appropriate protection must be offered to persons with diminished capacity for self-determination.
Entails an obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks of harm. The principle of beneficence underlies the need to engage in a risk/benefit analysis and to minimize risks.
Requires that the benefits and burdens of research be distributed fairly. Participants should be treated fairly. Selection of participants should be equitable so that benefits and burdens are shared fairly at both the individual and societal level.
These three principles are now accepted as the three quintessential requirements for the ethical conduct of research involving human subjects.
HHS regulations for the protection of human research subjects are set forth in Title 45 of the Code of Federal Regulations, part 46. Human subjects participating in HRSA-conducted or supported research must be afforded the protections provided for under these regulations.
HRSA staff involved in the conduct or oversight of research and demonstration projects should become familiar with the provisions of these regulations, the background of these regulations, and ethical principles governing the conduct of research on human subjects (see the Belmont Report). Extensive historical review and additional ethical guidance can be found in the Final Report of the Advisory Committee on Human Radiation Experiments, October, 1995, GPO Document 061-000-00-848-9.
Under HHS regulations at 45 CFR 46.103(a), each institution engaged in human subjects research conducted or supported by HRSA must have an approved applicable assurance of compliance on file with the HHS Office for Human Research Protections (OHRP), unless the research is exempt under HHS regulations at 45 CFR 46.101(b). Of note, some public benefit and service programs are exempt from HHS regulations under the provisions of 45 CFR 6.101(b)(5); criteria for such exemption are discussed in Federal Register 48: 9266-9270, March 4, 1983. The transfer of human research protection functions from the National Institutes of Health, Office for Protection from Research Risks, to the OHRP, Office of the Secretary, occurred on June 13, 2000.
Under HHS regulations at 45 CFR 46.103(f), each institution engaged in non-exempt research involving human subjects conducted or supported by HRSA must certify to appropriate officials at HRSA Bureaus and Offices that each application or proposal for human subjects research has been reviewed and approved by an institutional review board (IRB) designated under the institution's OHRP-approved assurance of compliance.
HRSA, through its Bureaus and Offices, administers a variety of service delivery and demonstration programs. While HRSA programs are not generally described as research programs, some HRSA-conducted or supported demonstration, evaluation, or service utilization studies may be designed to contribute to generalizable knowledge, and would be considered "research" as defined by HHS regulations at 45 CFR 46.101(d). HRSA Bureaus and Offices also administer some specific research programs and a variety of epidemiological and service utilization studies, surveys, and evaluations that should be considered, at least in part, "research."
HRSA policy considers that any service demonstration program, survey, or service utilization or evaluation study that involves obtaining individually identifiable private information about living individuals for purposes other than ordinary treatment, prevention, administrative, or project management purposes, may contain a "research" element. If any program conforms to the regulatory definition of "research," it must comply with an appropriate level of subject-protection procedures.
Because some HRSA staff are engaged in research involving human subjects, HRSA applied for, and now holds, an OHRP-approved Federal-wide Assurance (FWA) which sets out the responsibilities and procedures that must be followed whenever HRSA staff become engaged in the conduct of non-exempt research involving human subjects (see a summary of HRSA's responsibilities under its FWA). Among these are assurance that the institution will be guided by the ethical principles in the Belmont Report and compliance with 45 CFR part 46 and all of its subparts. Under its FWA, HRSA has designated the Centers for Disease Control and Prevention, National Center for Health Statistics (NCHS) IRB to review research proposals in accordance with 45 CFR part 46. Staff support for the IRB is provided by NCHS.
HRSA is committed to ensuring that all human subjects participating in any research activities that HRSA conducts or supports are appropriately protected, regardless of whether the research is exempt under HHS regulations at 45 CFR 46.101(b). This directive thus charges Associate Administrators and Office Directors to identify all research programs involving human subjects conducted or supported by their units, and ensure that they provide appropriate human subjects protections. This document explains specific criteria that can aid in determining the level of protection required. If exemption from the requirements of HHS regulations at 45 CFR part 46 is proposed, the directive prescribes that the program manager will submit his/her proposal to an appropriate official or body and obtain concurrence that the proposed claim of exemption is proper. Otherwise, the document prescribes that all requirements of 45 CFR part 46 will be complied with.
A. General Policy
All human subjects research activities conducted or supported by HRSA shall provide appropriate protections for human subjects, including, among other things, adequate provisions for minimizing risks to subjects, obtaining and documenting the legally effective informed consent of the subjects or the subjects legally authorized representative, protecting the privacy of subjects, and maintaining the confidentiality of data. All intramural and extramural humans subjects research activities conducted or supported by HRSA shall provide all "Basic Research Participant Protections" and comply with all applicable ethical guidelines and regulations.
In all HRSA programs, exempt or not, the confidentiality of client information must be protected by appropriate security procedures. Participation in any research project should be voluntary. Informed consent must be obtained before individually identifiable private data are to be collected for study purposes, unless informed consent is waived by an IRB under 45 CFR 46.116 (c) or (d). The informed consent must be documented by the use of a written consent form approved by the IRB and signed by the subject or the subjects legally authorized representative, unless the IRB waives documentation of consent under 45 CFR 46.117(c).
B. Identification of Programs or Projects Requiring Human Subjects Protection Measures
Each Bureau and Office will identify all programs and projects that contain research elements, i.e., activities that include any "systematic investigation including research, development, testing, and evaluation, designed to develop or contribute to generalizable knowledge." Many surveillance or evaluation activities contain research elements; if an activity contains research, subjects protection measures must be provided as appropriate to the specific situation involved. If a program or project meets the definition of research and involves human subjects, an appropriate level of human subjects protection will be determined as indicated below in Section VII C, Identification of Levels of Protection. If not, no further action is needed with respect to human subjects protection.
C. Identification of Levels of Protection
Each program manager or project director will determine the level of protection that is appropriate for each program or project.
There are two levels of protection that may apply to research projects involving human subjects:
1. For any activity defined as research, basic ethical requirements for human subjects protections as defined in the Belmont Report apply. These protections include, at a minimum: Respect for Persons; Beneficence; Justice; Privacy and Confidentiality; and Legal and Professional Standards. See Section IV, Basic Ethical Principles, for further information on these protections.
2. Specific regulatory requirements for additional protections, as set forth in 45 CFR part 46, may also apply. These require, among other things, that an Institutional Review Board approve protocols, data collection instruments and procedures, and consent forms and consent procedures. If these requirements apply, and there are no plans to request an exemption, proceed to Section VII D, Extramural Research Projects or Section VII E, Intramural Research Projects.
The level of protection which is to be required for any HRSA research program must be included in grant and project announcements, to enable applicants/offerors to address subject-protection issues appropriately. Programs must be designated in one of the following categories:
(1) overt research program, a service demonstration, survey, or service utilization study requiring Basic Research Subjects Protections, which has been determined to be exempt from institutional review requirements under 45 CFR 46.101(b); or
(2) An overt research program, an experimental service demonstration, survey, or service utilization study requiring human subjects protections as set forth in 45 CFR part 46.
D. Extramural Research Projects
In all requests, proposals, and applications for research activities involving human subjects, applicants or offerors for HRSA funds will be required to develop appropriate procedures for the protection of participants. All contractors and grantees will be required to comply with all applicable laws, regulations, and customary ethical practices for the protection of human subjects. For institutions engaged in non-exempt research activities involving human subjects supported by HRSA through grants, contracts, or other mechanisms, the filing of an appropriate Assurance of Compliance with HHS Policy for the Protection of Human Subjects with the HHS OHRP shall be accepted as adequate assurance of compliance with this policy.
In all research activities involving human subjects, it is HRSA's policy that grantees and contractors will ensure adequate protection of participants in accordance with the recommendations of the Belmont Report (Federal Register 44:23192, April 18, 1979). For programs which are not exempt from the provisions of 45 CFR part 46, awardees shall develop and implement appropriate procedures as called for in those regulations, submit their project plans to the appropriate IRBs for approval, and execute all necessary Assurances of Compliance with OHRP.
1. Grant or cooperative agreement programs
(a) For competing applications, the project officer will include a requirement that applicants state whether they hold an OHRP-approved assurance and, if so, provide Certification of IRB review and approval. Applicants without an assurance will be required to obtain an assurance from OHRP and provide Certification of IRB review and approval following HRSA's review of the application, but prior to award. Applicants needing guidance regarding assurances should be instructed to contact OHRP.
(b) For continuing applications, the project officer will include a requirement that applicants provide certification of IRB review and approval under an OHRP-approved assurance.
(c) The project officer will check all applications to see that required human subjects protection certifications and assurance information are included. If they are not included, applicants with an assurance will be advised to submit them before the application is formally reviewed. If certifications and assurance information have not been received in time for distribution to the reviewers, this will be flagged for the reviewers or review committee.
(d) The Grants Management or program staff will instruct the reviewers and/or review committee to identify grant applications that have human subjects protection issues that are not adequately addressed.
(e) The reviewers or review committee will describe any deficiencies in human subjects protection in their report, and may make recommendations regarding the design or suggest conditions of award.
(f) If the applicant does not hold an OHRP-approved assurance, the grants management officer will notify the applicant of the need to negotiate an assurance with OHRP and provide OHRP contact information for negotiation of an applicable assurance. The award should not be made until OHRP has approved the assurance, except in rare circumstances where appropriate restrictive language, developed in consultation with OHRP, is included as a condition of grant award.
For an applicant holding an OHRP - approved assurance, certification of IRB review and approval should be provided prior to research being initiated, except in rare circumstances where appropriate restrictive language, developed in consultation with OHRP, is included as a condition of grant award.
When applications involving human subjects research include additional collaborating (performance site) institutions which do not hold applicable OHRP -approved assurances, the grants management officer will notify the applicant of the need to negotiate an assurance with OHRP and provide OHRP contact information for negotiation of assurances for the collaborating institutions. In such cases, appropriate restrictive language, developed in consultation with OHRP, should be included as a condition of grant award.
(g) In all cases, the project officer will see that human subjects protection concerns are resolved before work on the project is initiated.
(a) The Project Officer will include a requirement in the Request for Proposals that proposals address the human subjects protection issues and include a plan for obtaining the necessary reviews and assurances as described above for competing applications in Section VII D 1 (a).
(b) The Contracting Officer or project officer will instruct the review committee to identify proposals that have human subjects protection issues that are not adequately addressed.
(c) The review committee will describe any deficiencies in human subjects protection in their report, and may recommend changes to the design or suggest appropriate contract provisions.
(d) In all cases, the project officer will see that all human subjects protection concerns are resolved, and any IRB Certification and Assurance have been satisfied, before work on the project is initiated.
E. Intramural Research Projects
HRSA bureau, offices, and centers conducting non-exempt research activities involving human subjects will comply with the Statement of Ethical Principles and Terms of Assurance for Protection of Human Subject provisions set forth in the HRSA FWA.
1. The program manager, project director, or principal investigator must arrange for an IRB review of the project by an IRB that is designated in the HRSA FWA. If the program manager, project director, or principal investigator wishes to use an alternate IRB not designated in the FWA, the requesting Bureau or Center must obtain a written Authorization Agreement signed by the IRB sponsoring Institution and the HRSA Signatory Official that complies with the designation provisions of OHRP and, that results in the inclusion and approval of the alternate IRB in the HRSA FWA by the OHRP.
2. The program manager, project director, or principal investigator will see that all human subjects protection concerns are resolved before beginning work on the project.
A. General Policy
There are two of several provisions allowing exemption from regulatory oversight requirements that are most frequently applicable to HRSA programs: the "public benefit and service program" exemption of 45 CFR 46.101(b) (5) and the "public or anonymous data" provisions of 45 CFR 46.101(b) (4). No HRSA-sponsored research activity shall be considered exempt from the requirements of 45 CFR part 46 unless it has been endorsed by the responsible Associate Administrator or Office Director to meet each of the criteria below specified, and if required by HRSA policy a request for exemption has been approved by the HRSA Committee for Human Research Protections.
If any intervention to be studied or any data-gathering process utilizes any experimental procedures or investigational drugs or devices, or requires or withholds any accepted treatment for study purposes, involves any significant physical invasion or intrusion on the privacy of participants, or places any patient, subject, or member of the target population at more than minimal risk (including risk of disclosure of information), all procedures required by 45 CFR part 46 will be followed, including mandatory oversight by a properly constituted IRB, the submission of an appropriate assurance of compliance to OHRP, and OHRP's approval of the assurance. No exemption from required review shall be claimed, even if the project or program might otherwise qualify for the "public benefit or service program" exemption of 45 CFR Section 46.101(b) (5). In no case shall a program, grantee, or contractor be prevented from submitting any such project or program for institutional review if it feels it appropriate for the protection of subjects.
Regardless of any exemption, the program manager or project director will ensure that the ethical protections outlined in the Belmont Report are applied to all research programs and projects involving human subjects. If the exemption request is disapproved, the project officer will additionally follow the procedures outlined in subsection V.B, Conduct of Research Under Human Subject Protection Regulations, 45 CFR part 46.
B. Public Benefit and Service Program Exemption
Guidance issued by the Office for Protection from Research Risks (the predecessor to OHRP) gives the following four criteria for use in determining when the exemption at 46.101(b)(5) would apply:
1. The program under study must deliver a public benefit (e.g., financial or medical benefits are provided under the Social Security Act) or service (e.g., social, supportive, or nutrition services as provided under the Older Americans Act.
2. The research or demonstration project must be conducted pursuant to specific federal statutory authority.
3. There must be no statutory authority that the project be reviewed by an IRB.
4. The project must not involve significant physical invasions or intrusions upon the privacy participants.
The program manager or project director may request an exemption under 45 CFR 46.101(b)(5) by submitting documentation to the responsible Associate Administrator or Office Director on how the program or project meets each of the above criteria. Upon examination and endorsement of compliance with HRSA and Department policy, the responsible Associate Administrator or Office Director will submit a request for exemption to the HRSA Committee for Human Research Protections for review and final approval.
C. Existing Data Documents, Records, and Specimens Exemption
Provisions of 45 CFR Part 46.101(b)(4) permit exemption of research involving the collection or study of existing 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.
The program manager or project director may request a Public or Anonymous Data exemption by submitting documentation to the responsible Associate Administrator or Office Director on how the program or project meets the applicable criteria. The Associate Administrator or Office Director will determine the appropriateness of the exemption by reference to the relevant criteria.
The Associate Administrator or Office Director may give final and definitive approval to a request for exemption when public records or publicly-available anonymous data sets (but not investigator-anonymized data) are the only data sources to be used. If existing data are to be anonymized by the investigator, requests for exemption shall be examined and endorsed by the responsible Associate Administrator or Office Director for compliance with HRSA and Department policy, and then submitted to the HRSA Committee for Human Research Protections for review and final approval.
D. Review and Processing of Requests for Exemption by the HRSA Committee for Human Research Protections
1. The HRSA Committee for Human Research Protections will provide project officers with guidelines on the format and content of requests for exemption from research subjects regulatory requirements.
2. If HRSA Committee for Human Research Protections review is required, within two weeks after receipt of a request for exemption, the Committee will review the documentation provided by the requesting Associate Administrator or Office Director. The requesting Bureau or program will provide any information required by the Committee in making its determination.
3. The Committee, by affirmative vote of two-thirds of its members eligible to vote, may determine that the claim of exemption meets the criteria of 45
CFR 46.101(b)(4) or (b)(5). Any member of the Committee employed by the proposing Bureau or Office will abstain from voting on any program sponsored by that Bureau or Office.
4. The Committee Chair will notify the Associate Administrator or Office Director in writing of its decision, briefly describing the exemption and the conditions under which the exemption was granted. If the Committee decides that the program or project is not exempt, the project officer will follow the procedures outlined in Section VII.A, Conduct of Research Under Human Subject Protection Regulations, 45 CFR part 46.
E. The Committee agrees that the program/project is exempt from regulatory requirements, the following procedures will apply.
1. Extramural Exempted Research
The project officer will include a statement in the request for proposal (RFP) or grant application guidance describing the exemption, the conditions under which the exemption was granted, and instructions for addressing human subjects protections if individual proposals do not meet the criteria for exemption (e.g., an applicant proposes an approach that involves some risk for participants).
2. Intramural Exempted Research
No further action is required.
Elizabeth M. Duke, Administrator
Health Resources and Services Administration