[Federal Register Volume 76, Number 22 (Wednesday, February 2, 2011)]
[Proposed Rules]
[Pages 5735-5755]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-1629]
[[Page 5735]]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 26
[EPA-HQ-OPP-2010-0785; FRL-8862-7]
RIN 2070-AJ76
Revisions to EPA's Rule on Protections for Subjects in Human
Research Involving Pesticides
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: EPA proposes to amend the portions of its rules for the
protection of human subjects of research applying to third parties who
conduct or support research with pesticides involving intentional
exposure of human subjects and to persons who submit the results of
human research with pesticides to EPA. The proposed amendments would
broaden the applicability of the rules to cover human testing with
pesticides submitted to EPA under any regulatory statute it
administers. They would also disallow participation in third-party
pesticide studies by subjects who cannot consent for themselves.
Finally the proposed amendments would identify specific considerations
to be addressed in EPA science and ethics reviews of proposed and
completed human research with pesticides, drawn from the
recommendations of the National Academy of Sciences (NAS). In seeking
comments on these proposed amendments, EPA does not imply that the
current Federal Policy for the Protection of Human Subjects (the
``Common Rule''), which governs research with human subjects conducted
or supported by EPA and many other Federal departments and agencies, is
inadequate. Indeed, the amendments proposed here would make no changes
to the Common Rule or EPA's codification of the Common Rule. Rather,
EPA is proposing these amendments to other portions of its regulation
as a result of a settlement agreement, and is now seeking comment on
these proposed amendments. The settlement agreement makes clear that
EPA retains full discretion concerning what amendments are proposed,
and what, if any, amendments are finalized. Furthermore, no research
has been identified that is outside the scope of EPA's current rule,
but that would be within the scope of these proposed amendments. EPA
seeks comments on the need for and value of the proposed changes.
DATES: Comments must be received on or before April 4, 2011.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2010-0785, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only
accepted during the Docket Facility's normal hours of operation (8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays).
Special arrangements should be made for deliveries of boxed
information. The Docket Facility telephone number is (703) 305-5805.
Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2010-0785. EPA's policy is that all comments received will be included
in the docket without change and may be made available on-line at
http://www.regulations.gov, 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 regulations.gov or e-
mail. The regulations.gov Web site is an ``anonymous access'' system,
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 regulations.gov,
your e-mail address will be automatically captured and included as part
of the comment that is placed in the 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.
Docket: All documents in the docket are listed in the docket index
available at http://www.regulations.gov. Although listed in the index,
some information is not publicly available, e.g., 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 in the electronic
docket at http://www.regulations.gov, or, if only available in hard
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The hours of
operation of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The Docket Facility telephone
number is (703) 305-5805.
FOR FURTHER INFORMATION CONTACT: Kelly Sherman, Immediate Office of the
Director (7501P), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 305-8401; fax number: (703) 308-4776; e-
mail address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this action apply to me?
You may be potentially affected by this action if you sponsor,
conduct, review, or submit to EPA research with pesticides involving
human subjects. Potentially affected entities may include, but are not
limited to:
Pesticide and other agricultural chemical manufacturers
(NAICS code 325320) who sponsor or conduct human research with
pesticides.
Other entities (NAICS code 541710) that sponsor or conduct
human research with pesticides, and Institutional Review Boards who
review human research with pesticides to ensure it meets applicable
standards of ethical conduct.
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes are provided to assist you and others in determining whether this
action might apply to certain entities. 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. What should I consider as I prepare my comments for EPA?
1. Submitting CBI. Do not submit confidential business information
(CBI)
[[Page 5736]]
to EPA through 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:
a. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
b. 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.
c. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
d. Describe any assumptions and provide any technical information
and/or data that you used.
e. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
f. Provide specific examples to illustrate your concerns and
suggest alternatives.
g. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
h. Make sure to submit your comments by the comment period deadline
identified.
II. Background
A. What would the proposed amendments do?
The proposed amendments would change the 2006 rule, published in
the Federal Register issue of February 6, 2006 (71 FR 6138) (FRL-7759-
8), subsequently amended on June 23, 2006 (71 FR 36171) (FRL-8071-6),
and codified at 40 CFR part 26, in the following substantive respects:
By broadening the applicability of 40 CFR part 26,
subparts K, L, M, and Q, so these subparts would apply not only to
research submitted to or considered by EPA under the pesticide laws,
but also to research involving a ``pesticide'' (as defined in the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C.
136(u)) which is submitted to or considered by EPA under any other
regulatory statute it administers.
By incorporating the definition of ``pesticide'' from
FIFRA, as a substance or mixture of substances intended for pesticidal
effect.
By deleting from 40 CFR part 26, subpart K, all references
to consent on behalf of a subject in research involving intentional
exposure to a pesticide by a subject's ``legally authorized
representative.''
By incorporating into 40 CFR part 26, subparts P and Q,
factors to be considered by EPA and the Human Studies Review Board
(HSRB) in their review of proposed and completed research, derived from
the recommendations of NAS in its 2004 Report to EPA, and from the
Nuremberg Code.
The amendments proposed here would make no changes to the Federal
Policy for the Protection of Human Subjects (the ``Common Rule''),
which governs research with human subjects conducted or supported by
EPA and many other Federal departments and agencies. EPA's codification
of the Common Rule appears as subpart A in 40 CFR part 26.
Subparts B, C, and D of 40 CFR part 26 would also be unchanged by
these proposed amendments. These subparts categorically prohibit any
EPA research involving intentional exposure to any substance of human
subjects who are children or pregnant or nursing women (40 CFR part 26,
subpart B), and provide extra protections for pregnant women and for
children who are the subjects of observational research conducted or
supported by EPA (40 CFR part 26, subparts C and D).
The proposed amendments would retain without substantive change the
core provisions of the 2006 rule applying to the conduct of human
pesticide research by third parties--i.e., research neither conducted
nor supported by EPA or another Common Rule Federal department or
agency. These substantively unchanged provisions:
Categorically prohibit new research involving intentional
exposure of pregnant or nursing women or of children to a pesticide (40
CFR part 26, subpart L).
Apply the provisions of the Common Rule to third-party
human research involving intentional exposure of non-pregnant, non-
nursing adults to a pesticide (40 CFR part 26, subpart K).
Require submission to EPA of proposals for new covered
research before it is initiated (40 CFR part 26, subpart K, Sec.
26.1125).
Require persons who submit to EPA reports of completed
human research on pesticides to document the ethical conduct of that
research (40 CFR part 26, subpart M).
Establish an independent HSRB to review and advise EPA
concerning both proposals for new human research involving intentional
exposure to a pesticide and reports of completed research on which EPA
proposes to rely in its actions (40 CFR part 26, subpart P).
The proposed amendments would make only minor editorial revisions
to 40 CFR part 26, subpart O, which defines administrative actions
available to EPA to address non-compliance with 40 CFR part 26,
subparts A through L.
The proposed amendments would retain the essential structure of 40
CFR part 26, subpart P, which defines the processes of EPA and HSRB
review of proposed and completed research. The amendments, however,
would also add substantial new clarifying language to 40 CFR part 26,
subpart P, as discussed in detail in Unit IV.C. of this document.
The proposed amendments would retain the essential structure of 40
CFR part 26, subpart Q, which defines the standards to be applied when
EPA proposes to rely on data from completed research involving
intentional exposure of human subjects to a pesticide. The amendments,
however, would also add substantial new clarifying language to 40 CFR
part 26, subpart Q, as discussed in detail in Unit IV.D. of this
document.
The proposed amendments would not change the provision in 40 CFR
part 26, subpart Q, forbidding EPA to rely on any otherwise
unacceptable research involving intentional exposure of human subjects
to a pesticide, except under extremely restrictive conditions. These
conditions require a public review by HSRB, an opportunity for public
comment, and a showing by EPA that to do so would result in a more
protective regulatory standard than could be justified without reliance
on the unethical research.
B. What is the agency's authority for taking this action?
The legal authority for the 2006 rule on human research is set
forth in the preamble to that final rule (71 FR 6138, February 6, 2006)
(FRL-7759-8). These proposed amendments to that rule rest upon the same
legal authority. In particular, the legal authority for expanding the
2006 rule to cover research involving the intentional exposure of a
human subject to a pesticide submitted under any EPA
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regulatory statute is provided by section 201 of the Department of the
Interior, Environment, and Related Agencies Appropriations Act, 2006,
Public Law 109-54 (2006 Appropriations Act), and FIFRA.
The 2006 Appropriations Act directly mandates that EPA promulgate a
rule on ``third-party intentional dosing human toxicity studies for
pesticides * * *'' without limiting the rule to pesticide studies
submitted under FIFRA or section 408 of the Federal Food, Drug, and
Cosmetic Act (FFDCA) (21 U.S.C. 346a).
Additionally, under FIFRA, EPA has the authority to issue
regulations as to both unregistered and registered pesticides used in
research involving the intentional exposure of a human subject, whether
or not that research is conducted for submission under FIFRA. Section
3(a) of FIFRA authorizes EPA to regulate the distribution, sale, or use
of any unregistered pesticide in any State ``[t]o the extent necessary
to prevent unreasonable adverse effects on the environment'' (defined
at FIFRA section 2(bb), in pertinent part, as ``any unreasonable risk
to man or the environment, taking into account the economic, social,
and environmental costs and benefits of the use of any pesticide'').
EPA concludes that there would be an unreasonable risk to humans if
unregistered pesticides were used in research involving intentional
exposure of human subjects (or sold and distributed for such use) that
is not already covered by the Common Rule absent compliance with the
applicable rules in 40 CFR part 26, as proposed. The importance of
these rules to the protection of human subjects is demonstrated in the
2004 Report from the National Research Council of the NAS, entitled
``Intentional Human Dosing Studies for EPA Regulatory Purposes:
Scientific and Ethical Issues'' (2004 NAS Report) (http://www.national-academies.org).
Section 25(a) of FIFRA authorizes EPA to ``prescribe regulations to
carry out the provisions of [FIFRA].'' (7 U.S.C. 136w(a)). Regulations
protecting human subjects in research involving the intentional
exposure of human subjects to registered pesticides fall within that
purview. FIFRA provides that a pesticide may not be registered unless
use of the pesticide under its labeling will not cause unreasonable
risks to humans or the environment, that a pesticide may not be used
inconsistent with its label, and that a pesticide may not be used in
human testing unless the subjects are fully informed regarding the
nature, purpose, and physical and mental health consequences of the
testing and freely volunteer. (See 7 U.S.C. 136(bb), 136a(c)(5),
136j(a)(2)(G), 136j(a)(2)(P)). The 2006 rule and the amendments
proposed in this document ensure that these provisions regarding use of
registered pesticides in a manner that does not cause unreasonable risk
and full and free consent in human testing with pesticides are
effectuated.
III. EPA's Human Subjects Protection Rules
A. Overarching Principles
EPA is committed to relying on scientifically sound research that
is ethically conducted, and to transparency in its review processes and
decision-making. EPA issued the 2006 rule to further these commitments
and nothing in the amendments proposed in this document will change
that. These proposed amendments can be seen as increasing the
transparency of EPA's decision-making process by clarifying the scope
and applicability of the requirements in 40 CFR part 26, codifying the
scope and approach used in EPA's science and ethics reviews of human
research involving pesticides.
B. Appropriations Act of 2006
In August 2005, in the 2006 Appropriations Act, which appropriated
funds for EPA and other Federal departments and agencies for FY 2006,
Congress included at section 201 the following provision:
None of the funds made available by this Act may be used by the
Administrator of the Environmental Protection Agency to accept,
consider or rely on third-party intentional dosing human toxicity
studies for pesticides, or to conduct intentional dosing human
toxicity studies for pesticides until the Administrator issues a
final rulemaking on this subject. The Administrator shall allow for
a period of not less than 90 days for public comment on the Agency's
proposed rule before issuing a final rule. Such rule shall not
permit the use of pregnant women, infants or children as subjects;
shall be consistent with the principles proposed in the 2004 report
of the National Academy of Sciences on intentional human dosing and
the principles of the Nuremberg Code with respect to human
experimentation; and shall establish an independent Human Subjects
Review Board. The final rule shall be issued no later than 180 days
after enactment of this Act.
In response, EPA published a proposed rule in the Federal Register
issue of September 12, 2005 (70 FR 53838) (FRL-7728-2), accepted public
comment until December 12, 2005, and promulgated on February 6, 2006, a
final rule which took effect on April 7, 2006 (71 FR 6138) (FRL-7759-
8). The 2006 rule, as subsequently amended on June 23, 2006, to extend
special protections to nursing women as well (71 FR 36171) (FRL-8071-
6), is discussed in Unit III.E. and is now being further amended by
this proposed rule.
C. EPA's 2006 Rule
1. Summary of contents. The 2006 rule established a set of
protections for people participating as subjects in third-party human
research with pesticides. (In this context ``third-party'' research is
research neither conducted (``first-party'') nor supported (``second-
party'') by EPA or another Common Rule Federal department or agency.)
The 2006 rule bans all third-party research on pesticides involving
intentional exposure of children or of pregnant or nursing women. It
further forbids EPA itself to conduct or support any research involving
intentional exposure of pregnant or nursing women or of children to any
substance. EPA was required to promulgate the 2006 rule by the 2006
Appropriations Act.
The 2006 rule also extends the ethical protections in the Common
Rule to third-party studies of non-pregnant, non-nursing adult subjects
intentionally exposed to pesticides. The key provisions of the 2006
rule include:
Requiring pre-implementation submission to EPA of
protocols and related information about proposed research to ensure any
future studies meet high ethical standards.
Establishing an independent HSRB to obtain expert peer
review of both proposals for new research intended for submission to
EPA and reports of completed human research involving intentional
exposure on which EPA proposes to rely in an action taken under the
pesticide laws.
Prohibiting EPA from relying on the results of research in
its actions under the pesticide laws unless EPA determines that the
research meets acceptance standards derived from the recommendations in
the 2004 NAS Report.
2. Research with pesticides since promulgation of the 2006 rule.
Contrary to some predictions, the 2006 rule has not led to an upsurge
in human research with pesticides for submission to EPA under FIFRA or
FFDCA. Since promulgation of the 2006 rule EPA has received no
proposals at all for research on the toxicity of a pesticide to human
subjects, and has received significantly fewer than were projected
proposals for new research of other kinds (e.g., insect repellent
studies). In the analyses supporting the 2006 rule, EPA estimated 33
new intentional exposure studies would be submitted each year; in fact,
only 26 proposals for new research on pesticides for submission to EPA
under
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FIFRA and FFDCA have been submitted over a span of approximately 5
years, or just over 5 per year.
3. Overview of HSRB reviews. EPA's experience in implementing the
2006 rule is critical to understanding the amendments proposed in this
document. The public meetings of HSRB have served as key milestones in
the implementation of the 2006 rule, and the implementation of the 2006
rule can be best characterized by summarizing what HSRB has been called
upon to review. HSRB met for the first time in April 2006, immediately
after the 2006 rule became effective, and has met 14 times since then,
most recently in October 2010. At these meetings, HSRB has reviewed
both reports of completed research and proposals for new research.
Specifically, HSRB has reviewed:
Completed reports of pre-2006 rule research reporting
toxic endpoints. These have included intentional exposure toxicity
tests initiated both before and after passage of the Food Quality
Protection Act (FQPA) in 1996, as well as therapeutic trials of
substances used both as drugs and as pesticides, reporting side effects
relevant to EPA pesticide risk assessments.
Proposals for and reports of new research involving
intentional exposure to materials used in the research as pesticides.
a. Pre-rule research reporting toxic endpoints. At its first two
meetings in April and May 2006, HSRB reviewed 28 reports of pre-rule
research conducted with 11 substances. At all its subsequent meetings
combined the Board has reviewed 14 more such reports. Half of these 42
reports were published; the rest were unpublished reports submitted
directly to EPA by pesticide companies. Of the 42 reports, 37 reported
non-therapeutic research, and 5 were published reports of therapeutic
trials that described side effects relevant to pesticide risk
assessments. We summarize the disposition of each of the 42 studies in
the following paragraphs, and additional details may be accessed in the
study specific reports available on the HSRB Web site at http://www.epa.gov/hsrb/index.htm.
Twenty-nine of the 37 non-therapeutic studies reviewed by HSRB were
initiated before the passage of FQPA in 1996; all reported toxic
endpoints. EPA conducted both science and ethic reviews of these
studies prior to submission of the studies to HSRB. EPA science
reviewers proposed to rely on 17 of these 29 studies. HSRB found 13 of
these 17 studies scientifically acceptable under the applicable
standards of the 2006 rule. EPA ethics reviewers found 5 of the 17
clearly acceptable, and deferred to HSRB concerning whether the
shortcomings noted in the conduct of the remaining 12 studies rose to
the level of ``significant'' deficiencies relative to prevailing
standards of ethical research conduct. HSRB found 15 of those 17
studies ethically acceptable under the applicable standards of the 2006
rule--Sec. 26.1703 and Sec. 26.1704. HSRB found 1 study ethically
unacceptable because of deficiencies in risk minimization procedures
that could have led to serious harm to subjects, and another
unacceptable because incomplete information provided to subjects
concerning previous studies seriously impaired their informed consent.
These 2 studies found by HSRB to be ethically unacceptable were among
those also found by HSRB to be scientifically unacceptable. EPA has not
subsequently relied on any studies deemed either scientifically or
ethically unacceptable by HSRB.
The 12 remaining pre-FQPA studies that EPA science reviewers had
proposed to reject concerned dichlorvos (DDVP). These reports on the
effects of dichlorvos had been submitted by the registrant to support a
proposal to reduce the inter-species uncertainty factor in EPA's DDVP
risk assessment. EPA reviewers found all 12 to be scientifically
unacceptable to reduce the inter-species factor since a dose response
could not be calculated due to numerous technical weaknesses. HSRB
concurred. Because the reported research was deemed scientifically
unacceptable for the proposed use, neither EPA nor HSRB explicitly
reviewed its ethical conduct. EPA has not relied on any of these 12
studies.
Turning to the 8 post-FQPA toxicity studies that EPA presented to
HSRB, we note that they were among a group of about 20 studies at the
center of controversy before promulgation of the 2006 rule. Other post-
FQPA human toxicity studies were deemed by EPA science reviewers to be
irrelevant to EPA's risk assessments, and have not been considered
further.
Of the eight relevant post-FQPA toxicity studies, EPA science
reviewers found six scientifically acceptable and proposed to rely on
them, found one more to be clearly scientifically unacceptable to set a
point of departure because no effect was measured from the single dose
level tested \1\, and deferred to HSRB with respect to the scientific
acceptability of the last one. HSRB concurred that the first six
studies were scientifically acceptable, and found both the others
unacceptable. EPA ethics reviewers found four of the eight studies
clearly acceptable, one clearly unacceptable, and deferred to HSRB's
judgment whether the shortcomings noted in the conduct of the remaining
three rose to the level of ``significant'' deficiencies relative to
prevailing standards of ethical conduct. HSRB found all but one of
these eight studies ethically acceptable under the applicable standards
in the 2006 rule. Studies found either scientifically or ethically
unacceptable by HSRB have not subsequently been relied on by EPA in any
actions.
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\1\ For more details on this finding, see the study report
available on the HSRD Web site at http://www.epa.gov/hsrb/index.htm.
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EPA also proposed to rely on five published reports of therapeutic
trials of materials that may be used as either drugs or as pesticide
active ingredients. In these studies the reported toxic endpoints
relevant to EPA pesticide risk assessments were not the main objective
of the research, they were reported side effects of treatment when a
test material (which is sometimes used as a pesticide) was administered
as a medication. HSRB concurred with the EPA science reviews that these
four studies were scientifically unacceptable, but found one study
scientifically unacceptable for the purpose EPA proposed. EPA ethics
reviewers and HSRB both found all five of these studies to be ethically
acceptable under the standards of the 2006 rule.
In summary, EPA and HSRB worked through the backlog of pre-rule
studies of pesticide toxicity awaiting review when the 2006 rule was
promulgated. EPA and HSRB agreed about the acceptability of these
studies in most cases; when there was disagreement, EPA has accepted
HSRB recommendation. Some pre-rule studies that met the scientific and
ethical standards defined in the 2006 rule have been relied upon by EPA
in actions under the pesticide laws, although EPA has not relied on any
studies found unacceptable by HSRB. Meanwhile, as EPA completed the
reassessment of tolerances mandated by FQPA, it found human toxicity
testing to be relevant to only a handful of those assessments.
b. New research involving intentional exposure of human subjects.
In addition to reviewing pre-2006 rule research, HSRB has reviewed
proposals for new research involving intentional exposure of human
subjects. EPA developed a detailed ``framework'' for its reviews of
these proposals (see the HSRB Web site at http://www.epa.gov/hsrb/index.htm). This framework has been used to guide all subsequent EPA
reviews, and has
[[Page 5739]]
been refined in detail to incorporate suggestions from HSRB. A
completed framework addressing concerns identified in the 2004 NAS
Report and subsequently by HSRB has been attached to each EPA review of
a proposal for new research under the 2006 rule.
Since promulgation of the 2006 rule EPA has received no proposals
at all for new research concerning pesticide toxicity or metabolism in
human subjects. All submitted proposals for new research have been for
research involving intentional exposure of human subjects to registered
pesticides used for pesticidal purposes in the research itself. This
has included proposals for research to measure the duration of
effectiveness of skin-applied repellents intended to keep mosquitoes,
ticks, and other pests away from the treated skin of human subjects,
and for research monitoring occupational exposure of pesticide handlers
as they mix, load, or apply pesticides in a variety of agricultural and
non-agricultural use scenarios.
Close scrutiny by both EPA and HSRB of proposals for new repellent
performance testing and worker exposure monitoring studies has led to
steady and substantial improvement both in the scientific design of
these studies and in their provision for ethical treatment of subjects.
These reviews have led to some delays in field research costly to the
study sponsors, but the sponsors and investigators proposing these
studies have learned how to design and execute them efficiently and in
full compliance with the standards of the 2006 rule. These studies
provide essential information about repellent performance and worker
exposure that is not available except from well designed, ethically
conducted research involving intentional exposure of human subjects to
pesticides.
i. Repellent performance studies. Repellent performance studies
using human subjects have been required by EPA for many years to
support registration of pesticide products bearing claims to keep
mosquitoes, ticks, or other pests away from treated human skin. Since
2006, HSRB has reviewed proposals for 13 new repellent performance
studies testing a total of 29 repellent formulations. EPA and HSRB
identified enough scientific and ethical deficiencies in their initial
review of the first 2 such proposals that a second review was required.
After they were revised and resubmitted, both proposals were reviewed
favorably by EPA and HSRB. All subsequent proposals for new repellent
performance studies have been found acceptable, with identified needed
refinements, upon their first review by EPA and HSRB.
Five of the 13 proposals have been for laboratory research with
caged insects or ticks reared in the laboratory and known to be
disease-free. The remaining studies have been for field studies of
repellency against wild populations of insects. Three of the 13 studies
have measured the duration of tick repellency in the laboratory--2 of
them concurrently testing repellency to 2 species of ticks. Two more
have measured the duration of repellency to biting flies--1 in the
laboratory with laboratory-reared stable flies, and another in the
field measuring repellency against black flies. The remaining 8 studies
have measured the duration of repellency against mosquitoes--7 of them
in the field, in areas where previous monitoring has not found evidence
of infection of potential disease vectors among the wild insects
present, and 1 in the laboratory with laboratory-reared, pathogen-free
mosquitoes.
In all these cases, HSRB has concurred with the EPA science and
ethics reviews, in some cases recommending further refinements. One
proposal was abandoned by its sponsor after a favorable HSRB review; 11
more have been amended consistent with EPA and HSRB recommendations and
executed. Reports of these 11 have been submitted to EPA and reviewed
by EPA and HSRB. The most recent proposal is expected to be executed in
the field in 2011.
In one case EPA and HSRB found the execution of a completed field
mosquito repellency test to have been non-compliant with 40 CFR part
26, subparts A-L. This study protocol was subsequently revised and re-
executed; the report of the re-executed study was found acceptable by
EPA and HSRB.
Reports of all the other ten completed repellent performance
studies were found both scientifically and ethically acceptable by EPA
and HSRB as first submitted.
ii. Studies of occupational exposure of pesticide handlers. All
other proposals for new research submitted to EPA since promulgation of
the 2006 rule have been for research monitoring exposure of
professional pesticide handlers as they mix, load, or apply pesticides
in well-defined agricultural and non-agricultural use scenarios. In
such research, experienced workers performing their usual tasks are
typically monitored at different sites, representing the range of
variation in use practices, equipment, and other factors likely to
affect exposure. Potential dermal exposure of the workers is measured
by analyzing residues in special ``long underwear'' worn under their
normal work clothing, and by rinsing their hands, face and neck.
Potential inhalation exposure is measured with a portable air sampler
worn in the breathing zone of each worker. This type of research has
also long been required by EPA to support its assessments of worker
risk.
Five proposals for field monitoring of worker exposure submitted to
EPA by an industry consortium were presented to HSRB in June 2006.
These proposals were from the Agricultural Handlers Exposure Task Force
(AHETF). HSRB review was highly critical, and called for substantially
greater information from both the consortium and from EPA concerning
the overall design of the research program, the statistical design of
the proposed studies, the uses to which the resulting data would be put
by EPA, and many other aspects of the proposed research. All five of
these proposals were subsequently withdrawn so that HSRB criticisms
could be addressed prior to resubmission.
Since that initial review, the overall designs of the umbrella
monitoring programs of AHETF and the designs from the Antimicrobial
Exposure Assessment Task Force (AEATF II) have been fully documented
and presented to HSRB. HSRB continues to review the design of
individual monitoring studies, but the soundness of the overall
approaches of both the AEATF II and AHETF programs have been
established.
Monitoring studies for four antimicrobial exposure scenarios
submitted by the AEATF II have been presented to HSRB and approved with
suggestions for refinements by both EPA and HSRB. These four scenarios
involve common methods of application of antimicrobial pesticide
products, including mopping, wiping down surfaces with a pre-soaked
ready-to-use wipe, spraying surfaces with a pump spray and wiping them
down with a cloth, and spraying surfaces with an aerosol product that
does not need to be wiped off. For each scenario, monitoring of workers
at three distinctive locations was proposed. After amendment of the
protocols consistent with EPA and HSRB recommendations, the first three
of these four studies have been executed; the first complete scenario
report was submitted to EPA and reviewed by HSRB in October 2010. The
remaining reports of completed AEATF II exposure research were
submitted to EPA in the fall of 2010, and are scheduled for
presentation to HSRB in early 2011.
Monitoring studies for four agricultural exposure scenarios
[[Page 5740]]
submitted by the AHETF have been presented to HSRB and approved, again
with suggestions for refinements by both EPA and HSRB. These scenarios
involve application of liquid pesticides to trellis and orchard crops
using ``air-blast'' spray equipment with closed cabs, application of
liquid pesticides using air-blast spray equipment with open cabs,
mixing and loading pesticides sold in water-soluble packaging into a
wide variety of application equipment, and application of herbicides to
rights-of-way. Each of these scenarios calls for monitoring workers in
five different regions of the United States, working with different
kinds of equipment and crops. The first two of these four studies have
been executed; the first complete scenario report was submitted to EPA
and reviewed by HSRB in October 2010. Reports of the remaining research
scenarios will be submitted to EPA and presented to HSRB in 2011.
D. Legal Challenge to the 2006 Rule
In early 2006, the Natural Resources Defense Council, Inc.,
Pesticide Action Network North American, Pineros y Campesinos Unido Del
Noroeste, Physicians for Social Responsibility--San Francisco, Farm
Labor Organizing Committee, ALF-CIO, and Migrant Clinicians Network
petitioned for review of the 2006 rule in the United States Court of
Appeals for the Second Circuit (Second Circuit Court of Appeals). (NRDC
v. EPA, No. 06-0820-ag (2d Cir.)). The Petitioners argued that the 2006
rule violated the 2006 Appropriations Act because it did not bar all
pesticide research with pregnant women and children, was inconsistent
with the 2004 NAS Report, and was inconsistent with the Nuremburg Code.
The following paragraphs describe the Petitioner's arguments in greater
detail.
1. Inadequate bar against research with pregnant women and
children. Petitioners argued that the scope of the 2006 rule's ban on
research with pregnant women and children was unlawfully narrow because
it was limited to studies intended for submission to EPA under FIFRA or
FFDCA--the pesticide regulatory laws EPA administers. Petitioners
argued that Congress's direction to EPA in the Appropriations Act to
``not permit the use of pregnant women, infants, or children as
subjects'' in ``intentional dosing human toxicity studies for
pesticides'' did not allow EPA to distinguish between studies
originally intended for publication and those intended for submission
to EPA, or between studies with pesticides conducted for consideration
under FIFRA or FFDCA and those conducted for consideration under the
Safe Drinking Water Act or any other regulatory statute. Petitioners
argued that EPA's 2006 rule violated the plain language of the 2006
Appropriations Act on this point.
2. Inconsistency with the 2004 NAS Report. The 2006 Appropriations
Act required EPA's rule to be consistent with the principles proposed
in the 2004 NAS Report. Petitioners argued that in citing the
``principles'' of the 2004 NAS Report, Congress was referring to the 17
recommendations in that report. Petitioners further argued that the
2006 rule was inconsistent with several specific recommendations in the
2004 NAS Report.
First, Petitioners argued that the 2006 rule did not incorporate
Recommendations 3-1 and 5-1 from the 2004 NAS Report, which recommend
factors to be considered in the scientific evaluation of human
research, including that such studies should have ``adequate
statistical power'' and involve ``representative populations for the
endpoint in question.''
Second, Petitioners argued that the 2006 rule did not incorporate
Recommendations 4-1 and 4-2 from the 2004 NAS Report, which suggest
ethical considerations relevant to evaluation of human studies.
Third, Petitioners argued that by adding qualifying language to the
acceptance standard for pre-rule research suggested in Recommendation
5-7 from the 2004 NAS Report, EPA made it inconsistent with the 2004
NAS Report. Petitioners argued that EPA's addition of the word
``significantly'' to the recommended acceptance standard, which permits
EPA to rely on research not ``significantly'' deficient relative to
prevailing standards, made the criterion in the 2006 rule unlawfully
inconsistent with the recommendations in the 2004 NAS Report.
Finally, Petitioners argued that the 2006 rule unlawfully failed to
require provision of medical care for study participants, as suggested
by Recommendation 5-5 from the 2004 NAS Report.
3. Inconsistency with the Nuremberg Code. The 2006 Appropriations
Act also required EPA's rule to be consistent with the principles in
the Nuremberg Code pertaining to human experimentation. Petitioners
argued that the 2006 rule was inconsistent with several principles in
the Nuremburg Code.
First, Petitioners argued that although the Nuremberg Code
specifies that consent must be given by the human subject, the 2006
rule permits consent to be given in certain situations by a legally
authorized representative of the subject.
Second, Petitioners argued that the 2006 rule was inconsistent with
the Nuremberg Code principle that a test subject ``should have
sufficient knowledge and comprehension of the elements of the subject
matter involved as to enable him to make an understanding and
enlightened decision.'' Petitioners argued that the 2006 rule consent
requirements were inadequate to ensure fully informed consent in the
context of research involving pesticides.
Third, Petitioners argued that the 2006 rule failed to address
adequately the Nuremberg Code principle that a subject must be ``so
situated as to be able to exercise free power of choice, without the
intervention of any element of force, fraud, deceit, duress, over-
reaching, or other ulterior form of constraint or coercion.''
Petitioners argued that the requirement of the 2006 rule that consent
should only be sought in circumstances that ``minimize the possibility
of coercion or undue influence'' did not address the potential for
fraud, deceit, over-reaching, or constraint. Petitioners asserted that
constraint was a particular problem when prisoners are used as subjects
in human studies, and the 2006 rule did not specifically address
research with prisoners.
Fourth, Petitioners argued that the 2006 rule was inconsistent with
the Nuremberg Code because it did not explicitly impose the Nuremburg
Code's requirement that human studies be ``designed and based on the
results of animal experimentation.''
Finally, Petitioners argued that the 2006 rule was inconsistent
with the Nuremberg Code principle that human testing ``should be such
as to yield fruitful results * * * unprocurable by other methods or
means of study, and not random and unnecessary in nature.'' Petitioners
argued that the 2006 rule requires no inquiry into whether human
testing is necessary given other methods of research.
E. Settlement of the Litigation
After briefing and argument, but before a decision was rendered by
the Second Circuit Court of Appeals, EPA and Petitioners began
negotiations to settle the litigation. In the settlement agreement
finalized on November 3, 2010, EPA agreed to conduct notice-and-comment
rulemaking on the issue of whether the 2006 rule should be amended. EPA
also agreed to propose, at a minimum, amendments to the 2006 rule that
are substantially consistent with language negotiated between the
[[Page 5741]]
parties and attached to the settlement agreement as Exhibit A. This
agreement, including Exhibit A, is available in the docket for this
action as described under ADDRESSES.
The settlement agreement further provides that EPA will propose the
negotiated amendments no later than January 18, 2011, and that EPA will
take final action on the amendments no later than December 18, 2011.
The settlement agreement, however, makes clear that EPA retains full
discretion concerning what amendments are proposed, and what, if any,
amendments are finalized.
Although the wording of the amendments proposed in this document
differs in a few details of construction and wording, they are
substantially consistent with the regulatory language negotiated with
Petitioners, and EPA considers these amendments to address the
Petitioners' major arguments outlined in Unit III.D. Specifically:
The proposed amendments would retain the scope of the 2006
rule to cover research submitted to EPA under FIFRA or FFDCA, and
extend that scope to cover as well research involving intentional
exposure to a pesticide, intended for submission to EPA under any other
regulatory statute administered by EPA.
The proposed amendments incorporate language from each of
the recommendations from the 2004 NAS Report cited by Petitioners in
their challenge to the 2006 rule, as well as other pertinent
recommendations from the 2004 NAS Report.
The proposed amendments address Petitioners' arguments
concerning the Nuremberg Code by dropping from 40 CFR part 26, subpart
K, all provisions for consent by a representative, and by requiring EPA
to consider whether subjects gave their ``free and fully informed
consent'' to participate in a study, whether the design of proposed new
human research takes into account the knowledge gained in earlier
animal testing, and whether proposed new human research is necessary.
Although these proposed amendments emerged from a settlement
agreement, EPA believes that proposing these amendments is consistent
with the language and purposes of the applicable statutes and because
they further the 2006 rule's goal of ensuring that EPA does not rely on
research involving intentional exposure of human subjects to pesticides
that is not ethically conducted or that is not scientifically sound.
EPA believes that many of the changes proposed in this document are
codifications of the manner in which EPA and HSRB have interpreted and
implemented the 2006 rule, but welcomes comment on these
interpretations. EPA will fully re-evaluate the appropriateness of the
proposed amendments in light of all comments received in response to
this proposed rule before making a final determination. In particular,
EPA seeks comment on the relative merits of the proposed changes
compared to retaining the current scope and content (i.e., current
wording) of the 2006 rule.
IV. Proposed Amendments, Rationale, and Request for Comment
This unit provides a description of each proposed change, the
rationale for the proposed change, and the anticipated effects of each
change relative to the current regulatory text (i.e., the 2006 rule).
EPA specifically requests comment on each of these proposed changes, as
well as on the changes in the aggregate. In particular, EPA asks for
comment on its conclusions regarding the effect of these proposed
changes, including the effect of these proposed changes on the volume
of studies covered by the rule, the likely statutes under which studies
may be submitted, and the impact on activities covered by those other
statutes, relative to the scope of the 2006 rule.
A. Redefining the Scope and Applicability of 40 CFR Part 26, Subparts
K, L, M, P, and O
1. Summary of proposed changes. EPA is proposing amendments that
would modify the scope and applicability of several subparts of the
2006 rule. The proposed changes would modify the criteria defining the
types of research covered by 40 CFR part 26, subparts K, L, and M--most
notably the criteria relating to the intentions of the sponsor or
investigator in conducting the research or the intentions of the person
submitting the research to EPA.
The specific changes proposed to the scope and applicability
sections of 40 CFR part 26, subparts K, L, M, P, and Q, are explained
here. Although EPA does not propose to change the text of the 2006 rule
defining the scope of 40 CFR part 26, subpart O, concerning
``Administrative Actions for Noncompliance,'' the scope of that subpart
would change nonetheless, because its applicability depends on the
scope provisions in other subparts that EPA is proposing to change.
More specifically, these changes alter the scope as follows: instead of
covering substances under FIFRA, the proposed amendments would cover
pesticides under all statutes.
In general, the proposed amendments would shift the focus from
whether the research on the substance was intended for EPA's
consideration and use under the pesticide laws, FIFRA and FFDCA, to
whether the research was conducted with a pesticide and was intended
for EPA's consideration and use in connection with an action under any
regulatory statute administered by EPA. The proposed amendments also
would add a new section to 40 CFR part 26, subpart P, defining its
scope and would change the scope and applicability of 40 CFR part 26,
subpart Q, to parallel the changes in 40 CFR part 26, subpart K.
2. Summary of anticipated effects. Although almost all studies with
pesticides are conducted and submitted to EPA for consideration under
FIFRA or FFDCA, it is possible that some pesticide studies may be
considered by EPA only under other regulatory authorities and not be
considered under FIFRA and FFDCA. If studies involving intentional
exposure of humans to a pesticide are submitted or considered under
other EPA regulatory statutes, with the proposed amendment, such
studies would be subject to the same requirements that would have
applied had they been submitted or considered under FIFRA or FFDCA. In
proposing these amendments, EPA finds that these changes in scope are
consistent with the focus in the 2006 Appropriations Act on intentional
dosing human toxicity studies with pesticides.
In sum, EPA does not believe that the several changes to the
``scope'' sections of 40 CFR part 26, subparts K and L--Sec. 26.1101
and Sec. 26.1201--and a new definition of ``pesticide'' at Sec.
26.1102(c), that expand the range of human research to which these two
subparts apply, will result in a significant increase in the number of
studies reviewed under the rule. However, EPA recognizes that this is a
possibility and requests comment on whether these proposed changes are
clear about which studies would fall under the scope of the rule. EPA
knows of no third-party research involving intentional exposure of a
human subject to a pesticide that has ever been proposed, conducted, or
submitted to EPA under regulatory authorities other than the pesticide
laws. The proposed expansion of the scope of these subparts, however,
would mean that any such studies that are proposed, conducted, or
submitted to EPA will be governed by the same standards as pesticide
studies submitted under FIFRA or FFDCA section 408.
3. 40 CFR part 26, subparts K and L--basic ethical requirements and
prohibitions applying to third-party research involving intentional
exposure of human subjects to a pesticide.
[[Page 5742]]
a. Current rule. Subpart K of 40 CFR part 26 extends the basic
protections of the Common Rule to subjects in certain third-party human
research; subpart L of 40 CFR part 26 forbids new third-party research
involving intentional exposure of children or of pregnant or nursing
women. In the 2006 rule these two subparts apply to ``research with a
human subject'' which meets four criteria. First, it was initiated
after April 7, 2006 (the effective date of the 2006 rule). Second, it
is ``research involving intentional exposure of a human subject'' as
defined at Sec. 26.1102(i). Third, it was conducted or supported by a
``person'' as defined at Sec. 26.1102(j). Fourth, it was intended by
any person conducting or supporting the research to be submitted to
EPA, or to be held for later inspection by EPA, under the pesticide
laws (FIFRA or FFDCA).
The two cited definitions are critical to understanding the scope
and applicability of subparts K and L of 40 CFR part 26. ``Research
involving intentional exposure of a human subject,'' is defined at
Sec. 26.1102(i) as ``a study of a substance in which the exposure to
the substance experienced by a human subject participating in the study
would not have occurred but for the human subject's participation in
the study.'' In applying this definition, EPA considers whether a test
subject would have experienced equivalent exposure to a test material
had the subject not participated in the research. If not, the research
is deemed to involve intentional exposure of the subject. Notably this
definition encompasses all classes of test substances--not only
pesticides.
A ``person'' is defined at Sec. 26.1102(j) to have the same
meaning as in FIFRA section 2(s) (7 U.S.C. 136(s)), except that it
excludes Federal agencies subject to the Common Rule and any person
when performing research supported by a Common Rule Federal department
or agency. This exclusion is appropriate because that research is
covered by the Common Rule, which provides necessary and appropriate
protections for the research subjects. Thus, research already covered
by the standards of the Common Rule is not also subject to subparts K
and L. These subparts, in short, apply only to ``third-party
research''--research that is neither conducted (``first-party'') nor
supported (``second-party'') by EPA or another Common Rule Federal
department or agency.
Finally, Sec. 26.1101(g) explains how EPA will approach
determination of the intent of sponsors or investigators to submit
research to EPA under the pesticide laws, or hold it for inspection by
EPA under the pesticide laws.
b. Proposed amendments, rationale, and anticipated effect. The
amendments proposed in this document would not change the definitions
of ``research involving intentional exposure of a human subject'' or of
``person.'' They would add a new definition of ``pesticide'' at Sec.
26.1102(c), and would modify the applicability provisions in Sec.
26.1101, as explained later in this Unit of the document.
The first of the four criteria for application of 40 CFR part 26,
subpart K, will change to incorporate the effective date of a final
rule amending the 2006 rule. EPA believes it would be inappropriate to
apply these proposed amendments retroactively. For example, if post-
2006 research newly covered by an amended rule as proposed in this
document were submitted to EPA, its acceptability should not be judged
by its compliance with a rule promulgated after it was conducted. Until
the 2006 rule is amended by a final rule, its provisions continue to
apply fully to new research. Hence no sponsor or investigator subject
to the 2006 rule would be relieved by the change in the effective date
of any obligation to comply with 40 CFR part 26, subparts K and L, for
research initiated between April 7, 2006, and the effective date of any
subsequent amendments.
The proposal would modify the second of the four criteria so that
40 CFR part 26, subparts K and L, would apply to research involving
intentional exposure of a human subject ``to a pesticide'' when the
research is intended for submission to EPA under any regulatory statute
other than FIFRA or FFDCA. The definition of ``research involving
intentional exposure of a human subject'' would not change, nor would
the applicability of these subparts to all new third-party research
involving intentional exposure of human subjects which is intended for
submission to EPA under FIFRA or FFDCA.
In determining whether research involves intentional exposure to a
pesticide, EPA will focus, as does the FIFRA definition of a
``pesticide,'' on the intended use of the substance. EPA expects that
application of this standard will nearly always be straightforward.
However, EPA recognizes that there may be cases where making such a
determination may not be as straightforward. EPA will apply this
criterion as follows.
Initially, EPA will examine the study on its face. If the study
states that it involves the testing of a pesticide, or if the tested
substance is used for pesticidal effect in the study, as it is in
insect repellent efficacy testing or in monitoring exposure of
pesticide applicators, there can be little question that the study
involves exposure to a pesticide. If on the other hand the study
reports testing of another type of substance, such as an industrial
chemical, waste product, or air pollutant, then absent compelling
evidence to the contrary, EPA will not treat the study as involving
exposure to a pesticide.
If it is not clear from the face of the study whether it involves
exposure to a pesticide, EPA will look to other objective factors to
determine whether a substance is being tested as a pesticide. Intent to
test a substance as a pesticide could be indicated by evidence that the
testing was conducted or supported by an entity regulated under FIFRA
or section 408 of FFDCA; the testing was conducted for the purpose of
attaining a FIFRA registration or FFDCA tolerance; there are not
significant commercial uses for the substance other than as a
pesticide; or human exposure to the substance occurs primarily from its
use as a pesticide. Absent any such evidence, EPA will generally treat
the study as not involving exposure to a pesticide.
EPA expects that in most cases, the question of whether the study
involves exposure to a pesticide will be quickly resolvable without
looking to other objective factors such as the four identified in the
previous paragraph. EPA believes that this would be true even for
multiple-use substances that may be used as a pesticide and may also
result in human exposure from other commercial uses or as a result of
deposition in the environment as a waste product.
A good example of how EPA will determine if studies on multi-use
substances are studies on a pesticide is presented by sulfur dioxide
(SO2)--a registered pesticide active ingredient used as a
fungicide in grape culture, and also a common air pollutant. Thousands
of tons of SO2 are released yearly into the atmosphere by
burning of coal and other fossil fuels. In promulgating National
Ambient Air Quality Standards (NAAQS) for SO2 under the
Clean Air Act (CAA) in 2010, EPA relied on numerous human studies
involving intentional exposure of subjects to SO2. Most of
these studies on their face indicate clearly that they tested
SO2 as an industrial air pollutant and not as a pesticide.
The few that do not expressly state they tested SO2 as an
air pollutant are, nonetheless, easily classified as not involving
exposure to a pesticide, because the testing was not conducted
[[Page 5743]]
or sponsored by a pesticide registrant, the studies do not indicate
they were performed in support of FIFRA registration, and there are
clearly other major sources of human exposure to SO2 in
addition to whatever pesticide exposure occurs. Thus, these studies
would not come within the scope of the 2006 rule if the scope is
modified as proposed.
EPA specifically requests comment on the implications of this
change for the volume of studies that may need to be reviewed under
such a proposed amendment.
The amendments proposed in this document would not change the
applicability of 40 CFR part 26, subparts K and L, to ``persons'' or
the definition of that term at Sec. 26.1102(j). Thus the third of the
four criteria would not be affected by these proposed amendments.
The fourth criterion would be broadened by the amendments proposed
in this document beyond the scope of the 2006 rule. The 2006 rule
applies to research with any substance, conducted with intent to submit
its results to EPA under FIFRA or FFDCA; as proposed here, the rule
would apply as well to research with a pesticide, conducted with intent
to submit its results to EPA ``for consideration in connection with any
action that may be performed under any regulatory statute administered
by EPA'' other than FIFRA or FFDCA.
The new element in this fourth criterion, putting aside the
proposed amendment to refer to ``pesticides,'' is the reference to
actions taken ``under any regulatory statute administered by EPA.''
Research intended for submission under FIFRA or FFDCA is covered by the
2006 rule and would continue to be covered under proposed Sec.
26.1101(a)(1). Proposed Sec. 26.1101(a)(2) would broaden the scope of
subparts K and L of 40 CFR part 26 to apply as well to research
involving intentional exposure of a human subject to a pesticide which
is intended for submission to EPA for consideration in connection with
any action that may be performed under any regulatory statute other
than FIFRA or FFDCA. Such submission could be made under CAA, the Safe
Drinking Water Act (SDWA), the Clean Water Act (CWA), the Resource
Conservation and Recovery Act (RCRA), the Comprehensive Environmental
Response, Compensation and Liability Act (CERCLA, or the Superfund
law), or other similar statutes. EPA specifically seeks comment on the
scope of this proposed change (i.e., the frequency with which it might
be triggered, including other statutes to which the proposed change
would apply) and the implications of the proposed changes on the
activities governed by those other regulations. EPA seeks comment on
the relative merits of this change compared to retaining the current
scope of the 2006 rule. As noted, EPA does not expect that these
wording changes will result in any substantive changes to the number or
manner in which studies are currently reviewed.
As an example, EPA's Office of Water has, in the past, set Maximum
Contaminant Levels (MCLs) under the SDWA with pesticides found in
drinking water. Under the proposed amendment to the scope of 40 CFR
part 26, subpart K, any new third-party study involving intentional
exposure of a human to a pesticide, and intended for submission to the
Office of Water for consideration in setting a MCL, would now be
subject to 40 CFR part 26, subpart K, including the requirement of
Sec. 26.1125 for submission of the proposal for prior review by EPA
and HSRB. EPA would note that this is a theoretical example in that it
is unaware of any such study having been submitted with regard to a
MCL.
EPA actions not taken under the authority of regulatory statutes
would not satisfy this fourth criterion. For example, an EPA comment on
another Federal department's or agency's Environmental Impact Statement
would not constitute an action taken under a regulatory statute, and
research intended for submission solely for consideration in such a
context would not be subject to 40 CFR part 26, subparts K and L.
EPA interprets the word ``action'' in this context broadly,
embracing both regulatory and non-regulatory actions. Regulatory
actions include, for example, cancellation or registration of a
pesticide, establishment of a tolerance for a pesticide residue in
food, or establishing a MCL for a pesticide active ingredient under
SDWA. Non-regulatory actions include, for example, risk assessments of
pesticide active ingredients, recommended (non-binding) safe levels of
exposure such as Health Advisory Limits when these pertain to
pesticides, or clean-up standards for pesticides at a Superfund site.
The amendments proposed in this document include two additional
editorial revisions to clarify the scope sections of 40 CFR part 26,
subparts K and L. One change would clarify the applicability of 40 CFR
part 26, subpart K, by moving the exposition of how EPA will determine
intent to submit from Sec. 26.1101(g), where it appears in the 2006
rule, to Sec. 26.1101(b), immediately following the presentation of
the four criteria. The other would amend Sec. 26.1201, the scope
section of 40 CFR part 26, subpart L, to state simply that 40 CFR part
26, subpart L applies to all research subject to 40 CFR part 26,
subpart K.
4. 40 CFR part 26, subpart M--requirement for documentation of the
ethical conduct of completed human research submitted to EPA.
a. Current rule. Subpart M of 40 CFR part 26 requires those who
submit the results of human research to EPA for consideration under the
pesticide laws to submit information documenting the ethical conduct of
the completed research. Under the 2006 rule, 40 CFR part 26, subpart M,
applies when a ``person'' as defined at Sec. 26.1102(j) submits after
the effective date of the 2006 rule a report containing the results of
any human research to EPA for consideration under the pesticide laws.
These criteria differ from those defining coverage by 40 CFR part
26, subparts K and L, in important ways. First, unlike other subparts
of the 2006 rule, subpart M applies to submissions after the effective
date of the rule of any and all human research, without regard to who
conducted it, when, or for what purpose, or whether or not the reported
research involved intentional exposure of a human subject. Second,
subpart M applies only when a person (other than a Federal department
or agency subject to the Common Rule) submits the results of human
research to EPA. Subpart M does not apply when EPA, on its own
initiative, retrieves published articles or otherwise obtains
information derived from human research.
b. Proposed amendments and rationale. EPA proposes to broaden the
applicability of 40 CFR part 26, subpart M, by amending Sec. 26.1301,
while leaving the substantive requirements of subpart M unchanged.
Specifically, EPA proposes to include submissions of reports of human
research on pesticides for consideration by EPA under regulatory
statutes other than FIFRA or FFDCA. Under the proposed amendments,
subpart M would apply when a ``person'' as defined at Sec. 26.1102(j)
submits after the effective date of the amended rule a report
containing the results of any human research to EPA for consideration
under FIFRA or FFDCA, or a report containing the results of any human
research on or with a pesticide for consideration under any other
regulatory statute administered by EPA.
The proposed amendments to 40 CFR part 26, subpart M, attempt to
balance the need for full information on ethical issues with a concern
that the public not be deterred from submitting scientific data
relevant to EPA information
[[Page 5744]]
requests. Section 26.1303 requires a submitter to provide ``information
concerning the ethical conduct'' of the human research, including
copies of relevant IRB records, and copies of records relevant to the
key ethical considerations outlined in Sec. 26.1117 and Sec.
26.1125(a). This requirement is qualified by the provision that such
records need only be provided ``[t]o the extent [the records] are
available to the submitter and not previously provided to EPA,'' but
any submitter not providing the information required must ``describe
the efforts made to obtain the information.''
To minimize the potential burden on commenters, EPA considered
excluding from the coverage of 40 CFR part 26, subpart M, submissions
of published scientific journal articles reporting human research, or
of citations to such articles. In some circumstances, however, EPA
believes it is important for submitters of even published human
research to bear the burden of gathering the information required by
Sec. 26.1303. Specifically, EPA believes a submitter of published
human research who is seeking action under a regulatory statute from
EPA that would directly benefit the submitter should be obliged to
gather records bearing on the conduct of the research, even if the
research is described in the public literature. For example, an
applicant for a pesticide registration or a party petitioning for a
pesticide tolerance should have to exercise reasonable efforts to
obtain records of the ethical conduct of research relied on to support
the EPA action sought, whether or not the research happens to be
described in a scientific journal. Reasonable efforts in these
circumstances may include seeking relevant records from the research
administrator or the overseeing IRB. On the other hand, if a member of
the public responds to an EPA request for information on a pesticide by
citing or submitting a published study, EPA believes that certification
that the submitter did not sponsor, participate in, or otherwise have
personal knowledge of or responsibility for the referenced research
would satisfy the submitter's obligation under 40 CFR part 26, subpart
M.
c. Anticipated effect. EPA's concern for the potential burden of 40
CFR part 26, subpart M, on the public is tempered by its experience
under the 2006 rule. Since promulgation of the 2006 rule EPA has
received very few submissions of reports of human research on or with a
pesticide for consideration under FIFRA or FFDCA, and EPA expects
submissions of such studies to EPA for consideration only under other
regulatory statutes will be even less common.
EPA specifically requests comments on this approach to and
interpretation of the requirements in 40 CFR part 26, subpart M. Such
comments should address whether the proposed rule language is adequate
to implement EPA's interpretation.
5. 40 CFR part 26, subpart P--EPA and HSRB review of proposed and
completed human research.
a. Current rule. Subpart P of 40 CFR part 26 applies to EPA and
HSRB reviews of proposals for new research involving intentional
exposure of a human subject, and EPA and HSRB reviews of reports of
completed research involving intentional exposure of a human subject
and on which EPA proposes to rely in an action under the pesticide
laws. Unlike other subparts of the 2006 rule, subpart P does not
include a ``scope'' section; its applicability is defined only
indirectly by references to other subparts.
b. Proposed amendments and rationale. EPA proposes to make explicit
the applicability of 40 CFR part 26, subpart P, in a new Sec. 26.1601.
This proposed new section provides that 40 CFR part 26, subpart P,
applies to EPA and HSRB reviews of (1) ``proposed research subject to
40 CFR Sec. 26.1125,'' and (2) ``reviews by EPA after [effective date
of the amended rule] and, to the extent required by Sec. 26.1604, by
the Human Studies Review Board, of reports of completed research
subject to 40 CFR 26.1701.''
c. Anticipated effect. Since 40 CFR 26.1125 is in subpart K and 40
CFR 26.1701 is in subpart Q, the broadened scope of these subparts as
proposed in these amendments would indirectly broaden the scope of 40
CFR part 26, subpart P.
6. 40 CFR part 26, subpart Q--ethical standards for assessing
whether to rely on the results of human research in EPA actions.
a. Current rule. Subpart Q of 40 CFR part 26 defines ethical
standards that must be met for EPA to rely on the results of human
research in actions taken under the pesticide laws. Specifically, 40
CFR part 26, subpart Q, applies to EPA decisions to rely on data from
completed studies involving intentional exposure of a human subject,
when EPA regards the data as scientifically valid and relevant to an
action taken under the pesticide laws.
b. Proposed amendments and rationale. For the same reasons it is
proposing to broaden the applicability of 40 CFR part 26, subpart K
(discussed in Unit IV.A.1.), EPA proposes to amend Sec. 26.1701 to
broaden the applicability of 40 CFR part 26, subpart Q. Proposed Sec.
26.1701(a) would retain without change the applicability of 40 CFR part
26, subpart Q, to research involving intentional exposure of human
subjects to any substance, in the context of EPA actions taken under
FIFRA or FFDCA. Proposed Sec. 26.1701(b) would extend the
applicability of 40 CFR part 26, subpart Q, to research involving
intentional exposure of human subjects to a pesticide, in the context
of EPA actions taken under any other regulatory statute administered by
EPA.
EPA intends to interpret ``action'' and ``regulatory statute
administered by EPA'' in 40 CFR part 26, subpart Q, just as these terms
would be interpreted for 40 CFR part 26, subpart K. To make this scope
provision consistent with the other scope provisions in this proposal,
EPA proposes to depart from the language negotiated in the settlement
agreement and define the scope of 40 CFR part 26, subpart Q, in terms
of the ``research'' covered rather than the ``decisions'' covered.
c. Anticipated effect. EPA expects this change in the scope of 40
CFR part 26, subpart Q, to affect few, if any, EPA actions. Although
such actions may occur in the future, EPA cannot identify any actions
taken since 2006 under any regulatory statute other than FIFRA or FFDCA
that relied on research involving intentional exposure of a human
subject to a pesticide.
As explained previously, EPA is authorized to propose this change
because it is consistent with the 2006 Appropriations Act. This
proposal would mean that all intentional human studies involving
pesticides submitted to EPA would be reviewed under the same ethical
and scientific criteria. On the other hand, EPA has also noted that it
expects this change will affect few additional studies and may create
some uncertainty as to what studies are covered by the rule.
EPA specifically invites comment on the value of making this change
and whether there are additional factors to be considered in evaluating
the appropriateness of the change, such as the frequency with which it
might be triggered, including other statutes to which the proposed
change would apply, and on the clarity of the proposed changes.
B. Disallowing Consent by a Surrogate (40 CFR Part 26, Subpart K)
1. Current rule. In the 2004 NAS Report to EPA, the NAS recommended
use of the Common Rule as the starting point for protecting human
subjects in research involving intentional exposure. Consistent with
this recommendation,
[[Page 5745]]
EPA incorporated much of the text of the Common Rule into subpart K of
40 CFR part 26, including language providing for consent for a
subject's participation in research by the subject's ``legally
authorized representative'' when the subject lacks the capacity to
consent for himself or herself. The Common Rule, drafted to protect
subjects in a wide variety of research settings, included these
provisions to permit research in various situations, including, for
example, research into emergency procedures to save lives of
unconscious patients, into improved care for people suffering psychosis
or schizophrenia, and to collect valuable data from research with other
subjects who lacked the legal capacity to provide fully informed, fully
voluntary consent.
2. Proposed amendments and rationale. EPA proposes to amend 40 CFR
part 26 by deleting from subpart K all references permitting consent by
a subject's legally authorized representative. The sections affected
are the definition of ``legally authorized representative'' at Sec.
26.1102(c); the ``Criteria for IRB approval of research'' at Sec.
26.1111; the ``General requirements for informed consent'' at Sec.
26.1116; and the requirements for ``Documentation of informed consent''
at Sec. 26.1117.
EPA proposes to disallow consent by a representative in third-party
studies because the types of research that are conducted on pesticides
would not use subjects for whom such a procedure is needed. (The
research covered by 40 CFR part 26, subpart K includes research
involving intentional exposure of non-pregnant, non-nursing adults to a
pesticide or research involving intentional exposure of non-pregnant,
non-nursing adults intended for submission under FIFRA or FFDCA.)
3. Anticipated effect. EPA has never seen, and cannot envision, any
such research in which it could be justified to enroll subjects lacking
the capacity to consent for themselves. EPA does not propose to modify
the provisions of 40 CFR part 26, subpart A, EPA's codification of the
Common Rule. 40 CFR part 26, subpart A, applies to a much broader range
of research with human subjects conducted or supported by EPA including
research for which consent by a legally authorized representative may
be appropriate.
C. Revised Standards for EPA and HSRB Reviews (40 CFR Part 26, Subpart
P)
1. Current rule. 40 CFR part 26, subpart P, defines in largely
procedural terms how EPA evaluates proposals for new research submitted
under Sec. 26.1125 of 40 CFR part 26, subpart K, and how EPA is to
review reports of completed research. Subpart P of 40 CFR part 26 also
defines the membership and responsibilities of HSRB.
2. Proposed amendments and rationale.
a. Revisions to 40 CFR part 26, subpart P, generally. The proposed
amendments to 40 CFR part 26, subpart P, include:
A proposed new Sec. 26.1601 explicitly defining the
applicability of 40 CFR part 26, subpart P, to EPA and HSRB reviews of
proposals for new research submitted under Sec. 26.1125 of subpart K
and to EPA and HSRB reviews of reports of completed research covered by
subpart Q. This change is discussed in Unit IV.A.3.
A proposed new Sec. 26.1602 references the definitions in
40 CFR part 26, subpart K.
A proposal to expand the discussion of EPA reviews of
proposed research in Sec. 26.1603, retaining all elements of Sec.
26.1601 from the 2006 rule, and including a new Sec. 26.1603(b)
listing considerations to be addressed by EPA in its science reviews of
proposed research, and a new Sec. 26.1603(c) listing considerations to
be addressed by EPA in its ethics reviews of proposed research.
A proposal to slightly revise discussion of EPA reviews of
completed research, redesignating Sec. 26.1602 in 40 CFR part 26 as
Sec. 26.1604, and revising paragraph (a) to emphasize the required
thoroughness of EPA's reviews and to extend its applicability to
reviews of completed human research on pesticides considered under
regulatory statutes other than FIFRA or FFDCA.
The unchanged text of Sec. 26.1603 in the 2006 rule would
be redesignated as Sec. 26.1605, defining the membership and
responsibilities of HSRB.
A proposed new Sec. 26.1606 requiring HSRB in its reviews
of proposed research to consider the same range of scientific, ethical,
and other topics addressed by EPA in its reviews under Sec. 26.1603.
A proposed new Sec. 26.1607 requiring HSRB in its reviews
of completed research to consider both the scientific and ethical
merits of the research, and to apply the appropriate acceptance
standards in 40 CFR part 26, subpart Q.
As indicated previously and again throughout this discussion, EPA
requests comment on each of these proposed changes, as well as on the
changes in the aggregate. EPA also seeks comments on particular points
as provided in the discussion.
b. Section 26.1603--EPA Review of proposed human research. Because
the most significant changes proposed are the new lists in Sec.
26.1603(b) and (c) of considerations to be addressed in EPA reviews of
proposed new research, those proposed changes will be discussed in
greater detail here. These proposed lists were derived primarily from
the following recommendations in the 2004 NAS Report (reproduced
verbatim here and referenced in the subsequent discussions):
Recommendation 3-1: Scientific Validity of Intentional Human Dosing
Studies
EPA should issue guidelines for determining whether intentional
human dosing studies have been:
a. Justified, in advance of being conducted, as needed and as
scientifically appropriate, in that they could contribute to
addressing an important scientific or policy question that cannot be
resolved on the basis of animal data or human observational data;
b. Designed in accordance with current scientific standards and
practices to (i) address the research question, (ii) include
representative study populations for the endpoint in question, and
(iii) meet requirements for adequate statistical power;
c. Conducted in accordance with recognized good clinical
practices, including appropriate monitoring for safety; and
d. Reported comprehensively to EPA, including the full study
protocol, all data produced in the study (including adverse events),
and detailed analyses of the data.
Recommendation 4-1: Value of Studies That Seek to Improve the
Accuracy of EPA's Decisions But Do Not Provide a Public Health or
Environmental Benefit
EPA should consider a human dosing study intended to reduce the
interspecies uncertainty factor (for example, a study of a biomarker
such as cholinesterase inhibition) as conferring a societal benefit
only if it was designed and conducted in a manner that would improve
the scientific accuracy of EPA's extrapolation from animal to human
data. Because the anticipated benefit would not be as great as that
conferred by studies intended to provide a public health or
environmental benefit, the study could be justified ethically only
if the participants' exposure to the pesticide could reliably be
anticipated to pose no identifiable risk or present a reasonable
certainty of no harm to study participants.
Recommendation 5-1: Criteria for Scientific and Ethical
Acceptability
Studies that do not meet the highest scientific and ethical
standards should not be carried out or accepted by EPA as input to
the regulatory decision-making process. Necessary conditions for
scientifically and ethically acceptable intentional human dosing
studies include:
a. Prior animal studies and, if available, human observational
studies;
b. A demonstrated need for the knowledge to be obtained from
intentional human dosing studies;
c. Justification and documentation of a research design and
statistical analysis that are adequate to address an important
scientific or policy question, including adequate power to detect
appropriate effects;
[[Page 5746]]
d. An acceptable balance of risks and benefits and minimization
of risks to participants;
e. Equitable selection of participants;
f. Free and informed consent of participants; and
g. Review by an appropriately constituted IRB or its foreign
equivalent.
Recommendation 5-2: Participant Selection Criteria
IRBs reviewing intentional human dosing studies should ensure
that the following conditions are met in selecting research
participants:
a. Selection should be equitable.
b. Selection of persons from vulnerable populations must be
convincingly justified in the protocol, which also must justify the
measures to be taken to protect those participants.
c. Selection of individuals with conditions that put them at
increased risk for adverse effects in such studies must be
convincingly justified in the protocol, which also must justify the
measures that investigators will use to decrease the risks to those
participants to an acceptable level.
Recommendation 5-3: Payment for Participation
IRBs, all relevant review boards, investigators, and research
sponsors should ensure that payments to participants in intentional
human dosing studies are neither so high as to constitute undue
inducement nor so low as to be attractive only to individuals who
are socioeconomically disadvantaged. Proposed levels of and purposes
for remuneration (e.g., time, inconvenience, and risk) should be
scrutinized in light of the principles of justice and respect for
persons. Moreover, EPA, in conjunction with other Federal agencies,
should consider developing further guidance on remuneration for
participation in intentional human dosing studies, including
guidance regarding whether remuneration should reflect the level of
risk as well as the time and inconvenience involved.
Recommendation 5-5: Compensation for Research-Related Injuries
At a minimum, sponsors of or institutions conducting intentional
human dosing studies should ensure that participants receive needed
medical care for injuries incurred in the study, without cost to the
participants. In addition, EPA should study whether broader
compensation for research-related injuries should be required.
Recommendation 6-1: IRB Review of All Studies
EPA should require that all human research conducted for
regulatory purposes be approved in advance by an appropriately
constituted IRB or an acceptable foreign equivalent. Research
conducted by EPA scientists should be reviewed by an EPA-authorized
IRB.
[Taken from pages 7-14 of the 2004 NAS Report (http://www.national-academies.org).]
c. Science Reviews--Sec. 26.1603(b). The provisions in proposed
Sec. 26.1603(b) include considerations that EPA must take into account
when conducting its science reviews of proposed research that would be
covered by the rule. In developing this list of considerations, EPA
relied on recommendations 3-1 and 5-1 from the 2004 NAS Report to
identify specific items that would be relevant to evaluating the
scientific merit of proposed human research. How EPA developed the
specific language for each provision follows.
Proposed Sec. 26.1603(b)(1): Whether the research would
be likely to produce data that address an important scientific or
policy question that cannot be resolved on the basis of animal data or
human observational research.
This language is a combination of recommendations 3-1(a) and 5-1(b)
and (c) from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). The language ``address an important scientific or policy
question'' reflects excerpts taken from recommendation 5-1(c). The
language ``that cannot be resolved on the basis of animal data or human
observation research'' is taken from recommendation 3-1(a). These
recommendations are intended to avoid unnecessary exposure for human
subjects. If animal data or human observational research were available
to address an important scientific or policy question, then there would
be no scientific need for additional human research. EPA relied
primarily on recommendation 5-1 in formulating the proposed language
because that recommendation addresses criteria for EPA acceptance of
human research, whereas recommendation 3-1describes topics that should
be covered in EPA guidelines.
Based on recommendation 5-1, EPA has phrased the proposed language
as whether the research ``addresses'' an important scientific question
rather than use the phraseology ``contributes to addressing'' in
recommendation 3-1. The Agency believes its formulation is clearer and
intends to interpret this as meaning that the research needs to be
designed to obtain data likely to provide significant insight into
important research questions.
EPA requests comment on whether its reliance primarily on the
language of recommendation 5-1(c) is appropriate here, or whether it
should have used the ``contributes to'' language from recommendation 3-
1(a).
Proposed Sec. 26.1603(b)(2): Whether the proposed
research is designed in accordance with current scientific standards
and practices to: Address the research question, include representative
study populations for the endpoint in question, and have adequate
statistical power to detect appropriate effects.
Again, this language is a combination of recommendations 3-1(b) and
5-1(c) from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). The recommendations highlight the need for adequate
statistical power and appropriate representative study populations to
ensure the scientific validity and reliability (and thus ethical
conduct) of human research. To accommodate these recommendations, EPA
is proposing to adopt language from the recommendations 3-1(b) and 5-
1(c).
For the reason stated in the previous discussion on proposed Sec.
26.1603(b)(1), EPA placed primary reliance on recommendation 5-1. The
Agency notes that the proposed Sec. 26.1603(b)(2)(iii), which reflects
the language in 5-1(c), differs from the language in 3-1(b), which says
``meets requirements for adequate statistical power.'' The Agency
prefers to propose the language as contained in 5-1(c) because it does
not believe that there is one specific set of ``requirements'' with
which to evaluate statistical power. The Agency intends to evaluate the
statistical power of a study while focusing on the ultimate goal of
ensuring that appropriate effects are detected rather than on some
arbitrary and undefined set of ``requirements.''
EPA requests comment on whether the proposed language is clear and
specifically on this language as compared to using the language
directly from the recommendation in the 2004 NAS Report.
Proposed Sec. 26.1603(b)(3): Whether the investigator
proposes to conduct the research in accordance with recognized good
research practices, including, when appropriate, good clinical practice
guidelines and monitoring for the safety of subjects.
This provision reflects excerpts taken from recommendation 3-1(c)
from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). Although the NAS focused on good clinical practice
guidelines, the Agency is proposing to apply a broader standard
``recognized good research practices'', which may include good clinical
practice guidelines when appropriate. The rationale for this is that
some human research--in fact, all human research proposed to EPA to be
conducted since promulgation of the 2006 rule--is not conducted in
clinical settings (e.g., field testing of repellents or worker
exposure) and thus good clinical practice guidelines would be
inappropriate to apply. However, there may be other general good
research practices that the research community
[[Page 5747]]
employs to ensure scientific integrity of their studies and safety of
the subjects that would be relevant for the Agency to consider. One
such practice that has currently been developed is the Guidelines for
Performance Testing of Skin-Applied Insect Repellent issued in October
2008, and incorporated into the OCSPP harmonized test guidelines
library in July 2010, entitled ``Product Performance Test Guidelines
No. 810.3700: Insect Repellents to be Applied to Human Skin'' (http://www.epa.gov/ocspp/pubs/frs/publications/Test_Guidelines/series810.htm).
EPA requests comment on this expansion and also welcomes
suggestions for other good research practice documents that could be
cited here as well.
d. Ethics Reviews--Sec. 26.1603(c). The provisions in proposed
Sec. 26.1603(c) address many important ethical concerns, including,
among other things, identification and minimization of risks to
participants, equitable selection of participants, and provision of
medical care for participants. In developing this list of
considerations, EPA relied on several recommendations from the 2004 NAS
Report, including 4-1, 5-1, 5-2, 5-3, and 5-5 (see verbatim text
provided in Unit IV.C.2.b.), to identify specific considerations that
would be relevant to evaluating the ethics of proposed human research.
Each proposed consideration is discussed below.
Proposed Sec. 26.1603(c)(1): Whether adequate information
is available from prior animal studies or from other sources to assess
the potential risks to subjects in the proposed research.
This provision reflects excerpts taken from recommendation 5-1(a)
from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.), which recommends that animal studies be available prior to
conducting human studies. This NAS recommendation also suggests
consideration of human observational studies if available. When EPA
conducts its ethics reviews, it does and will continue to consider
whether there is adequate information from prior animal and human
observational studies to understand the level of risk that may be
presented to subjects of the proposed research. Although the NAS does
not specify in its recommendation the specific purpose that the
information from prior animal studies or from other sources, including
human observational studies if available, serves, EPA believes its use
of these studies to assess potential risks in evaluating the ethics of
a human research proposal subject to this rule is reasonable and an
integral part of determining whether the benefits of the research
outweigh the risks of the research. The proposed language refers to
``information * * * from prior animal studies or from other sources.''
EPA intends the reference to ``other sources'' to include human
observational studies, consistent with recommendation 5-1.
EPA requests comment on whether the proposed language is clear and
specifically on this language as compared to using the language
directly from the recommendation in the 2004 NAS Report.
Proposed Sec. 26.1603(c)(2): Whether the research
proposal adequately identifies anticipated risks to human subjects and
their likelihood of occurrence, minimizes identified risks to human
subjects, and identifies likely benefits of the research and their
distribution.
This provision is based on recommendation 5-1(d) from the 2004 NAS
Report (see verbatim text provided in Unit IV.C.2.b.), which states
that the necessary conditions for human research include ``an
acceptable balance of risks and benefits and minimization of risks to
participants.'' EPA has separated these two conditions and addresses
minimization of risk in this paragraph and the balance of risks and
benefits in proposed Sec. 26.1603(c)(3). In this paragraph, EPA also
proposes to include a consideration of whether the research proposal
adequately identifies anticipated risks to human subjects and their
likelihood of occurrence and the likely benefits of the research and
their distribution. These additional considerations are important in
understanding the overall risk/benefit picture of proposed human
research covered by this rule. EPA does not believe that adding these
considerations will impose any additional burden on stakeholders since
this information is typically provided with research proposals that are
submitted to IRBs and to the Agency. EPA currently reviews human
research proposals submitted to it under the 2006 rule with these
considerations in mind.
EPA requests comment on whether it is appropriate to address
minimization of risk and the risk-benefit balance in separate
paragraphs. EPA has chosen this approach because it interprets
recommendation 5-1(d) as setting forth separate and independent
considerations and, given this interpretation, believes that repeating
the risk-benefit balance language in this paragraph would be
duplicative and confusing. EPA also recognizes an alternative view of
recommendation 5-1(d) is that separating the minimization of risk
consideration from the risk-benefit balance consideration alters the
collective context intended by recommendation 5-1(d) of the 2004 NAS
Report. As such, EPA requests comments on both approaches as they apply
to the proposed Sec. Sec. 26.1603(c)(2) and 26.1603(c)(3).
Proposed Sec. 26.1603(c)(3): Whether the proposed
research presents an acceptable balance of risks and benefits. In
making this determination for research intended to reduce the
interspecies uncertainty factor in a pesticide risk assessment, the
Administrator must consider Recommendation 4-1 in the 2004 Report from
the National Research Council of the National Academy of Sciences
(NAS), entitled ``Intentional Human Dosing Studies for EPA Regulatory
Purposes: Scientific and Ethical Issues.''
This provision reflects excerpts taken from recommendations 5-1(d)
and 4-1 from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). For each human research proposal submitted to the Agency
that is covered by this rule, in addition to considering whether a
study proposal minimizes risks to the human subjects, EPA is proposing
to consider whether the proposed research presents an acceptable
balance of risks and benefits based on, among other things, the
information it considers under the proposed paragraphs (c)(1) and
(c)(2) in Sec. 26.1603.
Recommendation 5-1(d) also refers to ``the minimization of risks to
participants.'' EPA addressed that consideration in proposed Sec.
26.1603(c)(2). The Agency requests comment on whether another reference
to minimization of risk is nonetheless needed in this paragraph for
consistency with the 2004 NAS Report.
For research that is intended specifically to reduce the
interspecies uncertainty factor in a pesticide risk assessment, the
Agency is proposing to consider whether that study presents an
acceptable balance of risks and benefits in accordance with process
laid out for evaluating that type of study in recommendation 4-1 and
the attendant discussion in the 2004 NAS report that informs the
application of that recommendation. EPA lacks experience in reviewing
proposals for research intended to reduce the interspecies uncertainty
factor. Since the promulgation of the 2006 rule, EPA has received no
proposals for such research and, as noted in Unit IV.A.2. and A.3., EPA
knows of no third-party research involving intentional exposure of a
human subject to a pesticide that has ever been proposed, conducted, or
[[Page 5748]]
submitted to EPA under regulatory authorities other than the pesticide
laws. However, EPA recognizes that this is a possibility in the future.
The Agency asks for comment on how it should consider NAS
recommendation 4-1, if this proposed amendment were finalized and EPA
received a study proposal for that purpose, and, given the context of
the proposed expansion to the scope of the 2006 rule as discussed in
Unit IV.A., whether the proposed Sec. 26.1603(c)(3) is clear about how
NAS recommendation 4-1 might apply to future studies.
Proposed Sec. 26.1603(c)(4): Whether subject selection
will be equitable.
This provision is taken directly from recommendations 5-1(e) and 5-
2(a) from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.).
Proposed Sec. 26.1603(c)(5): Whether subjects'
participation would follow free and fully informed consent.
This provision reflects excerpts taken from recommendations 5-1(f)
from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.), which mentions free and informed consent, and the Nuremberg
Code.\2\
---------------------------------------------------------------------------
\2\ The Nuremburg Code states the importance of free and fully
informed consent and describes the elements of such consent: ``The
voluntary consent of the human subject is absolutely essential. This
means that the person involved should have legal capacity to give
consent; should be so situated as to be able to exercise free power
of choice, without the intervention of any element of force, fraud,
deceit, duress, over-reaching, or other ulterior form of constraint
or coercion; and should have sufficient knowledge and comprehension
of the elements of the subject matter involved as to enable him to
make an understanding and enlightened decision * * *'' http://ohsr.od.nih.gov/guidelines/nuremberg.html.
---------------------------------------------------------------------------
Key aspects or indicators of free and fully informed consent or
legally effective consent are set out in detail in Sec. 26.1116. They
include that information be provided in a form understandable to the
subject, including information on the purposes and duration of the
research as well as on the procedures, risks, and any compensation
involved in the research. Further, the subject must be made aware that
participation in the research is voluntary, that there is no penalty
for not participating, and that the subject may withdraw from the
research at any time. The reference in Sec. 26.1603(c)(5) to ``free
and fully informed consent'' emphasizes the centrality of this concept
to the ethics evaluation process.
Proposed Sec. 26.1603(c)(6): Whether an appropriately
constituted Institutional Review Board or its foreign equivalent has
approved the proposed research.
This provision reflects excerpts taken from recommendations 5-1(g)
and 6-1 from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). Section 26.1125 already requires third-parties covered by
the 2006 rule to obtain IRB approval before submitting proposals to EPA
under subpart P, and section 26.1601(c) of the current rule allows the
Agency to consider whether foreign proposed research has undergone
equivalent protective procedures.
Proposed Sec. 26.1603(c)(7): If any person from a
vulnerable population may become a subject in the proposed research,
whether there is a convincing justification for selection of such a
person, and whether measures taken to protect such human subjects are
adequate.
This provision reflects excerpts taken from recommendation 5-2(b)
from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). EPA recognizes that some individuals who may become
subjects in human research may be more vulnerable to coercion or undue
influence, for example, prisoners, persons with mental disabilities, or
economically or educationally disadvantaged persons. As such, for
proposals in which such individuals may become a subject of the
research, EPA is proposing to consider whether the proposal contains a
convincing justification for the selection of those persons as well as
whether any measures taken to protect those persons are adequate. The
specific language of recommendation 5-2(b) states that ``IRBs * * *
should ensure that the following conditions met in selecting research
participants * * * (b) Selection of persons from vulnerable populations
must be convincingly justified in the protocol, which also must justify
the measures to be taken to protect the participants.'' In drafting
this provision EPA rephrased recommendation 5-2(b) to convert it to
regulatory language. In doing so, EPA first made this provision
conditional (the ``if'' clause) because EPA does not expect that
vulnerable populations will often be included in human research and
there is no reason to impose a burden on researchers to justify a
situation when it is inapplicable. EPA also substituted the requirement
that measures taken to protect such human subjects be ``adequate''
instead of requiring a ``convincing justification'' for them.
EPA requests comment on whether the proposed language is clear and
specifically on this language as compared to using the language
directly from recommendation 5-2(b) in the 2004 NAS Report.
Proposed Sec. 26.1603(c)(8): If any person with a
condition that would put them at increased risk for adverse effects may
become a subject in the proposed research, whether there is a
convincing justification for selection of such a person, and whether
measures taken to protect such human subjects are adequate.
This provision reflects excerpts taken from recommendation 5-2(c)
from the 2004 NAS Report (see verbatim text provided in Unit
IV.C.2.b.). Although EPA anticipates that persons with conditions that
put them at increased risk for adverse effects would likely be screened
from participating in human research subject to this rule, there may be
circumstances when an exception is warranted. In those instances where
such persons may become subjects in research covered by this rule, EPA
is proposing to consider whether the research contains a convincing
justification for the selection of those persons as well as whether any
measures taken to protect those persons are adequate to decrease risks
to an acceptable level. The specific language of recommendation 5-2(b)
states that ``IRBs * * * should ensure that the following conditions
met in selecting research participants * * * (c) Selection of
individuals with conditions that put them at increased risk for adverse
effects in such studies must be convincingly justified in the protocol,
which also must justify the measures that investigators will use to
decrease the risks to those participants to an acceptable level.'' For
this provision, EPA followed a similar path in converting the NAS
recommendation into regulatory language as it did with proposed Sec.
26.1603(c)(7), i.e., EPA made the provision conditional and used an
adequacy test rather than a convincing justification as to evaluating
the measures to protect the subjects.
EPA requests comment on whether the proposed language is clear and
specifically on this language as compared to using the language
directly from recommendation 5-2(c) in the 2004 NAS Report.
Proposed Sec. 26.1603(c)(9): Whether any proposed
payments to subjects are consistent with the principles of justice and
respect for persons, and whether they are so high as to constitute
undue inducement or so low as to be attractive only to individuals who
are socioeconomically disadvantaged.
This provision reflects excerpts taken from recommendation 5-3 from
the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.).
Although this provision overlaps slightly with proposed Sec. Sec.
26.1603(c)(4) and Sec. 26.1603(c)(7), EPA is proposing to enumerate a
specific consideration for whether the level of remuneration for
[[Page 5749]]
participation in any proposal for human research covered by this rule
is appropriate, i.e., consistent with the principles of justice and
respect for persons, and whether it is likely to induce participation
from individuals from vulnerable populations and affect the equitable
selection of subjects. In converting the affirmative statement in
recommendation 5-3 into a ``whether'' statement for regulatory
language, EPA dropped the recommendation's ``neither--nor'' phrasing
because it is potentially confusing. EPA believes that, as drafted,
this provision requires consideration of whether payments are either
too high or too low but requests comment on this point.
EPA requests comment on whether the proposed language is clear and
specifically on this language as compared to using the language
directly from recommendation 5-3 in the 2004 NAS Report.
Proposed Sec. 26.1603(c)(10): Whether the sponsor or
investigator would provide needed medical care for injuries incurred in
the proposed research, without cost to the human subjects.
This provision reflects excerpts taken from recommendation 5-5 from
the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.). EPA
is proposing to consider in its ethics review of proposed human
research subject to this rule whether medical care resulting from
participation in the research will be provided without cost to the
human subjects.
As noted throughout this section, EPA requests comment on whether
the provisions of proposed Sec. 26.1603 are consistent with the
recommendations from the 2004 NAS Report and whether the regulatory
language chosen by EPA adequately captures EPA's intended goal and is
otherwise clear and easily understood.
D. Revised Acceptance Standards for Completed Research (40 CFR part 26,
subpart Q)
1. Overview
a. Current rule. 40 CFR part 26, subpart Q, establishes standards
governing reliance by EPA under the pesticide laws on ``scientifically
valid and relevant data from research involving intentional exposure of
human subjects.'' Section 26.1703 forbids EPA to rely on any research
involving intentional exposure of a subject who was a pregnant woman, a
nursing woman, or a child. Section 26.1704 forbids EPA to rely on
research initiated before the effective date of the 2006 rule in the
face of clear and convincing evidence that ``the conduct of the
research was fundamentally unethical (e.g., the research was 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 research was conducted.'' Section 26.1705
forbids EPA to rely on research initiated after the effective date of
the 2006 rule unless EPA has ``adequate information to determine that
the research was conducted in substantial compliance with subparts A
through L * * *'' Section 26.1706 permits EPA to rely on the results of
human research unacceptable under the standards of Sec. Sec. 26.1703-
26.1705 only if EPA determines, after public notice and comment and
consultation with HSRB, that reliance on the research is necessary to
support ``a more stringent regulatory restriction that would improve
protection of public health * * * than could be justified without
relying on the data.'' The Agency is not proposing to amend the
substance of Sec. 26.1706.
b. Summary of proposed changes. In addition to broadening the scope
of 40 CFR part 26, subpart Q, to apply to research relied on by EPA
under regulatory statutes other than FIFRA or FFDCA, EPA proposes to
amend the substantive standards in Sec. Sec. 26.1703, 26.1704, and
26.1705 for determining the acceptability of completed research
involving intentional exposure of a human subject to a pesticide. As
noted throughout this document, EPA requests comment on each of these
proposed changes, as well as on the changes in the aggregate. In
particular, EPA seeks comment on its conclusions regarding the effect
of these proposed changes relative to the scope of the 2006 rule,
including the effect of these proposed changes on the volume of studies
covered by the rule, the likely statutes under which studies may be
submitted, and the impact on activities covered by those other
statutes.
c. Anticipated effects. If a covered study does not meet the
applicable standards in 40 CFR part 26, subpart Q, EPA would be
prohibited from relying on the data in any action it takes under any of
its regulatory authorities except under the extremely restrictive
conditions defined in Sec. 26.1706.
2. Sec. 26.1703: Standards Applicable to all Covered Research
a. Proposed changes and rationale. Consistent with the changes
proposed in 40 CFR part 26, subpart P, and discussed in Unit IV.C., EPA
proposes to add in Sec. 26.1703(a) an explicit prohibition against
reliance on data from completed research ``unless EPA determines that
the data are relevant to a scientific or policy question important for
EPA decision-making, that the data were derived in a manner that makes
them scientifically valid and reliable, and that it is appropriate to
use the data for the purpose proposed by EPA.''
In making this determination, EPA would be required to assess these
four aspects of the research:
Whether the research was designed and conducted according
to ``appropriate scientific standards and practices prevailing at the
time the research was conducted.''
The extent to which the test subjects represent the
population whose response the data will be used to predict.
The statistical power of the data to support the
scientific conclusions drawn by EPA.
Whether, in a study that reports a No Observed Effect
Level (NOEL) or a No Observed Adverse Effect Level (NOAEL), some dose
level elicited a biological effect.
These four aspects of the research are derived from Recommendations
3-1 and 5-1 from the 2004 NAS Report. They do not establish fixed
criteria for acceptance or rejection of a study, but they identify
specific aspects of a study that EPA must consider in determining that
it is relevant, scientifically valid and reliable, and appropriate for
a particular use.
b. Anticipated effect. As noted previously, 40 CFR part 26, subpart
Q, applies to EPA decisions to rely on ``scientifically valid and
relevant data'' from covered research. Since 2006, EPA's practice in
reviewing reports of covered human research has been to examine
carefully the scientific merit of the reported studies and to refuse to
use research deemed invalid or irrelevant. EPA proposes to delete these
factors from the scope of 40 CFR part 26, subpart Q, as defined in
Sec. 26.1701, and to codify them as factors in Sec. 26.1703(a) to
ensure that they remain central to determinations of scientific
validity and relevance. If this proposed amendment is finalized, EPA
would likely make minor revisions to its internal review procedures to
highlight the consideration given to these four aspects of the
research.
3. Sec. 26.1704: Acceptance Standards for Research not Subject to
Sec. 26.1705
a. Proposed changes and rationale. The Agency based the ethical
acceptability standard in Sec. 26.1704 on Recommendation 5-7 from the
2004 NAS Report, which states in relevant part:
[[Page 5750]]
EPA should accept scientifically valid studies conducted before
its new rules are implemented unless there is clear and convincing
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 that the
conduct was deficient relative to then-prevailing standards.
Section 26.1704 provides in relevant part (emphasis added):
* * * EPA shall not rely on data from any research initiated
before [the effective date of the 2006 rule], if there is clear and
convincing evidence that the conduct of the research was
fundamentally unethical (e.g., the research was 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 research was conducted.
EPA adopted the recommendation from the 2004 NAS Report nearly
verbatim, with the notable insertion of the word ``significantly''
before ``deficient.'' EPA explained in the preamble to the 2006 rule
(at 71 FR 6161) that this was to allow it the flexibility to consider
the impact on subjects of any ethical shortcomings in the conduct of
the research. EPA stated in that preamble (at 71 FR 6161) that ``EPA
expects [the meaning of ``significantly''] to acquire greater clarity
over time, through HSRB and public review of Agency decisions
concerning reliance on completed human research.''
EPA believes that greater clarity has, indeed, been achieved
through the application of the 2006 rule by EPA and HSRB. EPA now
proposes to revise Sec. 26.1704 by deleting the word
``significantly,'' proposing instead to characterize explicitly the
kinds of deficiencies that would make a study unacceptable.
This language is derived from the advice of HSRB as they have
applied the standard of Sec. 26.1704 in the 2006 rule. See, for
example, their comments on studies involving aldicarb, methomyl,
oxamyl, azinphos-methyl, DDVP, ethephon, sodium cyanide, and amitraz
at: http://www.epa.gov/osa/hsrb/files/meeting-materials/apr-4-6-2006-public-meeting/april2006mtgfinalreport62606.pdf. For each study they
found ethically acceptable, HSRB found ``no evidence of significant
deficiencies in the ethical procedures that could have resulted in
serious harm (based on the knowledge available at the time the study
was conducted) nor that information provided to participants seriously
impaired their informed consent.''
Finally, EPA proposes to redefine the applicability of Sec.
26.1704 in a new paragraph (a) as the complement of the more detailed
scope of Sec. 26.1705, thereby eliminating any gaps or overlap in the
applicability of the two standards.
b. Anticipated effect. Proposed Sec. 26.1704 would forbid EPA to
rely on research not covered by 40 CFR part 26, subpart K, or the
Common Rule in the face of clear and convincing evidence that its
conduct ``placed participants at increased risk of harm (based on
knowledge available at the time the study was conducted) or impaired
their informed consent.'' EPA specifically requests comment on the
incremental value of this change as well as the extent to which this
change might inappropriately reduce EPA's access to human research.
4. Sec. 26.1705: Standards for Completed Research Conducted Under 40
CFR Part 26 or Another Codification of the Common Rule
a. Proposed changes and rationale. The standard in 40 CFR part 26
applying to completed research initiated after the effective date of
the rule is Sec. 26.1705, based on Recommendation 5-6 from the 2004
NAS Report, which states in relevant part (italics in the original;
footnote omitted):
EPA should operate on the strong presumption that data obtained
in studies conducted after implementation of the new rules that do
not meet the ethical standards described in this report will not be
considered in its regulatory decisions.
EPA adapted this recommendation in its drafting of Sec. 26.1705,
which provides in relevant part:
EPA shall not rely on data from any research initiated after
[the effective date of the 2006 rule] unless EPA has adequate
information to determine that the research was conducted in
substantial compliance with subparts A through L of this part, or if
conducted in a foreign country, under procedures at least as
protective as those in subparts A through L of this part.
EPA now proposes to amend both the applicability of Sec. 26.1705
and the substance of the standard itself. In the 2006 rule, Sec.
26.1705 applies to any scientifically valid and relevant research
involving intentional exposure of human subjects and initiated after
the effective date of the rule. EPA proposes now to limit application
of the Sec. 26.1705 standard to research subject, at the time it was
conducted, either to subparts A through L of 40 CFR part 26 or to
another Federal department or agency's codification of the Common Rule.
EPA recognizes that it could in the future wish to rely on data
from third-party research conducted after 2006 but which fell outside
the scope of 40 CFR part 26, subpart K, and for which EPA therefore
would not have conducted a protocol review under 40 CFR part 26,
subpart P, before the research was conducted. For example, as discussed
in Unit IV.A., 40 CFR part 26, subpart K, as now proposed would not
apply to a new clinical trial evaluating the therapeutic efficacy of a
drug that was also a pesticide. Because this research would fall
outside the scope of 40 CFR part 26, subpart K, investigators would not
have submitted the protocol to EPA under 40 CFR part 26, subpart K, and
EPA and HSRB would not have reviewed it under 40 CFR part 26, subpart
P. Yet, if data from such research were to be relied on by EPA, the
standards of subpart Q would apply. As Sec. 26.1705 is currently
worded in 40 CFR part 26, such a study could only be relied on if ``EPA
has adequate information to determine that the research was conducted
in substantial compliance with subparts A through L.'' But because the
protocol would not have been submitted for review by EPA and HSRB, the
research in this example would not have been conducted in substantial
compliance with 40 CFR part 26, subpart K.
EPA believes that it would be inappropriate to reject otherwise
meritorious and ethical research for failure to comply with provisions
in 40 CFR part 26, subparts A-L that did not apply when the research
was conducted. Thus EPA proposes to make Sec. 26.1705 applicable only
to studies that were initiated after the effective date of the 2006
rule and that were subject to EPA's rules for the protection of human
subjects (40 CFR part 26, subparts A through L) or another codification
of the Common Rule. A companion change in Sec. 26.1704(a) would apply
the standard of Sec. 26.1704 to all other completed research
considered by EPA under 40 CFR part 26, subpart Q, without regard to
when the research was initiated.
EPA proposes further changes to Sec. 26.1705 to help make this
clear. Proposed Sec. 26.1705(b)(1) defines the applicable standard as
either 40 CFR part 26, subparts A through L, or another Federal
department or agency's codification of the Common Rule, whichever set
of rules covered the research when it was conducted. In proposed Sec.
26.1705(b)(2), corresponding changes are made applicable to research
conducted in foreign countries.
Finally, in a new paragraph (c) in Sec. 26.1705, EPA proposes to
require substantial compliance of covered research with its protocol. A
study reviewed as a proposal under subpart P of 40 CFR part 26 could be
relied on only if it had been conducted in substantial compliance with
the
[[Page 5751]]
protocol found acceptable by EPA, and if the investigator did not
further amend or deviate from the protocol in ways that placed
participants at increased risk of harm (based on knowledge available at
the time the study was conducted) or impaired their informed consent.
If a completed study was not reviewed as a proposal under 40 CFR part
26, subpart P, the study could only be relied on if it had been
conducted in substantial compliance with a protocol that would have
been found acceptable, and if the investigator did not amend or deviate
from the protocol in ways that placed participants at increased risk of
harm (based on knowledge available at the time the study was conducted)
or impaired their informed consent.
b. Anticipated effect. Taken together, these proposed changes in
Sec. 26.1705 reflect the interpretations and methods used by EPA and
HSRB since 2006 in reviewing completed, post-rule research. Codifying
these interpretations will ensure consistency and transparency in
future decision-making and is consistent with the 2006 Appropriations
Act.
E. Request for Public Comment on Possible Re-Codification of 40 CFR
Part 26, Subparts K-Q
1. Current rule. Subparts A-D of 40 CFR part 26 all apply to
research with human subjects which is conducted or supported by EPA in
its role as a research agency. Subparts K-Q of 40 CFR part 26 apply to
pesticide research with human subjects that is conducted by regulated
third parties, and to EPA's regulatory oversight of that research. Some
stakeholders have suggested that this important distinction would be
clearer if 40 CFR part 26 contained only those subparts applying to EPA
as a research agency, and if 40 CFR part 26, subparts K-Q, were moved
to a different section of EPA's regulations, within the range where
other pesticide-specific regulations are found.
2. Proposed amendments and rationale. EPA is not now proposing such
a re-codification, but invites public comment on the idea. Although it
would necessitate many non-substantive revisions--mainly of internal
cross-references--re-codification would not be difficult to accomplish.
40 CFR part 26 would retain current 40 CFR part 26, subparts A-D, and
at least parts of current 40 CFR part 26, subpart O. A previously
unused part within 40 CFR, within the numerical range of parts 150-180
where other pesticide-related regulations appear, would include current
40 CFR part 26, subparts K, L, M, O, P, and Q. 40 CFR part 26, subpart
O, potentially applies to both EPA research and to third-party research
and would need to be adapted to fit into both parts of a separated
codification in 40 CFR.
3. Anticipated effect. Although this proposed re-codification may
better distinguish those requirements applying to EPA as a research
agency, and those applying to third-party studies, it would only change
the location of the regulation within 40 CFR, and would not otherwise
have any effect on the requirements.
V. FIFRA Review Requirements
In accordance with FIFRA section 25(a), EPA has submitted a draft
of the proposed rule to the FIFRA Scientific Advisory Panel (SAP), the
Secretary of Agriculture (USDA), and appropriate Congressional
Committees. The FIFRA SAP waived its review of this proposal on October
12, 2010, because the significant scientific issues involved have
already been reviewed by the SAP and additional review is not
necessary. USDA responded without comments, but participated in the
interagency review process under Executive Order 12866.
VI. Statutory and Executive Order Reviews
A. Regulatory Planning and Review
Under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993), this has been identified as a
``significant regulatory action.'' Accordingly, EPA submitted the draft
proposed rule to the Office of Management and Budget (OMB) for review
under Executive Order 12866 and any changes made in response to OMB
recommendations have been documented in the docket for this rulemaking
as required by the Executive Order.
The incremental costs of these proposed amendments both to industry
and to EPA are expected to be negligible. EPA has not, therefore,
prepared a new economic analysis for this rulemaking. Because no
research has been identified that is outside the scope of the 2006 rule
but that would be within the scope of these proposed amendments, EPA
has no basis on which to revise the cost estimates that were provided
in the economic analysis for the 2006 rulemaking or those most recently
provided in the 2008 renewal of the Information Collection Request
(ICR) for the existing regulation at 40 CFR part 26. The recent
estimates included in the ICR are summarized in Unit VI.B. and a copy
of the ICR is available in the docket.
B. Paperwork Reduction Act
This action does not impose any new information collection burden
that would require additional review or approval by OMB under the
Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq. OMB previously
approved the information collection requirements contained in the
existing regulations at 40 CFR part 26 under OMB Control No. 2070-0169
(EPA ICR No. 2195). Burden is defined at 5 CFR 1320.3(b).
In its 2008 analysis supporting the most recent renewal of this
ICR, EPA estimated that respondents would submit to the Agency some 34
proposals for or reports of research involving intentional exposure of
human subjects each year. EPA estimated that preparation of information
required by the 2006 rule would require about 598 hours per study at a
cost of $45,927 per study, for a total estimated annual burden for
affected entities of 20,332 hours at an estimated cost of $1,561,518.
In addition, EPA estimated annual submission of 20 reports of research
requiring only documentation of ethical conduct at a cost of 12 hours/
$879 per report, or 240 hours/$17,580 per year. The total estimate of
the annual respondent burden and cost was the sum of these two
estimates, or 2,572 hours/$1,579,098.
These paperwork burden and cost estimates include activities
related to initial rule familiarization, as well as activities that
researchers would have to perform even without the Agency's rulemaking
in this area, such as developing a protocol and maintaining records.
The average annual burden on EPA for reviewing each of the 34 study
submissions was estimated to be 178 hours/$16,850 per study, or 6,052
hours/$572,900 per year. The average annual burden on EPA for reviewing
each of the 20 additional submissions was estimated to be 44 hours/
$3,158 per study, or 880 hours/$63,160 per year. The total estimate of
the annual burden on EPA was the sum of these two estimates, or 6,932
hours/$636,000 per year.
In no year since promulgation of the 2006 rule have more than 7
protocols been submitted to EPA by industry; the average annual rate
has been just over 5 for the 5-year period of 2006-2010. Somewhat fewer
completed reports have been submitted during this period, so the
average of new protocols and finished studies has been about 11 per
year, less than a third of the projected 34 per year covered by the
ICR. There is no evidence to suggest an upward trend, and nothing in
these amendments
[[Page 5752]]
is believed likely to lead to a significant change in the rate of
protocol and study submissions.
An agency may not conduct or sponsor, and a person is not required
to respond to, a collection of information unless it displays a
currently valid OMB control number. The OMB control numbers for EPA's
regulations in 40 CFR are listed in 40 CFR part 9.
C. Small Entity Impacts
Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA),
5 U.S.C. 601 et seq., the Agency hereby certifies that this action will
not have a significant adverse economic impact on a substantial number
of small entities. Under RFA, small entities include small businesses,
small organizations, and small governmental jurisdictions. For purposes
of assessing the impacts of this proposed rule on small entities, small
entity is defined in accordance with RFA section 601 as:
1. A small business as defined by the Small Business
Administration's (SBA) regulations at 13 CFR 121.201.
2. A small governmental jurisdiction that is a government of a
city, county, town, school district or special district with a
population of less than 50,000.
3. A small organization that is any not-for-profit enterprise which
is independently owned and operated and is not dominant in its field.
Because no small entities have been identified that are directly
regulated by these proposed amendments, EPA has not attempted to reduce
the impact of this proposed rule on small entities. Comments are
invited on all aspects of the proposal and its impacts on small
entities.
D. Unfunded Mandates
This action does not impose any enforceable duty, contain any
unfunded mandate, or otherwise have any effect on small governments
subject to the requirements of sections 202, 203, 204, or 205 of the
Unfunded Mandates Reform Act (UMRA), 2 U.S.C. 1531-1538. These
amendments are unlikely to affect State, local, and tribal governments
at all, and are likely to affect the private sector only trivially. The
action does not contain a Federal mandate that may result in
expenditures of $100 million or more for State, local, and tribal
governments, in the aggregate, or the private sector in any 1 year.
E. Federalism
This action does not have federalism implications because it is not
expected to have substantial direct effects on the States, on the
relationship between the national government and the States, or on the
distribution of power and responsibilities among the various levels of
government, as specified in Executive Order 13132, entitled Federalism
(64 FR 43255, August 10, 1999). It makes marginal changes in the scope
of an existing rule applying to sponsors and investigators conducting
certain kinds of research involving human subjects, and refines the
standards for EPA oversight of and reliance on such research.
In the spirit of Executive Order 13132, and consistent with EPA
policy to promote communications between EPA and State and local
governments, EPA specifically requests comments on this proposed action
from State and local officials.
F. Tribal Implications
This action does not have tribal implications as specified in
Executive Order 13175, entitled Consultation and Coordination with
Indian Tribal Governments (65 FR 67249, November 9, 2000). This action
is not expected to have substantial direct effects on Indian Tribes,
will not significantly or uniquely affect the communities of Indian
Tribal governments, and does not involve or impose any requirements
that affect Indian Tribes. Thus, Executive Order 13175 does not apply
to this action.
G. Children's Health Protection
EPA interprets Executive Order 13045, entitled Protection of
Children from Environmental Health Risks and Safety Risks (62 FR 19885,
April 23, 1997), as applying only to those regulatory actions that
concern health or safety risks, such that the analysis required under
section 5-501 of the Executive Order has the potential to influence the
regulation. This action is not subject to Executive Order 13045 because
it does not establish an environmental standard intended to mitigate
health or safety risks, nor is it an ``economically significant
regulatory action'' as defined in Executive Order 12866. The 2006 rule
applies to the conduct and review of research involving intentional
exposure of human subjects, and prohibits the conduct of or EPA
reliance on any such research involving subjects who are children, or
pregnant or nursing women. These provisions would not be affected by
the proposed amendments.
H. Affect on Energy Supply, Distribution, or Use
This action is not a ``significant energy action'' as defined in
Executive Order 13211, entitled Actions Concerning Regulations That
Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355,
May 22, 2001), because this action is not likely to have any affect on
the supply, distribution, or use of energy.
I. Technical Standards
Because this action does not involve any technical standards,
section 12(d) of the National Technology Transfer and Advancement Act
of 1995 (NTTAA) (15 U.S.C. 272 note), does not apply to this action.
J. Environmental Justice
This action does not entail special considerations of environmental
justice related issues as delineated by Executive Order 12898, entitled
Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations (59 FR 7629, February 16, 1994).
The strengthened protections for human subjects participating in
covered research established in the 2006 rule would not be altered by
these proposed amendments.
List of Subjects in 40 CFR Part 26
Environmental protection, Administrative practice and procedures,
Human research, Pesticides and pests.
Dated: January 18, 2011.
Lisa P. Jackson,
Administrator.
Therefore, it is proposed that 40 CFR chapter I be amended as
follows:
PART 26--[AMENDED]
1. The authority citation for part 26 is revised to read as
follows:
Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) and 136w(a)(1); 21
U.S.C. 346a(e)(1)(C); sec. 201, Pub. L. 109-54, 119 Stat. 531; and
42 U.S.C. 300v-1(b).
2. Amend Sec. 26.1101 as follows:
a. Remove paragraphs (a), (c), and (g);
b. Redesignate paragraph (b) as (c), (f) as (g), (e) as (f), and
(d) as (e); and
c. Add new paragraphs (a), (b), and (d) to read as follows.
Sec. 26.1101 To what does this subpart apply?
(a) Except as provided in paragraph (c) of this section, this
subpart applies to all research initiated on or after [effective date
of final rule] involving intentional exposure of a human subject to:
(1) Any substance if, at any time prior to initiating such
research, any person who conducted or supported such research intended
either to submit results of the research to EPA for consideration in
connection with any action that may be performed by EPA under the
Federal Insecticide,
[[Page 5753]]
Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136-136y) or section
408 of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C.
346a), or to hold the results of the research for later inspection by
EPA under FIFRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C.
346a); or
(2) A pesticide if, at any time prior to initiating such research,
any person who conducted or supported such research intended either to
submit results of the research to EPA for consideration in connection
with any action that may be performed by EPA under any regulatory
statute administered by EPA other than those statutes designated in
paragraph (a)(1) of this section, or to hold the results of the
research for later inspection by EPA under any regulatory statute
administered by EPA other than those statutes designated in paragraph
(a)(1) of this section.
(b) For purposes of determining a person's intent under paragraph
(a) of this section, EPA may consider any available and relevant
information. EPA must rebuttably presume the existence of intent if:
(1) The person or the person's agent has submitted or made
available for inspection the results of such research to EPA; or
(2) The person is a member of a class of people who, or whose
products or activities, are regulated by EPA and, at the time the
research was initiated, the results of such research would be relevant
to EPA's exercise of its regulatory authority with respect to that
class of people, products, or activities.
* * * * *
(d) The Administrator retains final judgment as to whether a
particular activity is covered by this subpart.
* * * * *
3. In Sec. 26.1102, revise paragraphs (a) and (c) and add
paragraph (k) to read as follows:
Sec. 26.1102 Definitions.
(a) Administrator means the Administrator of the Environmental
Protection Agency (EPA) and any other officer or employee of EPA to
whom authority has been delegated.
* * * * *
(c) Pesticide means any substance or mixture of substances meeting
the definition in 7 U.S.C. 136(u) [Federal Insecticide, Fungicide, and
Rodenticide Act, section 2(u)].
* * * * *
(k) Common Rule refers to the Federal Policy for the Protection of
Human Subjects that was established in 1991 by the Office of Science
and Technology Policy and codified in 1991 by EPA and 14 other federal
departments and agencies (see 56 FR 28003, June 18, 1991) and
subsequently codified by other Federal departments and agencies. The
Common Rule contains a widely accepted set of standards for conducting
ethical research with human subjects, together with a set of procedures
designed to ensure that the standards are met. Once codified by a
Federal department or agency, the requirements of the Common Rule apply
to research conducted or sponsored by that Federal department or
agency. EPA's codification of the Common Rule currently appears in 40
CFR part 26, subpart A.
Sec. 26.1111 [Amended]
4. In Sec. 26.1111, remove from paragraph (a)(4) the phrase ``or
the subject's legally authorized representative''.
5. In Sec. 26.1116, revise the introductory text of the section to
read as follows:
Sec. 26.1116 General requirements for informed consent.
No investigator may involve a human being as a subject in research
covered by this subpart unless the investigator has obtained the
legally effective informed consent of the subject. An investigator must
seek such consent only under circumstances that provide the prospective
subject sufficient opportunity to consider whether or not to
participate and that minimize the possibility of coercion or undue
influence. The information that is given to the subject must be in
language understandable to the subject. No informed consent, whether
oral or written, may include any exculpatory language through which the
subject is made to waive or appear to waive any of the subject's legal
rights, or releases or appears to release the investigator, the
sponsor, the institution or its agents from liability for negligence.
* * * * *
6. Revise Sec. 26.1117 to read as follows:
Sec. 26.1117 Documentation of informed consent.
(a) Informed consent must be documented by the use of a written
consent form approved by the IRB and signed by the subject. A copy
shall be given to the subject.
(b) The consent form may be either of the following:
(1) A written consent document that embodies the elements of
informed consent required by Sec. 26.1116. This form may be read to
the subject, but in any event, the investigator must give the subject
adequate opportunity to read it before it is signed; or
(2) A short form written consent document stating that the elements
of informed consent required by Sec. 26.1116 have been presented
orally to the subject. When this method is used, there must be a
witness to the oral presentation. Also, the IRB shall approve a written
summary of what is to be said to the subject. Only the short form
itself is to be signed by the subject. However, the witness must sign
both the short form and a copy of the summary, and the person actually
obtaining consent must sign a copy of the summary. A copy of the
summary must be given to the subject, in addition to a copy of the
short form.
7. Revise the heading for subpart L to read as follows:
Subpart L--Prohibition of Third-Party Research Involving
Intentional Exposure to a Pesticide of Human Subjects Who Are
Children or Pregnant or Nursing Women
8. Revise Sec. 26.1201 to read as follows:
Sec. 26.1201 To what does this subpart apply?
This subpart applies to any research subject to subpart K of this
part.
9. Revise Sec. 26.1301 to read as follows:
Sec. 26.1301 To what does this subpart apply?
This subpart applies to any person who submits to EPA after
[effective date of final rule] either of the following:
(a) A report containing the results of any human research for
consideration in connection with an action that may be performed by EPA
under FIFRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C.
346a).
(b) A report containing the results of any human research on or
with a pesticide for consideration in connection with any action that
may be performed by EPA under any regulatory statute administered by
EPA.
Sec. 26.1302 [Amended]
10. In Sec. 26.1302 remove the word ``shall''.
Sec. 26.1502 [Amended]
11. Amend Sec. 26.1502 as follows:
a. In the first sentence of paragraph (a) remove the period after
the phrase ``during an inspection.'' and add in its place a comma; and
b. In the second sentence of paragraph (a) remove the phrase ``The
agency'' and add in its place ``EPA''.
c. In the last sentence of the introductory text of paragraph (b)
remove the phrase ``the Agency'' and add in its place ``EPA''.
[[Page 5754]]
Sec. 26.1505 [Amended]
12. In Sec. 26.1505 remove from the last sentence, the phrase
``Sec. 26.1502(c)'' and add in its place ``Sec. 26.1502(b)(4)''.
Sec. 26.1507 [Amended]
13. In Sec. 26.1507 remove from the last sentence, the phrase
``The Agency'' and add in its place ``EPA''.
Sec. Sec. 26.1601 through 26.1603 [Redesignated as Sec. Sec. 26.1603
through 26.1605]
14. Amend subpart P by redesignating Sec. Sec. 26.1601 through
26.1603 as Sec. Sec. 26.1603 through 26.1605.
15. Add new Sec. Sec. 26.1601 and 26.1602 to read as follows:
Sec. 26.1601 To what does this subpart apply?
This subpart applies to both of the following:
(a) Reviews by EPA and by the Human Studies Review Board of
proposals to conduct new research subject to 40 CFR 26.1125.
(b) Reviews by EPA after [effective date of the final rule] and, to
the extent required by Sec. 26.1604, by the Human Studies Review Board
of reports of completed research subject to 40 CFR 26.1701.
Sec. 26.1602 Definitions.
The definitions in Sec. 26.1102 apply to this subpart as well.
16. Amend newly redesignated Sec. 26.1603 as follows:
a. Remove paragraphs (a) and (e).
b. Redesignate paragraphs (b) through (d) as (e) through (g).
c. Add new paragraphs (a), (b), (c), (d), and (h) to read as
follows.
Sec. 26.1603 EPA review of proposed human research.
(a) EPA must review all proposals for new human research submitted
under Sec. 26.1125 in a timely manner.
(b) In reviewing proposals for new human research submitted under
Sec. 26.1125, the EPA Administrator must consider and make
determinations regarding the proposed research, including:
(1) Whether the research would be likely to produce data that
address an important scientific or policy question that cannot be
resolved on the basis of animal data or human observational research.
(2) Whether the proposed research is designed in accordance with
current scientific standards and practices to:
(i) Address the research question.
(ii) Include representative study populations for the endpoint in
question.
(iii) Have adequate statistical power to detect appropriate
effects.
(3) Whether the investigator proposes to conduct the research in
accordance with recognized good research practices, including, when
appropriate, good clinical practice guidelines and monitoring for the
safety of subjects.
(c) In reviewing proposals for new research submitted under Sec.
26.1125, the EPA Administrator must consider and make determinations
regarding ethical aspects of the proposed research, including:
(1) Whether adequate information is available from prior animal
studies or from other sources to assess the potential risks to subjects
in the proposed research.
(2) Whether the research proposal adequately identifies anticipated
risks to human subjects and their likelihood of occurrence, minimizes
identified risks to human subjects, and identifies likely benefits of
the research and their distribution.
(3) Whether the proposed research presents an acceptable balance of
risks and benefits. In making this determination for research intended
to reduce the interspecies uncertainty factor in a pesticide risk
assessment, the Administrator must consider Recommendation 4-1 in the
2004 Report from the National Research Council of the National Academy
of Sciences (NAS), entitled ``Intentional Human Dosing Studies for EPA
Regulatory Purposes: Scientific and Ethical Issues.''
(4) Whether subject selection will be equitable.
(5) Whether subjects' participation would follow free and fully
informed consent.
(6) Whether an appropriately constituted IRB or its foreign
equivalent has approved the proposed research.
(7) If any person from a vulnerable population may become a subject
in the proposed research, whether there is a convincing justification
for selection of such a person, and whether measures taken to protect
such human subjects are adequate.
(8) If any person with a condition that would put them at increased
risk for adverse effects may become a subject in the proposed research,
whether there is a convincing justification for selection of such a
person, and whether measures taken to protect such human subjects are
adequate.
(9) Whether any proposed payments to subjects are consistent with
the principles of justice and respect for persons, and whether they are
so high as to constitute undue inducement or so low as to be attractive
only to individuals who are socioeconomically disadvantaged.
(10) Whether the sponsor or investigator would provide needed
medical care for injuries incurred in the proposed research, without
cost to the human subjects.
(d) With respect to any research or any class of research, the EPA
Administrator may recommend additional conditions which, in the
judgment of the EPA Administrator, are necessary for the protection of
human subjects.
* * * * *
(h) EPA must provide the submitter of the proposal copies of the
EPA and Human Studies Review Board reviews.
17. Amend newly redesignated Sec. 26.1604 by revising paragraph
(a) to read as follows:
Sec. 26.1604 EPA review of completed human research.
(a) When considering, under any regulatory statute it administers,
data from completed research involving intentional exposure of humans
to a pesticide, EPA must thoroughly review the material submitted under
Sec. 26.1303, if any, and other available, relevant information and
document its conclusions regarding the scientific and ethical conduct
of the research.
* * * * *
18. Add Sec. Sec. 26.1606 and 26.1607 to read as follows:
Sec. 26.1606 Human Studies Review Board review of proposed human
research.
In commenting on proposals for new research submitted to it by EPA,
the Human Studies Review Board must consider the scientific merits and
ethical aspects of the proposed research, including all elements listed
in Sec. 26.1603(b) and (c) and any additional conditions recommended
pursuant to Sec. 26.1603(d).
Sec. 26.1607 Human Studies Review Board review of completed human
research.
In commenting on reports of completed research submitted to it by
EPA, the Human Studies Review Board must consider the scientific merits
and ethical aspects of the completed research, and must apply the
appropriate standards in subpart Q of this part.
19. Revise the heading for subpart Q to read as follows:
Subpart Q--Standards for Assessing Whether To Rely on the Results
of Human Research in EPA Actions
20. Revise Sec. Sec. 26.1701 through 26.1705 to read as follows:
* * * * *
Sec.
26.1701 To what does this subpart apply?
[[Page 5755]]
26.1702 Definitions.
26.1703 Prohibitions applying to all research subject to this
subpart.
26.1704 Prohibition of reliance on unethical human research with
non-pregnant, non-nursing adults which is not subject to Sec.
26.1705.
26.1705 Prohibition of reliance on unethical human research with
non-pregnant, non-nursing adults initiated after April 7, 2006, and
subject to subparts A through L of this part, or the codification of
the Common Rule by another Federal department or agency.
* * * * *
Sec. 26.1701 To what does this subpart apply?
(a) For decisions under FIFRA (7 U.S.C. 136-136y) or section 408 of
FFDCA (21 U.S.C. 346a), this subpart applies to research involving
intentional exposure of human subjects to any substance.
(b) For decisions under any regulatory statute administered by EPA
other than those statutes designated in paragraph (a) of this section,
this subpart applies to research involving intentional exposure of
human subjects to a pesticide.
Sec. 26.1702 Definitions.
The definitions in Sec. 26.1102 and Sec. 26.1202 apply to this
subpart as well.
Sec. 26.1703 Prohibitions applying to all research subject to this
subpart.
(a) Prohibition of reliance on scientifically invalid research. EPA
must not rely on data from research subject to this subpart unless EPA
determines that the data are relevant to a scientific or policy
question important for EPA decisionmaking, that the data were derived
in a manner that makes them scientifically valid and reliable, and that
it is appropriate to use the data for the purpose proposed by EPA. In
making such determinations, EPA must consider:
(1) Whether the research was designed and conducted in accordance
with appropriate scientific standards and practices prevailing at the
time the research was conducted.
(2) The extent to which the research subjects are representative of
the populations for the endpoint or endpoints in question.
(3) The statistical power of the data to support the scientific
conclusion EPA intends to draw from the data.
(4) In a study that reports only a No Observed Effect Level (NOEL)
or a No Observed Adverse Effect Level (NOAEL), whether a dose level in
the study gave rise to a biological effect, thereby demonstrating that
the study had adequate sensitivity to detect an effect of interest.
(b) Prohibition of reliance on research subject to this subpart
involving intentional exposure of human subjects who are pregnant women
(and therefore their fetuses), nursing women, or children. Except as
provided in Sec. 26.1706, EPA must not rely on data from any research
subject to this subpart involving intentional exposure of any human
subject who is a pregnant woman (and therefore her fetus), a nursing
woman, or a child.
Sec. 26.1704 Prohibition of reliance on unethical human research with
non-pregnant, non-nursing adults which is not subject to Sec. 26.1705.
(a) This section applies to research subject to this subpart that
is not subject to Sec. 26.1705.
(b) Except as provided in Sec. 26.1706, EPA must not rely on data
from any research subject to this section if there is clear and
convincing evidence that:
(1) The conduct of the research was fundamentally unethical (e.g.,
the research was intended to seriously harm participants or failed to
obtain informed consent); or
(2) The conduct of the research was deficient relative to the
ethical standards prevailing at the time the research was conducted in
a way that placed participants at increased risk of harm (based on
knowledge available at the time the study was conducted) or impaired
their informed consent.
(c) The prohibition in this section is in addition to the
prohibitions in Sec. 26.1703.
Sec. 26.1705 Prohibition of reliance on unethical human research with
non-pregnant, non-nursing adults initiated after April 7, 2006, and
subject to subparts A through L of this part, or the codification of
the Common Rule by another Federal department or agency.
(a) This section applies to research subject to this subpart, that:
(1) Was initiated after April 7, 2006.
(2) Was subject, at the time it was conducted, either to subparts A
through L of this part, or to the codification of the Common Rule by
another Federal department or agency.
(b) Except as provided in Sec. 26.1706, EPA must not rely on data
from any research subject to this section unless EPA determines that
the research was conducted in substantial compliance with either:
(1) All applicable provisions of subparts A through L of this part,
or the codification of the Common Rule by another Federal department or
agency; or
(2) If the research was conducted outside the United States, with
procedures at least as protective of subjects as those in subparts A
through L of this part, or the codification of the Common Rule by
another Federal department or agency.
(c) Except as provided in Sec. 26.1706, EPA must not rely on data
from any research subject to this section unless EPA determines that
the research was conducted in substantial compliance with either:
(1) A proposal that was found to be acceptable under Sec.
26.1603(c), and no amendments to or deviations from that proposal
placed participants at increased risk of harm (based on knowledge
available at the time the study was conducted) or impaired their
informed consent. If EPA discovers that the submitter of the proposal
materially misrepresented or knowingly omitted information that would
have altered the outcome of EPA's evaluation of the proposal under
Sec. 26.1603(c), EPA must not rely on that data.
(2) A proposal that would have been found to be acceptable under
Sec. 26.1603(c), if it had been subject to review under that section,
and no amendments to or deviations from that proposal placed
participants at increased risk of harm (based on knowledge available at
the time the study was conducted) or impaired their informed consent.
(d) The prohibition in this section is in addition to the
prohibitions in Sec. 26.1703.
Sec. 26.1706 [Amended]
21. In paragraph (d) of Sec. 26.1706 remove the word ``publishes''
and add in its place the phrase ``has published''.
[FR Doc. 2011-1629 Filed 2-1-11; 8:45 am]
BILLING CODE 6560-50-P