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Program Protection of Human Subjects Participating
in Research Programs Conducted or Supported by HRSA
Policy
HRSA Circular 03
I. Purpose
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.
II. Scope
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.
III. Definitions
A. Research
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.
IV. Basic Ethical Principles for Protecting Human
Subjects Participating in HRSA Conducted or Supported
Research
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.
B. Beneficence
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.
C. Justice
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.
V. HHS Regulations for the Protection of 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. The Code of Federal
Regulations is available electroncially from the Department
of Health and Human Services at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.
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.
VI. HRSA Programs Involving Human Subjects Research
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.
VII. Conduct of Research Under Human Subject Protection
Regulations, 45 CFR part 46
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.
2. Contracts
(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.
VIII. EXEMPTIONS FROM HUMAN SUBJECTS PROTECTION
REQUIREMENTS UNDER 45 CFR PART 46
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.
IX. Internet References for Protection of Human
Subject Research
Date: 1/21/04
Elizabeth M. Duke, Administrator
Health Resources and Services Administration
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