Human Testing; Proposed Plan and Description of Review Process
[Federal Register: February 8, 2005 (Volume 70, Number 25)]
[Notices]
[Page 6661-6667]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08fe05-60]
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ENVIRONMENTAL PROTECTION AGENCY
RIN: 2070-AD57
[OPP-2003-0132; FRL-7695-4]
Human Testing; Proposed Plan and Description of Review Process
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces EPA's plan to establish a comprehensive
framework for making decisions about the extent to which it will
consider or rely on certain types of research with human participants.
Among other actions the plan provides for: Issuing proposed and final
rules, and providing in this Notice a description of the Agency's case-
by-case process for evaluating human studies, which is to
[[Page 6662]]
remain in effect until superseded by rulemaking. This Notice invites
public comments on the overall plan and particularly on the current
case-by-case process.
DATES: Comments must be received on or before May 9, 2005.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number OPP-2003-0132, by one of the following methods:
? Agency website: http://www.epa.gov/edocket/. EDOCKET,
EPA's electronic public docket and comment system, is EPA's preferred
method for receiving comments. Follow the on-line instructions for
submitting comments.
? E-mail: Comments may be sent by e-mail to
opp-docket@epa.gov, Attention: Docket ID Number OPP-2003-0132.
? Mail: Public Information and Records Integrity Branch
(PIRIB) (7502C), Office of Pesticide Programs (OPP), Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001, Attention: Docket ID Number OPP-2003-0132.
? Hand delivery: Public Information and Records Integrity
Branch (PIRIB), Office of Pesticide Programs (OPP), Environmental
Protection Agency, Rm. 119, Crystal Mall #2, 1801 S. Bell St.,
Arlington, VA, Attention: Docket ID Number OPP-2003-0132. Such
deliveries are only accepted during the Docket's normal hours of
operation, and special arrangements should be made for deliveries of
boxed information.
Instructions: Direct your comments to docket ID number OPP-2003-
0132. EPA's policy is that all comments received will be included in
the public docket without change and may be made available online at
http://www.epa.gov/edocket/, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through EDOCKET,
regulations.gov, or e-mail. The EPA EDOCKET and the regulations.gov
websites are ``anonymous access'' systems, which means EPA will not
know your identity or contact information unless you provide it in the
body of your comment. If you send an e-mail comment directly to EPA
without going through EDOCKET or regulations.gov, your e-mail address
will be automatically captured and included as part of the comment that
is placed in the public docket and made available on the Internet. If
you submit an electronic comment, EPA recommends that you include your
name and other contact information in the body of your comment and with
any disk or CD ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA
may not be able to consider your comment. Electronic files should avoid
the use of special characters, any form of encryption, and be free of
any defects or viruses. For additional information about EPA's public
docket visit EDOCKET on-line or see the Federal Register of May 31,
2002 (67 FR 38102) (FRL-7181-7).
Docket: All documents in the docket are listed in the EDOCKET index
at http://www.epa.gov/edocket/. Although listed in the index, some
information is not publicly available, i.e., CBI or other information
whose disclosure is restricted by statute. Certain other material, such
as copyrighted material, is not placed on the Internet and will be
publicly available only in hard copy form. Publicly available docket
materials are available either electronically in EDOCKET or in hard
copy at the Public Information and Records Integrity Branch (PIRIB),
Rm. 119, Crystal Mall #2, 1801 S. Bell St., Arlington, VA. This
Docket Facility is open from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The Docket telephone number is (703)
305-5805.
FOR FURTHER INFORMATION CONTACT: William L. Jordan, Mailcode 7501C,
Office of Pesticide Programs, Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington, DC 20460; telephone number: 703-
305-1049; fax number: 703-308-4776; e-mail address:
jordan.william@epa.gov.
SUPPLEMENTARY INFORMATION: This Notice is organized into five Units.
Unit I. contains ``General Information'' about the applicability of
this Notice, how to obtain additional information, how to submit
comments in response to the request for comments, and certain other
related matters. Unit II. provides background and historic information
pertaining to human subject research. Unit III. describes the
activities that EPA is planning to pursue to establish a framework
within which it will address the broad range of issues related to the
Agency's consideration of or reliance on research with human
participants. Unit IV. describes the current case-by-case process that
EPA will continue to follow pending completion of the rulemaking
efforts described in its plan. The last unit describes procedures
followed in the development of this Notice and certain statutes and
Executive Orders that the public may wish to consider in preparing
comments.
I. General Information
A. Does this Action Apply to Me?
This action is directed to the public in general. This action may,
however, be of particular interest to those who conduct testing of
substances regulated by EPA. Since other entities may also be
interested, the Agency has not attempted to describe all the specific
entities that may be affected by this action. If you have any questions
regarding the applicability of this action to a particular entity,
consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Access Electronic Copies of this Document and Other
Related Information?
In addition to using EDOCKET, http://www.epa.gov/edocket/, you may
access this Federal Register document electronically through the EPA
Internet under the ``Federal Register'' listings at
http://www.epa.gov/fedrgstr/.
C. What Should I Consider as I Prepare My Comments for EPA?
1. Submitting CBI. Do not submit this information to EPA through
EDOCKET, regulations.gov, or e-mail. Clearly mark the part or all of
the information that you claim to be CBI. For CBI information in a disk
or CD ROM that you mail to EPA, mark the outside of the disk or CD ROM
as CBI and then identify electronically within the disk or CD ROM the
specific information that is claimed as CBI. In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information
claimed as CBI must be submitted for inclusion in the public docket.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2.
2. Tips for preparing your comments. When submitting comments,
remember to:
i. Identify the rulemaking by docket number and other identifying
information (subject heading, Federal Register date, and page number).
ii. Follow directions. The agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
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iv. Describe any assumptions and provide any technical information
and/or data that you used.
v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
vi. Provide specific examples to illustrate your concerns, and
suggest alternatives.
vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
viii. Make sure to submit your comments by the comment period
deadline identified.
II. Introduction
A. Background on Federal Standards for Conducting Human Research
Over the years, scientific research with human subjects has
provided much valuable information to help characterize and control
risks to public health, but its use has also raised particular ethical
concerns for the welfare of the human participants in such research as
well as scientific issues related to the role of such research in
assessing risks. Society has responded to these concerns by defining
general standards for conducting human research.
In the United States, the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research issued in 1979 The
Belmont Report: Ethical Principles and Guidelines for the Protection of
Human Subjects of Research. This document can be found on the web at
http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm. 
For
many Federal agencies and departments in the United States, the principles
of the Belmont Report are implemented through the Federal Policy for
the Protection of Human Subjects (also known as the Common Rule). The
Common Rule, which was promulgated by 15 Federal departments and
agencies, including the EPA, on June 18, 1991 (56 FR 28003), applies to
all research involving human subjects conducted, supported or otherwise
subject to regulation by any Federal department or agency that has
adopted the Common Rule and has taken appropriate administrative action
to make it applicable to such research. The Common Rule as promulgated
by EPA (40 CFR part 26) has applied to human subjects research
conducted or supported by EPA since it was put into place in 1991.
More broadly, the international medical research community has
developed and maintains ethical standards documented in the Declaration
of Helsinki, first issued by the World Medical Association in 1964 and
revised several times since then. The latest version of the Declaration
is available at: http://www.wma.net/e/policy/b3.htm. These
standards apply to research on matters relating to the diagnosis and
treatment of human disease, and to research that adds to understanding of
the causes of disease and the biological mechanisms that explain the
relationships between human exposures to environmental agents and disease.
In addition, many public and private research and academic
institutions and private companies, both in the United States and in
other countries, including non-federal U.S. and non-U.S. governmental
organizations, have their own specific policies related to the
protection of human participants in research.
Much of the scientific information supporting EPA's actions is
generated by researchers who are not part of or supported by a Federal
agency, including a significant portion of the research with human
subjects submitted to the Agency or retrieved by the Agency from
published sources. Such research, referred to here as ``third-party''
research, may be governed by specific institutional policies intended
to protect research participants, may fall within the scope of the
Declaration of Helsinki, or might actually be covered by the Common
Rule if the particular testing institution holds an assurance approved
for federalwide use by the Department of Health and Human Services'
(HHS) Office for Human Research Protections and the institution has
voluntarily extended the applicability of the assurance to such
research. In some instances, research is reported in such a manner that
EPA cannot readily determine whether institutional policies are
consistent with or as protective of human subjects as the Common Rule,
or even the extent to which such policies or standards have been
followed in the conduct of any particular study. Thus, even well-
conducted third-party human studies may raise difficult questions for
the Agency when it seeks to determine their acceptability for
consideration. Unit IV. of this Notice contains a description of EPA's
case-by-case process for review of third-party human studies.
B. Human Research Issues in EPA's Pesticide Program
Although data from human studies has contributed to assessments and
decisions in most EPA programs, issues about consideration of and
reliance on third-party human research studies have arisen most
frequently, but not exclusively, with respect to pesticides. Under the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA is
authorized to require pesticide companies to conduct studies with human
subjects, for example, to measure potential exposure to pesticide users
or to workers and others who re-enter areas treated with pesticides, or
to evaluate the effectiveness of pesticide products intended to repel
insects and other pests from human skin. In addition, EPA sometimes
encourages other research with human subjects, including tests of the
potential for some pesticides--generally those designed for prolonged
contact with human skin--to irritate or sensitize human skin, and tests
of the metabolic fate of pesticides in the human body. These latter
studies typically precede monitoring studies of agricultural workers
and others to protect them from exposure to potentially dangerous
levels of pesticide residues.
In addition to these kinds of research which have been required or
encouraged by EPA, other kinds of studies involving human subjects
intentionally exposed to pesticides have occasionally been submitted to
the agency voluntarily. Among these voluntarily submitted studies have
been tests involving intentional dosing of human subjects to establish
a No Observed Adverse Effect Level (NOAEL) or No Observed Effect Level
(NOEL) for systemic toxicity of certain pesticides to humans. (Often
the researchers reported observing no treatment-related responses in
test participants.) For some two decades before passage of the Food
Quality Protection Act (FQPA) in 1996, submission of such studies was
rare. EPA considered and relied on human NOAEL/NOEL studies in a few
regulatory decisions on pesticides made prior to 1996. After passage of
FQPA, submission of these types of studies to EPA's Office of Pesticide
Programs increased; the Agency has received some 20 studies of this
kind since 1996.
In response to concerns about human testing expressed in a report
of a non-governmental advocacy organization, the Environmental Working
Group, in July 1998, the Agency began a systematic review of its policy
and practice. In a press statement on July 28, 1998, EPA noted that it
had not relied on any such studies in any final decisions made under FQPA.
In further response to growing public concern over pesticide
research with human subjects, EPA convened an advisory committee under
the joint auspices of the EPA Science Advisory
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Board (SAB) and the FIFRA Scientific Advisory Panel (SAP) to address
issues of the scientific and ethical acceptability of such research.
This advisory committee, known as the Data from Testing of Human
Subjects Subcommittee (DTHSS), met in December 1998 and November 1999,
and completed its report in September 2000. Their report is available
in the Docket cited above in this Notice, and on the web at:
http://www.epa.gov/science1/pdf/ec0017.pdf.
The DTHSS advisory committee heard many comments at their two
public meetings, and further comments have been submitted in response
to their published report. No clear consensus emerged from the advisory
committee process on the acceptability of NOAEL or NOEL studies of
systemic toxicity of pesticides to human subjects, and significant
differences of opinion remained on both their scientific merit and
ethical acceptability. A vigorous public debate continued about the
extent to which EPA should accept, consider, or rely on third-party
intentional dosing human toxicity studies with pesticides.
In December 2001, EPA asked the advice of the National Academy of
Sciences (NAS) on the many difficult scientific and ethical issues
raised in this debate, and also stated the Agency's interim approach on
third-party intentional dosing human subjects studies. The Agency's
press release on this subject is on the web at http://yosemite.epa.gov/
opa/admpress.nsf/b1ab9f485b098972852562e7004dc686/c232a45f5473717085256b
2200740ad4?OpenDocument. At that time the Agency committed
that when it received the NAS report, ``EPA will engage in an open and
participatory process involving federal partners, interested parties
and the public during its policy development and/or rulemaking
regarding future acceptance, consideration or regulatory reliance on
such human studies.'' In addition, the press release also stated that
while the Academy was considering these issues, EPA ``will not consider
or rely on any such human studies in its regulatory decision-making.''
In early 2002, various parties from the pesticide industry filed a
petition with the U. S. Court of Appeals for the District of Columbia
for review of EPA's December 2001 press release. These parties argued
that the Agency's interim approach constituted a ``rule'' promulgated
in violation of the procedural requirements of the Administrative
Procedure Act and the Federal Food, Drug, and Cosmetic Act. On June 3,
2003, the Court of Appeals concluded that:
For the reasons enumerated above, we vacate the directive
articulated in EPA's December 14, 2001 Press Release for a failure
to engage in the requisite notice and comment rulemaking. The
consequence is that the agency's previous practice of considering
third-party human studies on a case-by-case basis, applying
statutory requirements, the Common Rule, and high ethical standards
as a guide, is reinstated and remains in effect unless and until it
is replaced by a lawfully promulgated regulation.
See Crop Life America v. Environmental Protection Agency, 329 F.3d 876,
884 - 85 (D.C. Cir. 2003) (referred to as the Crop Life America case).
In the meantime, under a contract with EPA, the NAS convened a
committee to provide the requested advice. The committee met publicly
in December 2002, and again in January and March 2003. The membership,
meeting schedule, and other information about the work of this
committee can be found on the NAS website at: http://www4.nas.edu/
webcr.nsf/5c50571a75df494485256a95007a091e/9303f725c15902f685256c44005
d8931?OpenDocument&Highlight=0,EPA. The
committee issued its final report, ``Intentional Human Dosing Studies
for EPA Regulatory Purposes: Scientific and Ethical Issues,'' in
February 2004. That report is available at:
http://www.nap.edu/books/0309091721/html/.
On May 7, 2003, EPA issued an advance notice of proposed rulemaking
(ANPR) on Human Testing (68 FR 24410) in which EPA announced its
intention to undertake notice-and-comment rulemaking on the subject of
its consideration of or reliance on research involving human
participants. The ANPR also invited public comment on a broad range of
issues related to this subject. EPA received over 600 submissions in
response to the ANPR. Approximately 15 were from pesticide companies,
pesticide users, and associated trade associations and groups. These
comments mostly favored the Agency's use of data from scientifically
sound, ethically appropriate studies conducted with human participants.
Several of these groups urged EPA to apply the Common Rule to human
research conducted for EPA by third parties. About 60 submissions came
from religious groups, farm-workers' and children's advocacy groups,
and environmental and public health advocacy organizations. Most of
these groups generally opposed EPA's consideration of results from
human testing, especially those involving intentional dosing of test
participants with pesticides, on ethical grounds. Some of these
commenters suggested, however, that, under certain strict conditions,
EPA might appropriately consider data from human studies that complied
with the Common Rule. Over 500 private citizens sent identical comments
opposing the use of data from human studies with pesticides in EPA's
regulatory decision-making. A sizeable number of other private citizens
expressed dismay in their comments at what they misunderstood to be an
EPA proposal to test pesticides on human subjects.
C. EPA's Agency-wide Focus on Human Research Issues
Human research issues affect all programs in EPA. In its Office of
Research and Development, EPA conducts research with human subjects to
provide critical information on environmental risks, exposures, and
effects in humans. This is referred to as first-party research. In both
its Office of Research and Development and its program offices
(including the Office of Air and Radiation, the Office of Water, the
Office of Solid Waste and Emergency Response, and the Office of
Prevention, Pesticides and Toxic Substances), EPA also supports
research with human subjects conducted by others. This is referred to
as second-party research. In all this work EPA has been and remains
committed to full compliance with the Common Rule. This research has
provided many important insights and has contributed to the protection
of human health. The Agency will continue to conduct and support such
research, and to consider and rely on its results in Agency assessments
and decisions.
EPA also remains committed to scientifically sound assessments of
the hazards of environmental agents, taking into consideration all
available, relevant, and appropriate scientific research. In at least
some cases, some of the available, relevant, and appropriate scientific
research is conducted with human subjects by third parties, without
Federal government support. EPA programs have on occasion relied on
such studies to more completely characterize and understand
environmental risks to humans; the Agency will continue to do so when
it is appropriate.
EPA recognizes that its approach to the issues surrounding human
research needs to be consistent across the Agency. EPA is interested in
addressing the broad range of issues involving the consideration of and
reliance on data from human subjects studies, particularly tests
conducted by third
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parties. After consideration of the Court of Appeals' decision in the
Crop Life America case, the public comments on the ANPR, and the report
from the NAS, EPA has concluded that it should undertake a number of
activities to address these issues fully. The Agency's plan is
described in Unit III. of this Notice.
D. Legal Authority
The actions described below are authorized under a variety of
provisions of the different environmental statutes EPA administers.
Section 25(a) of the Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA) gives the Administrator authority to ``prescribe
regulations to carry out the purposes of [FIFRA].'' Such a rule would
implement EPA's authority to require data in support of registration of
pesticides (see, for example, FIFRA sections 3(c)(1)(F) and 3(c)(2)(B))
and to interpret the provision making it unlawful for any person ``to
use any pesticide in tests on human beings unless such human beings (i)
are fully informed of the nature and purposes of the test and of any
physical and mental health consequences which are reasonably
foreseeable therefrom, and (ii) freely volunteer to participate in the
test.'' (FIFRA section 12(a)(2)(P)). In addition, section 408(e)(1)(C)
of the Federal Food, Drug, and Cosmetic Act (FFDCA) authorizes the
Administrator to issue a regulation establishing ``general procedures
and requirements to implement this section.''
The Clean Air Act authorizes the Administrator to promulgate
regulations necessary to carry out the Agency's functions under that
Act at 42 U.S.C. 7601(a). The Clean Water Act contains a comparable
provision at 33 U.S.C. 1361. Section 42 U.S.C. 9615 in the
Comprehensive Environmental Response, Compensation, and Liability Act
authorizes the President to establish regulations to implement the
statute; this authority has been delegated to EPA by Executive Order
12580. The Emergency Planning and Community Right-to-Know Act also
contains a general rulemaking provision, 42 U.S.C. 11048, authorizing
the Administrator to promulgate rules necessary to carry out the Act.
The Resource Conservation and Recovery Act specifically authorizes the
Administrator to prescribe regulations necessary to carry out EPA's
functions under the Act, 42 U.S.C. 6912. The Safe Drinking Water Act
contains similar language, authorizing the Administrator to prescribe
such regulations ``as are necessary and appropriate'' to carry out
EPA's functions under the Act, 42 U.S.C. 300j-9. In addition, EPA has
broad authority under 5 U.S.C. 301 and 42 U.S.C. 300v-1(b).
III. EPA's Proposed Plan for Addressing Issues Relating to Human Testing
As a consequence of the public debate over whether it is
appropriate to consider or rely on data from intentional dosing of
humans, EPA recognizes that it is essential that the Agency state its
positions on these issues so that the public can understand under what
circumstances the Agency would take particular actions. The public
debate has made clear that a number of aspects of EPA's policy and
procedures are affected and that changes should be considered. Thus,
EPA has identified a number of activities including the issuance of a
clarifying description of the current case-by-case approach,
rulemakings, and administrative/organizational changes that appear
appropriate. EPA's overall goals for these activities are: That human
participants in any research required by, conducted for, or considered
by EPA are treated ethically; and that all scientifically sound data
relevant to EPA decision-making is considered and used appropriately in
reaching decisions under our authorities.
EPA has identified a variety of activities that, collectively, will
establish a comprehensive framework to address the broad range of
issues relating to the consideration of or reliance on data from human
studies, particularly when conducted by third parties. EPA has drawn
heavily on the recommendations contained in the NAS report in designing
this framework.
1. Publication of a clarifying description of the current case-by-
case review of completed third-party human studies. Consistent with the
Court's opinion in the Crop Life America case, EPA will continue to
evaluate third-party human studies on a case-by-case basis, applying
statutory requirements, the Common Rule, and high ethical standards as
a guide, until such time as this practice is replaced by a rulemaking.
EPA is issuing a clarifying description of its current process in Unit
IV. of this Notice. EPA intends to continue this process until such
time as it is superseded by rulemaking. EPA, however, welcomes public
comment on the description of its current process, and after reviewing
comments, EPA may choose to publish additional clarification.
2. Intent to publish a policy statement to third parties
encouraging them to submit protocols for proposed human studies to EPA
for review. EPA intends to develop and make public a policy statement
that encourages, but does not require, ``third-party'' researchers,
i.e., researchers who are not part of or supported by a Federal agency,
who are planning to conduct studies involving human participants to
support an EPA regulatory decision, to submit a proposed protocol to
EPA prior to conducting the research. The policy statement would
explain EPA's intent to review and provide comments to the researcher
concerning the ethical and scientific attributes of the proposal.
3. Intent to publish guidance concerning compliance with the Common
Rule for any future human studies specifically required by EPA. EPA
intends to publish non-binding guidance reflecting its plans to extend
the Common Rule to specifically cover third-party human subject studies
that are intended to be submitted to the Agency either voluntarily or
in response to an Agency-imposed requirement and setting forth its
expectation that any such study intended to be submitted in the interim
should endeavor to include protections such as those included in the
Common Rule.
Additionally, in the interim, the Agency intends to utilize
existing authority, where appropriate, to require that test sponsors
and testing facilities and personnel adhere to the Common Rule in
conducting human studies if such studies are submitted to the Agency to
satisfy specific data requirements, for example, studies with human
participants that may be submitted to the Agency to satisfy data
requirements under FIFRA section 3(c)(2)(B) or pursuant to a TSCA
section 4 testing rule.
4. Intent to conduct outreach to scientific journals encouraging
improved reporting of the ethics of published human studies. Many
biomedical journals have adopted voluntary, uniform requirements for
submitted manuscripts. These requirements include reporting on the
protection of human subjects, through indicating whether the procedures
followed were in accordance with the ethical standards of the
responsible institution and with the Declaration of Helsinki or other,
comparable, ethics codes. EPA intends to conduct outreach to these
journals to determine the extent of coverage and compliance, and to
encourage the reporting of this ethics information in connection with
publication of the results of research conducted with human participants.
5. Intent to expand the functions of the EPA Human Subjects
Research Review Official and to relocate the HSRRO office. Within EPA,
the Human Subjects Research Review Official (HSRRO) has responsibility
for assuring
[[Page 6666]]
that all human subjects research that is conducted or supported by EPA
complies with the requirements of the Common Rule. The HSRRO's specific
responsibilities are described in EPA Order 1000.17 Change A1. See
http://www.epa.gov/oamrtpnc/forms/1000_17a.pdf. These
responsibilities, in effect, entail addressing the scientific and
ethical issues raised by human studies. The HSRRO reviews and approves
about 50 projects a year, of which only a few involve intentional
dosing of human participants with environmental pollutants. Currently,
the HSRRO is located within EPA's Office of Research & Development,
which is the Office within EPA that conducts or sponsors most of the
research programs reviewed by the HSRRO.
The NAS report included the recommendation that ``[t]o ensure
intentional dosing human studies conducted for EPA regulatory purposes
meet the highest scientific and ethical standards, EPA should establish
a Human Studies Review Board to address in an integrated way the
scientific and ethical issues raised by such studies.'' The NAS further
recommended that the Human Studies Review Board ``should report
directly to the Office of the [EPA] Administrator.'' Consistent with
the NAS recommendation, EPA intends to expand the functions of the
HSRRO and is looking at where to relocate those functions. In addition
to the existing function of ensuring compliance with the Common Rule
for human subjects research conducted or supported by EPA, the Agency
intends that the HSRRO will have responsibility for overseeing
implementation of the ethics screening of completed studies (see Unit
IV.), overseeing the review of proposals to conduct new human studies,
identifying emerging ethical issues for research not subject to the
Common Rule, and developing additional policies, training, and best
practices guidance. The Agency welcomes public comment on this part of
its plan.
6. Intent to pursue rulemaking. EPA intends to publish a proposed
rule to make the provisions of the Common Rule, 40 CFR part 26,
applicable to certain newly conducted third-party human studies and may
propose to adopt some or all of the HHS regulations that provide
additional protections for certain populations of vulnerable subjects.
These HHS regulations are contained in HHS regulations at 45 CFR part
46, subpart B (Additional Protections for Pregnant Women, Human Fetuses
and Neonates Involved in Research), subpart C (Additional Protections
Pertaining to Biomedical and Behavioral Research Involving Prisoners as
Subjects), and subpart D (Additional Protections for Children Involved
as Subjects in Research), and apply to all research involving these
respective vulnerable subject groups that is conducted or supported by
HHS. This proposal may also require a sponsor or investigator to
provide to EPA, for prior review and approval, the protocol for certain
human studies. EPA will also consider whether to propose a rule
applying to certain previously conducted human studies. In developing
its proposals, EPA will consider both the report from the NAS and
public comments on the ANPR and this Notice.
IV. Description of EPA's Current Case-by-Case Review Process for Third-
Party Human Studies
This unit describes the Agency's process for reviewing and relying
on completed, third-party studies that involve intentional dosing of
human participants to identify or quantify a toxic endpoint. It is
important to note that this is a case-by-case process. As such, it
binds no one to a particular process or result--not the regulated
community, not advocacy groups, not the public, and not EPA. Therefore,
in any decision before EPA, any stakeholder may urge EPA to: (1)
Conclude that this process is inapplicable; (2) consider factors other
than those described here; or (3) make an exception to the process as
described. EPA notes that it may determine, based on individual
circumstances to act at variance from the review process as described.
Thus, affected parties should not assume that EPA will follow a
prescribed method of reviewing a particular human study in each and
every instance. In any action involving consideration and review of a
third-party, intentional dosing human study, EPA will explicitly state
the basis upon which such a study has been evaluated.
As mandated by the D.C. Circuit in the Crop Life America case, EPA
has resumed consideration of third-party human studies on a case-by-
case basis, applying statutory requirements, the Common Rule, and high
ethical standards as a guide. In its consideration and review of human
studies submitted to the Agency, EPA will continue to generally accept
scientifically valid studies unless there is clear evidence that the
conduct of those studies was fundamentally unethical (e.g., the studies
were intended to seriously harm participants or failed to obtain
informed consent), or was significantly deficient relative to the
ethical standards prevailing at the time the study was conducted. The
Agency notes that this approach is consistent with Recommendation 5-7
of the February 2004, NAS report.
Primary responsibility for conducting case-by-case science and
ethics reviews of third-party, intentional dosing human studies for
toxic effects is vested in the EPA Office responsible for the relevant
Agency action or risk assessment. To maintain high ethical standards
the Agency screens all ``priority'' studies involving intentional
dosing of human participants for toxic effects for existing ethics and
scientific review information, and the responsible Office documents
such reviews. A priority study is one which is expected to
significantly affect the assessment, either by itself or as a
substantial component of the weight of evidence, in determining: A
regulatory standard, decision, or risk assessment value; determining an
uncertainty factor or safety factor; or defining exposure or effects.
The Agency also reviews as a ``priority'' study any study which was not
relied on but which, if considered, arguably would change the outcome
of the Agency's risk assessment or regulatory judgement or
significantly affect the record underlying the Agency's conclusions. In
addition, an Office may selectively review the ethics of any non-
priority study, as it deems appropriate.
If a study raises potential ethical concerns or if there is
uncertainty, the primary Office consults with the Human Subjects
Research Review Official (HSRRO) and they jointly develop an evaluation
plan for the study, which may include soliciting outside ethics advice.
Senior Agency officials decide the appropriate action to take
concerning ethically problematic studies on a case-by-case basis.
Depending on the context, senior officials could include senior
executives in the program office of concern, the Agency's HSRRO, and/or
the Agency Science Advisor. If appropriate, the senior Agency officials
may seek independent advice from an external peer review group such as
the Science Advisory Board or the FIFRA Scientific Advisory Panel.
V. Statutory and Executive Order Reviews
Since this Notice does not impose any requirements, and instead
describes EPA's current case-by-case approach for reviewing certain
human studies, and seeks comments on EPA's plans for amending that
process and any suggestions for the Agency to consider in developing a
subsequent notice of proposed rulemaking, the various other
[[Page 6667]]
review requirements that apply when an agency imposes requirements do
not apply to this action.
As part of your comments on this Notice you may include any
comments or information that you have regarding these requirements. In
particular, any comments or information that would help the Agency to
assess the potential impact of a rule on small entities pursuant to the
Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et seq.); to consider
voluntary consensus standards pursuant to section 12(d) of the National
Technology Transfer and Advancement Act of 1995 (NTTAA), Public Law
104-113, section 12(d) (15 U.S.C. 272 note); or to consider
environmental health or safety effects on children pursuant to
Executive Order 13045, titled Protection of Children from Environmental
Health Risks and Safety Risks (62 FR 19885, April 23, 1997). The Agency
will consider such comments during the development of any subsequent
notice of proposed rulemaking as it takes appropriate steps to address
any applicable requirements.
List of Subjects
Environmental protection, Protection of human research subjects.
Dated: February 2, 2005.
Susan B. Hazen,
Acting Assistant Administrator, Office of Prevention, Pesticides and
Toxic Substances.
[FR Doc. 05-2371 Filed 2-3-05; 11:43 am]
BILLING CODE 6560-50-S
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