[Federal Register: March 25, 2005 (Volume 70, Number 57)]
[Notices]
[Page 15322-15327]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25mr05-56]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Protection of Human Subjects, Proposed Criteria for
Determinations of Equivalent Protection
AGENCY: Department of Health and Human Services, Office of the
Secretary.
ACTION: Notice.
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SUMMARY: The Office of Public Health and Science, Department of Health
and Human Services (HHS) solicits public comment on criteria that have
been recommended to the Office for Human Research Protections (OHRP)
for making determinations of whether procedures prescribed by
institutions outside the United States afford protections that are at
least equivalent to those provided in the Federal Policy for the
Protection of Human Subjects (codified by HHS as 45 CFR part 46,
subpart A, and equivalent regulations of 14 Departments and Agencies,
collectively referred to as the Federal Policy or the Common Rule).
DATES: Submit written or electronic comments on the recommended
criteria for making determinations of equivalent protection on or
before May 24, 2005.
ADDRESSES: Submit written comments to Ms. Gail Carter, Division of
Policy and Assurances, Office for Human Research Protections, 1101
Wootton Parkway, Suite 200, The Tower Building, Rockville, MD 20852,
telephone number (301) 402-4521 (not a toll-free number). Comments also
may be sent via facsimile to (301) 402-0527 or by e-mail to:
EQFRN@osophs.dhhs.gov.
FOR FURTHER INFORMATION CONTACT: Glen Drew, Office for Human Research
Protections, Office of Public Health and Science, The Tower Building,
1101 Wootton Parkway, Suite 200, Rockville, MD 20852, (301) 402-4994,
facsimile (301) 402-2071; e-mail: gdrew@osophs.dhhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
The HHS codification of the Federal Policy states at 45 CFR
46.101(h):
(h) When research covered by this policy takes place in foreign
countries, procedures normally followed in the foreign countries to
protect human subjects may differ from those set forth in this
policy. [An example is a foreign institution which complies with
guidelines consistent with the World Medical Assembly Declaration
(Declaration of Helsinki amended 1989) issued either by sovereign
states or by an organization whose function for the protection of
human research subjects is internationally recognized.] In these
circumstances, if a Department or Agency head determines that the
procedures prescribed by the institution afford protections that are
at least equivalent to those provided in this policy, the Department
or Agency head may approve the substitution of the foreign
procedures in lieu of the procedural requirements provided in this
policy. Except when otherwise required by statute, Executive Order,
or the Department or Agency head, notices of these actions as they
occur will be published in the Federal Register or will be otherwise
published as provided in Department or Agency procedures.
No formal findings of equivalent protection have been published in
the Federal Register since the Federal policy was finalized in June,
1991. Use of the authority provided by 45 CFR 46.101(h) has been
advocated by various parties, including the National Bioethics Advisory
Commission in its April, 2001 report ``Ethical and Policy Issues in
International Research: Clinical Trials in Developing Countries,'' and
the HHS Inspector General in the September, 2001 Report ``The
Globalization of Clinical Trials: A Growing Challenge in Protecting
Human Subjects.'' The authority of the Secretary of Health and Human
Services has been delegated to OHRP (68 FR 60392), and in considering
use of the 45 CFR 46.101(h) authority, OHRP recognized a need for using
consistent criteria as a basis for decisions regarding equivalent
protections. During 2002, the OHRP Director established a working group
of representatives from interested HHS agencies, with staff support
from OHRP, to consider potential criteria for use in making such
decisions. The working group delivered its report in July 2003. That
report recommends a framework
[[Page 15323]]
for implementing the existing regulatory authority of 45 CFR 46.101(h).
The full working group report recommends the approach and criteria
described in this notice and is available at http://www.hhs.gov/ohrp/international/EPWGReport2003.pdf
and the appendix table is available at
http://www.hhs.gov/ohrp/international/FPGWFramework.pdf, or by request
to either of the addresses given above.
II. Request for Comments
OHRP has solicited and considered comments from the other agencies
that have adopted the Federal Policy, and now solicits public comment
on the working group's recommended criteria for making determinations
whether procedures prescribed by institutions outside the United States
provide protections that are at least equivalent to those provided by
the Federal Policy. OHRP will consider all public comments in deciding
whether, and if so how, to proceed with implementing the authority
under 45 CFR 46.101(h). Draft guidance describing OHRP's proposed
method of implementing this authority would be published for public
comment before OHRP would issue final guidance on this topic.
OHRP neither endorses nor rejects the content, conclusions, or
recommendations in the working group's report, but particularly
solicits public comment on several questions related to the approach
and criteria recommended in the report:
1. Is the recommended approach appropriate for implementing the
authority under 45 CFR 46.101(h)?
1.a. Is it preferable to make determinations of equivalent
protections on the basis of submissions by individual institutions or
on the basis of national or international procedural standards that may
be relied upon by multiple institutions without repeated assessments?
2. Could an alternative approach provide equal or greater
effectiveness and efficiency for implementation of this authority?
2.a. If so, what approach and why would effectiveness or efficiency
be improved?
3. Do the recommended criteria appropriately and adequately
describe the protections provided to human subjects by the Federal
Policy?
3.a. Do the regulatory provisions the working group cited as
contributing to particular protections provided by the Federal Policy
relate directly to those protections? (See Table 1.)
3.b. Should other regulatory provisions be cited as relating to
particular protections?
3.c. What, if any, alterations or additions to the proposed
criteria would be helpful in assessing whether procedures followed in
foreign countries provide protections at least equivalent to those
provided by the Federal Policy?
4. Is the procedure recommended by the working group for seeking a
finding of equivalent protections under 45 CFR 46.101(h) appropriate?
III. Framework Proposed in Working Group Report
The working group report concluded that
The primary focus of the U.S. policy is the accountability of
the research institution for the welfare and rights of human
subjects. The overarching goal of the specific accountability
mechanisms and procedures described in the policy is to establish
expectations of ethical conduct within the research institution. The
responsibility for achieving these aims is shared by the
institution, the Institutional Review Board (IRB), or Research
Ethics Committee (REC), and the relevant U.S. Agency or Department
head. Although investigators are critical actors in achieving these
goals, the policy provides very little explicit guidance to
investigators and therefore suggests that the protection of human
subjects depends largely on the proper promotion and conscientious
execution of standard practices and procedures, including those
related to research ethics review, within the institution.
The working group proposed an approach to equivalent protections
that involves five separate steps, the first of which is to identify
the specific protections provided by 45 CFR part 46 subpart A, followed
by three steps of determining the equivalence of the protections
offered by the set of procedures employed in foreign research
institutions, and the fifth step is to provide an assurance that these
procedures will be followed within the institution.
Steps in determining equivalence.
(1) Articulation of the specific protections embodied in 45 CFR
part 46 subpart A.
(2) Assessment of the protections provided by the institution's
procedures.
(3) Comparison of the protections provided by the institution's
procedures with those provided by 45 CFR part 46 subpart A and
determination whether or not the institution's procedures provide at
least equivalent protections.
(4) Approval of the relevant department or agency head for the
substitution of the institutional procedures in lieu of the procedures
of 45 CFR part 46 subpart A.
Mechanism of assurance with OHRP.
(5) Assurance from the institution that the substituted procedures
will be followed in the conduct of human subjects research funded by
HHS. The assurance will be completed and filed with OHRP.
The working group identified 7 specific protections afforded by 45
CFR part 46 subpart A that it recommended be included in the
determination of equivalence:
Establish norms of ethical conduct and due diligence in review and
performance of research within the institution;
Ensure adequate authority and independence of the IRB/Research
Ethics Committee;
Protect against biased decision making and arbitrary decisions in
research ethics review;
Ensure sufficient quality and comprehensiveness of research ethics
review;
Ensure research ethics review and oversight are commensurate with
risks to research subjects and vulnerability of the study population;
Protect against unnecessary or unjustified risk throughout the
course of the study; and
Ensure voluntary participation after adequate disclosure of
information related to the study.
The working group concluded that each of these protections is
necessary for a determination of equivalent protections. It also
concluded that each protection may be achieved in a number of different
ways, including the use of procedures that differ from those provided
in 45 CFR part 46 subpart A. In making determinations of equivalence,
the working group recommended that OHRP assess whether the procedures
employed by the foreign institution are able to satisfy each of these
protections individually and in the aggregate.
The working group also recommended that, based on a recommendation
from OHRP following a comparison of the protections provided by the
institution's procedures and 45 CFR part 46 subpart A, the Secretary of
HHS may find that the institution's procedures provide at least
equivalent protections and approve the substitution of these procedures
in lieu of those of 45 CFR part 46 subpart A. The working group
concluded that a determination of equivalent protections does not
affect OHRP's oversight authority for HHS funded research conducted
within the institution. The working group considered the authority of
OHRP to conduct on-going assessment of the equivalence of the
institution's procedures and protections to be a protection implied in
45 CFR part 46 subpart A, though not part of the
[[Page 15324]]
assessment of the protections provided by an institution's procedures.
Similarly, the substitution of the institution's procedures in lieu
of those of 45 CFR part 46 subpart A does not obviate the need for the
institution to enter into an assurance with OHRP that the procedures
will be followed by the institution in the conduct of HHS funded
research. An assurance is a legal promise to comply with certain
conditions attached to the provision of U.S. federal research funding.
To show the relationship between the Federal Policy and each of the
seven protections the working group discerned in the Federal Policy, it
developed a table matching the protections with provisions of 45 CFR
part 46 subpart A that contribute to each of the protections. The
center column of the table provides examples of procedures that the
working group thought institutions might use to provide the protection
related to those regulatory provisions. The table appears below.
Appendix
Table 1.--Framework for Equivalent Protections
------------------------------------------------------------------------
Example 45 CFR part 46
Specific protection procedures subpart A authority
------------------------------------------------------------------------
INSTITUTIONAL RESPONSIBILITIES
------------------------------------------------------------------------
Establish norms of ethical --Institutional 46.103(a); 46.103 (f)
conduct and due diligence in statement of Establish and
review and performance of principles. satisfy terms of
research within the --Procedures for assurance.
institution. review. 46.103(b)(1) Develop
--Procedures for or adopt statement
reporting to of principles
Research Ethics governing
Committee (REC). institution's human
--Procedures for subjects protections
REC record responsibilities.
keeping. 46.103(b)(4) Ensure
initial and
continuing review of
research; determine
necessary frequency
of review for each
study; determine
where external
verification is
necessary that no
material changes
have occurred since
last IRB review;
establish procedures
for IRB reporting of
findings and actions
to institution and
investigator(s).
--Statement of 46.103(b)(5)
investigator Establish and 46.108
responsibilities. (a) follow written
--Effective procedures for
dissemination of prompt reporting to
REC submission IRB and
procedures. Institutional
--Investigator officials of:
training. --Unanticipated
problems involving
risk to subjects or
others, or non-
compliance with the
policy;
--Suspension or
termination of IRB
approval.
46.103(b)(4) Ensuring
prompt reporting to
the IRB of proposed
changes in a
research activity,
and for ensuring
that such changes in
approved research,
during the period
for which IRB
approval has already
been given, may not
be initiated without
IRB review and
approval except when
necessary to
eliminate apparent
immediate hazards to
the subject.
46.103(b)(5) Written
procedures for
ensuring prompt
reporting to the
IRB, appropriate
institutional
officials, and the
Department or Agency
head of (i) any
unanticipated
problems involving
risks to subjects or
others or any
serious or
continuing
noncompliance with
this policy or the
requirements or
determinations of
the IRB; and (ii)
any suspension or
termination of IRB
approval.
46.115 An
institution, or when
appropriate an IRB,
shall prepare and
maintain adequate
documentation of IRB
activities. The
records required by
this policy shall be
retained for at
least 3 years, and
records relating to
research which is
conducted shall be
retained for at
least 3 years after
completion of the
research. All
records shall be
accessible for
inspection and
copying by
authorized
representatives of
the Department or
Agency at reasonable
times and in a
reasonable manner.
-------------------------------
Ensure adequate authority, and --Documentation 46.109(a); 46.109 (e)
independence of IRB. of REC authority. grant and ensure
necessary authority
for IRB, including:
discretion to
review, approve,
require
modifications, or
disapprove research
activities; increase
information for
informed consent,
observe, or have
third party observe
consent process and
research.
46.112 Research
covered by this
policy that has been
approved by an IRB
may be subject to
further appropriate
review and approval
or disapproval by
officials of the
institution.
However, those
officials may not
approve the research
if it has not been
approved by an IRB.
46.113 An IRB shall
have authority to
suspend or terminate
approval of research
that is not being
conducted in
accordance with the
IRB's requirements
or that has been
associated with
unexpected serious
harm to subjects.
46.110(b) Under an
expedited review
procedure, the
review may be
carried out by the
IRB chairperson or
by one or more
experienced
reviewers designated
by the chairperson
from among members
of the IRB. In
reviewing the
research, the
reviewers may
exercise all of the
authorities of the
IRB except that the
reviewers may not
disapprove the
research. A research
activity may be
disapproved only
after review in
accordance with the
non-expedited
procedure set forth
in Sec. 46.108(b).
[[Page 15325]]
--REC member(s) 46.107(d) Each IRB
unaffiliated shall include at
with the least one member who
institution. is not otherwise
affiliated with the
institution and who
is not part of the
immediate family of
a person who is
affiliated with the
institution.
-------------------------------
Research Ethics Committee (REC) Responsibilities
Appropriate Scope and Quality of Review:
------------------------------------------------------------------------
Protect against biased --Public 46.103(b)3 A list of
decision making and arbitrary accessibility of IRB members
decisions in research ethics REC membership identified by name;
review. and affiliation earned degrees;
within representative
institution. capacity;
indications of
experience such as
board
certifications,
licenses, etc.,
sufficient to
describe each
member's chief
anticipated
contributions to IRB
deliberations.
Disclosure of any
employment or other
relationship between
each [IRB] member
and the institution.
46.107(a) IRB
membership. (see 45
CFR 46 for specific
criteria).
46.107(b) Gender
balance.
--Institutional 46.107(c) Each IRB
policy on REC shall include at
conflict of least one member
interest. whose primary
concerns are in
scientific areas and
at least one member
whose primary
concerns are in
nonscientific areas.
--REC membership 46.107(d) Each IRB
to reflect: shall include at
independence, least one member who
unaffiliated is not otherwise
member(s). affiliated with the
institution and who
is not part of the
immediate family of
a person who is
affiliated with the
institution.
46.107(e) No IRB may
have a member
participate in the
IRB's initial or
continuing review of
any project in which
the member has a
conflicting
interest, except to
provide information
requested by the
IRB.
-------------------------------
Ensure sufficient quality and --REC membership 46.107(b) Gender
comprehensiveness of review. to reflect balance.
competence, 46.107(c) Each IRB
comprehensivenes shall include at
s of review; least one member
adequate whose primary
expertise for concerns are in
study scientific areas and
population; at least one member
diversity of whose primary
representation; concerns are in
gender balance. nonscientific areas.
46.107(d) Each IRB
shall include at
least one member who
is not otherwise
affiliated with the
institution and who
is not part of the
immediate family of
a person who is
affiliated with the
institution.
46.107(f) An IRB may,
in its discretion,
invite individuals
with competence in
special areas to
assist in the review
of issues which
require expertise
beyond or in
addition to that
available on the
IRB. These
individuals may not
vote with the IRB.
46.108(b) Except when
an expedited review
procedure is used
(see Sec. 46.110),
review proposed
research at convened
meetings at which a
majority of the
members of the IRB
are present,
including at least
one member whose
primary concerns are
in nonscientific
areas. In order for
the research to be
approved, it shall
receive the approval
of a majority of
those members
present at the
meeting.
Ensure research ethics review --Procedures for 46.109(e) An IRB
and oversight are continuing shall conduct
commensurate with risks to review and continuing review of
research subjects and monitoring research covered by
vulnerability of the study commensurate this policy at
population. with risk. intervals
--Procedures for appropriate to the
evaluating risk degree of risk, but
and benefit. not less than once
Procedures for per year, and shall
reviewing have authority to
selection of observe or have a
subjects and third party observe
safeguards the consent process
provided. and the research.
--Procedures for 46.110(b) Expedited
IRB reporting to Review.
investigators. 46.111(a)(2) In
evaluating risks and
benefits, the IRB
should consider only
those risks and
benefits that may
result from the
research (as
distinguished from
risks and benefits
of therapies
subjects would
receive even if not
participating in the
research). The IRB
should not consider
possible long-range
effects of applying
knowledge gained in
the research (for
example, the
possible effects of
the research on
public policy) as
among those research
risks that fall
within the purview
of its
responsibility.
46.111(a)(3)
Selection of
subjects as
equitable. In making
this assessment the
IRB should take into
account the purposes
of the research and
the setting in which
the research will be
conducted and should
be particularly
cognizant of the
special problems of
research involving
vulnerable
populations, such as
children, prisoners,
pregnant women,
mentally disabled
persons, or
economically or
educationally
disadvantaged
persons.
46.113 Any suspension
or termination or
approval shall
include a statement
of the reasons for
the IRB's action and
shall be reported
promptly to the
investigator,
appropriate
institutional
officials, and the
Department or Agency
head.
-------------------------------
[[Page 15326]]
Protect against unnecessary or --REC membership 46.107(a) If an IRB
unjustified risk throughout policy reflects regularly reviews
the course of the study. adequate research that
expertise and involves a
experience. vulnerable category
of subjects, such as
children, prisoners,
pregnant women, or
handicapped or
mentally disabled
persons,
consideration shall
be given to the
inclusion of one or
more individuals who
are knowledgeable
about and
experienced in
working with these
subjects.
--Policy has 46.111(a)(1) Risks to
provisions for subjects are
supplementing minimized: (i) by
expertise, using procedures
experience and which are consistent
disciplinary with sound research
perspective as design and which do
required. not unnecessarily
expose subjects to
risks, and (ii)
whenever
appropriate, by
using procedures
already being
performed on the
subjects for
diagnostic or
treatment purposes.
46.111(a)(2) Risks to
subjects are
reasonable in
relation to
anticipated
benefits, if any, to
subjects, and the
importance of the
knowledge that may
reasonably be
expected to result.
--Procedures for 46.111(a)(3)
review of Selection of
minimization of subjects is
risk. equitable. In making
this assessment the
IRB should take into
account the purposes
of the research and
the setting in which
the research will be
conducted and should
be particularly
cognizant of the
special problems of
research involving
vulnerable
populations, such as
children, prisoners,
pregnant women,
mentally disabled
persons, or
economically or
educationally
disadvantaged
persons.
--Procedures for 46.111(b) When some
reviewing or all of the
selection of subjects are likely
subjects and to be vulnerable to
safeguards coercion or undue
provided. influence, such as
children, prisoners,
pregnant women,
mentally disabled
persons, or
economically or
educationally
disadvantaged
persons, additional
safeguards have been
included in the
study to protect the
rights and welfare
of these subjects.
46.111(a)(6) When
appropriate, the
research plan makes
adequate provision
for monitoring the
data collected to
ensure the safety of
subjects.
--Procedures for 46.109(e) An IRB
continued shall conduct
oversight and continuing review of
monitoring. research covered by
this policy at
intervals
appropriate to the
degree of risk, but
not less than once
per year, and shall
have authority to
observe or have a
third party observe
the consent process
and the research.
-------------------------------
Ensure voluntary participation --Policies on 46.116 Except as
after adequate disclosure of obtaining provided elsewhere
information related to the verifiable in this policy, no
study. informed consent. investigator may
involve a human
being as a subject
in research covered
by this policy
unless the
investigator has
obtained the legally
effective informed
consent of the
subject or the
subject's legally
authorized
representative. An
investigator shall
seek such consent
only under
circumstances that
provide the
prospective subject
or the
representative
sufficient
opportunity to
consider whether or
not to participate
and that minimize
the possibility of
coercion or undue
influence.
46.111(a)(4) Informed
consent will be
sought from each
prospective subject
or the subject's
legally authorized
representative, in
accordance with, and
to the extent
required by Sec.
46.116.
46.111(a)(5) Informed
consent process will
be appropriately
documented, in
accordance with, and
to the extent
required by Sec.
46.117.
46.116 The
information that is
given to the subject
or the
representative shall
be in language
understandable to
the subject or the
representative.
46.117(a) Except as
provided in
paragraph (c) of
this section,
informed consent
shall be documented
by the use of a
written consent form
approved by the IRB
and signed by the
subject or the
subject's legally
authorized
representative.
--Policies on 46.109(b) An IRB
types of shall require that
information to information given to
be disclosed in subjects as part of
the informed informed consent is
consent process. in accordance with
Sec. 46.116. The
IRB may require that
information, in
addition to that
specifically
mentioned in Sec.
46.116, be given to
the subjects when in
the IRB's judgment
the information
would meaningfully
add to the
protection of the
rights and welfare
of subjects.
46.109(c) An IRB
shall require
documentation of
informed consent or
may waive
documentation in
accordance with Sec.
46.117.
46.109(e) An IRB
shall conduct
continuing review of
research covered by
this policy at
intervals
appropriate to the
degree of risk, but
not less than once
per year, and shall
have authority to
observe or have a
third party observe
the consent process
and the research.
[[Page 15327]]
46.111(a)(4) Informed
consent will be
sought from each
prospective subject
or the subject's
legally authorized
representative, in
accordance with, and
to the extent
required by Sec.
46.116.
46.116(a)(1-8)
Necessary elements
of disclosure.
46.116(b)(1-6)
Necessary elements
of disclosure.
46.116(c)(1-2) Waiver
of informed consent.
46.116(d)(1-4)
Approval of
alternate consent
procedures or
waiver.
46.117(a) Written
informed consent.
------------------------------------------------------------------------
Bernard A. Schwetz,
Director, Office for Human Research Protections.
[FR Doc. 05-5947 Filed 3-24-05; 8:45 am]
BILLING CODE 4150-36-P