Federal Register, Volume 78 Issue 31 (Thursday, February 14, 2013)

[Federal Register Volume 78, Number 31 (Thursday, February 14, 2013)]
[Rules and Regulations]
[Pages 10538-10546]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-03456]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 26

[EPA-HQ-OPP-2010-0785; FRL-9353-4]
RIN 2070-AJ76

Protections for Subjects in Human Research Involving Pesticides

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: EPA is finalizing narrowly tailored amendments to 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
amendments broaden the applicability of the rules to cover human
testing with pesticides submitted to EPA under any regulatory statute
it administers. The amendments also disallow participation in third-
party pesticide studies by subjects who cannot consent for themselves.
Finally, the amendments 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). The amendments make no changes to
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.

DATES: This rule is effective April 15, 2013.

ADDRESSES: The docket for this action, identified by docket
identification (ID) number EPA-HQ-OPP-2010-0785, is available at http://www.regulations.gov or at the OPP Docket in the Environmental
Protection Agency Docket Center (EPA/DC), located in the EPA West
Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001.
The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
Public Reading Room is (202) 566-1744, and the telephone number for the
OPP Docket is (703) 305-5805. Please review the visitor instructions
and additional information about the docket available at http://www.epa.gov/dockets.

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;
email address: sherman.kelly@epa.gov.

SUPPLEMENTARY INFORMATION:

I. Executive Summary

A. Does this action apply to me?

You may be potentially affected by this action if you conduct or
sponsor research that may be submitted to EPA and which involves
intentional exposure of human subjects. The following list of North
American Industrial Classification System (NAICS) codes is not intended
to be exhaustive, but rather provides a guide to help readers determine
whether this document might apply to them. Although EPA has in the past
received such third-party research from pesticide registrants, other
entities could submit such information to EPA.
Pesticide and other Agricultural Chemical Manufacturing
(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 (IRBs)
who review human research with pesticides to ensure it meets applicable
standards of ethical conduct. Under these new provisions, EPA must
consider the ethical aspects and scientific validity and reliability of
research in a manner that is consistent with the requirements of the
Common Rule as codified in 40 CFR part 26, subpart A. The ``Common
Rule'' is the name generally used to refer to the Federal Policy for
the Protection of Human Subjects, 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.

B. What action is the agency taking?

The amendments contained in this final rule change the 2006 rule,
published in the Federal Register issue of February 6, 2006 (71 FR
6138) (FRL-7759-8), subsequently amended in the Federal Register issue
of 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

[[Page 10539]]

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 human research,
derived from the recommendations by the National Research Council of
NAS in its 2004 Report entitled ``Intentional Human Dosing Studies for
EPA Regulatory Purposes: Scientific and Ethical Issues'' (hereafter,
2004 NAS Report) to EPA.

C. What is the agency's authority for taking this action?

Sections 3(a) and 25(a) of FIFRA (7 U.S.C. 136a(a) and 136w(a)) and
section 408(e)(1)(C) of the Federal Food, Drug, and Cosmetic Act
(FFDCA) (21 U.S.C. 364a(e)(1)(C)), provide the legal authority for
these amendments to the 2006 rule on human research.

D. What are the incremental costs and benefits of this action?

The incremental costs of these amendments both to industry and to
EPA are expected to be negligible. EPA has not, therefore, prepared a
new economic analysis for this rule. Because no research has been
identified that is outside the scope of the 2006 rule but that would be
within the scope of these amendments, EPA has no basis on which to
revise the cost estimates that were provided in the economic analysis
for the 2006 rule 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 estimates included in the ICR are summarized in
Unit VI.B. and a copy of the ICR is available in the docket.

II. Background

A. EPA's 2006 Rule

As required by section 201 of the Department of the Interior,
Environment, and Related Agencies Appropriations Act, 2006 (2006
Appropriations Act), Public Law 109-54, 119 Stat. 531, EPA promulgated
a rule in 2006 establishing a set of protections for people
participating as subjects in third-party human research with pesticides
in 40 CFR part 26. (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 prohibits EPA from relying on third-party research on
pesticides involving intentional exposure of children or of pregnant or
nursing women, unless relying on the data is crucial to a decision that
would impose a more stringent regulatory restriction that would improve
protection of public health than could be justified without relying on
the data. 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.

B. Petition for Review of the 2006 Rule and Settlement Agreement

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.
After briefing and argument, but before a decision was rendered by
the Second Circuit Court of Appeals, EPA and Petitioners entered a
settlement agreement in which 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
were substantially consistent with language negotiated between the
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 makes
clear that EPA retained full discretion concerning what amendments were
proposed, and what, if any, amendments are finalized.

C. Proposed Amendments to the 2006 EPA Rule

Consistent with the settlement agreement, on January 18, 2011, EPA
Administrator Lisa Jackson signed a notice of proposed rulemaking for
proposed amendments to the 2006 rule. The proposed amendments were
substantially consistent with the regulatory language negotiated with
Petitioners. The notice of proposed rulemaking published in the Federal
Register issue of February 2, 2011 (76 FR 5735) (FRL-8862-7).

D. Retrospective Review of the Common Rule

On July 26, 2011, after issuance of EPA's proposed rule, the
Department of Health and Human Services (HHS), in coordination with the
Office of Science and Technology Policy (OSTP), issued an advance
notice of proposed rulemaking concerning modernization of the Common
Rule which governs research with human subjects conducted or supported
by EPA and many other Federal departments and agencies (76 FR 44512,
July 26, 2011). HHS and OSTP sought comment on ``how to better protect
human subjects who are involved in research, while facilitating
valuable research and reducing burden, delay, and ambiguity for
investigators.'' Id. HHS and OSTP identified seven areas of concern
regarding the Common Rule. Most relevant to EPA's proposed amendments
to the 2006 rule, was a concern with ``the multiple, differing
regulatory requirements that can apply to a single research study * * *
.'' These requirements, according to HHS and OSTP, ``have been
criticized as complex, inconsistent, and lacking in clarity,'' and can
result in ``unwarranted variability across institutions and their
[Institutional Review Boards] in how the requirements are interpreted
and implemented'' (76 FR at 45514). HHS and OSTP stressed the
importance of clarifying and harmonizing human subject protections
across the Federal Government and sought comment on the means by which
this could be accomplished (76 FR at 44528).

III. The Final Rule

EPA is finalizing the amendments to the 2006 rule as proposed. This
includes changes to the scope and consent provisions, and the
incorporation of selected individual recommendations from the 2004 NAS
Report as the specific ethical and scientific factors to be considered
by EPA and the HSRB in reviewing proposed and completed human research
(i.e., proposed

[[Page 10540]]

Sec. Sec. 26.1603 and 26.1703, see 76 FR 5745-5749).
The amendments finalized in this rule are consistent with the
recommendations in the 2004 NAS Report and EPA practice under the 2006
rule. That practice has been modeled primarily on EPA's practice under
its Common Rule. Sections 26.109, 26.111, 26.116, and 26.117 of EPA's
Common Rule explicitly address most of the specific ethical
considerations included in the amendments to the 2006 rule, including
whether risks to subjects are minimized (compare Sec. 26.1603(c)(2)
with existing Sec. 26.111(a)(2)); whether risks are reasonable in
comparison to benefits (compare Sec. 26.1603(c)(3) with Sec.
26.111(a)(2)); whether subject selection would be equitable (compare
Sec. 26.1603(c)(4) with existing Sec. 26.111(a)(3)); whether consent
will be free and voluntary (compare Sec. 26.1603(c)(5) with existing
Sec. Sec. 26.116 and 26.117); whether an appropriately constituted
institutional review board (IRB) has reviewed the proposed research
(compare Sec. 26.1603(c)(6) with Sec. 26.109); and whether the
``special problems'' of research involving vulnerable populations are
taken into account (compare Sec. 26.1603(c)(7) and (8) with existing
Sec. 26.111(a)(3)). Other considerations are implicitly addressed.
The Common Rule's requirement to ``minimize risks'' in Sec.
26.111(a)(1) necessitates consideration of whether adequate animal data
is available to assess potential risks to subjects (see Sec.
26.1603(c)(1)). It would involve consideration of whether medical care
is to be provided for injuries incurred in the proposed research (see
Sec. 26.1603(c)(10)). Section 26.111(b)'s requirement that additional
safeguards be in place to protect against undue influence of
``economically'' disadvantaged persons ensures that consideration of
whether any proposed payments are so high as to constitute undue
inducement or so low as to be attractive only to individuals who are
socioeconomically disadvantaged (see Sec. 26.1603(c)(9)). Although
scientific considerations are not addressed in similar detail in the
Common Rule requirements, nonetheless, the requirement to consider
scientific validity and reliability and the Common Rule's emphasis on
the need for ``sound research design'' in Sec. 26.111(a)(1) and the
need to take ``the importance of the knowledge that may reasonably be
expected to result'' from the study into account, mandate that EPA
focus on considerations addressing scientific validity such as those
included in Sec. Sec. 26.1603 and 26.1703. At a minimum, NAS
Recommendations 3-1, 4-1, 5-1, 5-2, 5-3, and 5-5 are critical to proper
consideration of the Common Rule's ethical requirements and its
requirement for ``sound research design.''

IV. Public Comments on the Proposed Amendments

This unit discusses, in general terms, the public comments on the
proposed amendments and EPA's responses to those comments. EPA received
a total of 10 public comments on the proposed amendments during the 60-
day comment period. Comments were submitted by 4 individual citizens
and 6 different entities--the Agricultural Handler Exposure Task Force,
the American Chemistry Council (on behalf of the Antimicrobial Exposure
Assessment Task Force II), Beyond Pesticides, CropLife America, Natural
Resources Defense Council, and SC Johnson & Son, Inc. The docket (under
docket ID number EPA-HQ-OPP-2010-0785) includes all of the comments
submitted to EPA on the proposed amendments, as well as EPA's Response
to Comments document, which provides detailed responses to all comments
received.

A. Comments on Proposal To Expand Scope To Include Research Submitted
to EPA Under Any Regulatory Statute EPA Administers

Two comments addressed the proposed changes to the scope of the
2006 rule. One commenter stated that the 2006 Appropriations Act did
not permit an expansion of scope beyond pesticide studies performed in
the FIFRA and FFDCA context, and another argued that the 2006
Appropriations Act required that the scope of the rule be further
expanded beyond studies submitted, or intended for submission, to EPA.
After considering these comments, EPA has decided to finalize the
rule text relating to scope as it was proposed, i.e., expanding the
scope to cover research involving intentional exposure of human
subjects to pesticides where that research is submitted, or intended to
be submitted, to EPA under any regulatory statute that EPA administers.
As noted in EPA's Response to Comments document, EPA no longer regards
the 2006 Appropriations Act as authority for this rule. Therefore, EPA
believes it is unnecessary to address whether the 2006 Appropriation
Act either requires or does not allow EPA to establish a different
scope for this rule.
Nevertheless, EPA regards FIFRA as providing adequate legal
authority for the scope of research covered by this final rule.
Sections 3(a) and 25(a) of FIFRA provide EPA with authority to regulate
pesticides, including research involving intentional exposure of a
human subject to a substance, when the substance is being tested as a
``pesticide.'' That includes research intended for submission to EPA,
whether under FIFRA, FFDCA, or any of EPA's other regulatory
authorities. EPA believes it makes sense to apply the same standards to
all human studies involving pesticides submitted to EPA. On the other
hand, EPA believes that it is not in the public interest to extend the
prohibition against research involving intentional exposure of children
or pregnant women to pesticides beyond the scope delineated in the
proposed rule because such a prohibition, if enforceable, could have
the unintended effect of prohibiting valuable research.

B. Comments on Inclusion of NAS-Derived Considerations

Two commenters questioned whether new regulatory text proposed at
Sec. 26.1603(b)(2)(ii) and (iii) would change the ways in which EPA
has been reviewing proposed studies to measure exposures experienced by
people who mix, load, or apply pesticides. As proposed, EPA would have
been required to consider whether the proposed research includes
representative study populations for the endpoint in question and has
adequate statistical power to detect appropriate effects. These
commenters expressed the same concern regarding the proposed regulatory
text at Sec. 26.1703(a)(2) and (3), which would require EPA to
consider these factors in determining whether to rely on the research.
As explained in more detail in EPA's Response to Comments document, EPA
does not believe that the adoption of the specific ethical and
scientific factors will impose any additional burden on sponsors of
exposure studies or on the types of exposure studies referenced by the
commenters.
As explained previously, EPA has decided to finalize the proposed
text detailing specific scientific and ethical aspects of proposed and
completed research--including the text proposed at Sec.
26.1603(b)(2)(ii) and (iii) and at Sec. 26.1703(a)(2) and (3)--that
EPA and the HSRB must consider when reviewing such research. EPA also
notes that, under the 2006 rule as amended through this final rule, EPA
does not intend to change the way in which it reviews exposure research
with respect to the inclusion of representative populations or the
statistical power of the study, although EPA will consider whether
further guidance on this issue

[[Page 10541]]

is needed. In addition, EPA does not believe the codification of the
specific ethical and scientific factors derived from the 2004 NAS
Report represents a material change in the way a particular pesticide
study would have been reviewed. Thus, EPA believes that particular
pesticides studies that have been approved under the 2006 rule, would
also meet the standards reflected in this final rule.

C. Other Comments, Including Comments on Narrowing the Scope of the
2006 Rule To Include Only Intentional Dosing Studies

The remainder of the public comments addressed issues beyond the
scope of the proposed amendments. These comments included arguments
that the burden of the requirements of the 2006 rule (as opposed to any
burden connected to this amendment) are unjustified, and assertions
that EPA's interpretation in the 2006 rule of the language ``research
involving intentional exposure of a human subject'' incorrectly
expanded the scope of the rule beyond that required in the 2006
Appropriations Act, which addressed only ``intentional dosing human
toxicity studies.'' The commenters are referring to Sec. 26.1101(a) of
the 2006 rule, which defines the scope of the rule as applying to ``all
research initiated after April 7, 2006 involving intentional exposure
of a human subject * * *.'' As EPA explained in the preamble to the
proposal for the 2006 rule, this scope was intended to capture ``all
intentional dosing human studies intended for submission to EPA under
the pesticide laws'', i.e., studies involving intentional dosing to
measure a toxic effect and studies involving intentional dosing to
measure other scientific endpoints, like exposure (Federal Register
issue of September 12, 2005 (70 FR at 53845) (FRL-7728-2)). Additional
discussion in the preambles to the proposal for the 2006 rule and 2006
rule further explains what studies EPA intended to be included within
the scope of the 2006 rule (70 FR at 53845-53847; 71 FR 6138, 6146,
6149-6150).
Because these comments were directed at provisions in the 2006 rule
that EPA did not reopen for reconsideration as part of the proposed
amendments, these comments are beyond the scope of this final rule, and
no response to them is required to finalize this rule. Nonetheless, EPA
appreciates the concerns expressed by the commenters with regard to the
burdens imposed by the 2006 rule and recognizes that there may be value
in considering further amendments to the 2006 rule in a way that
reduces the burdens on investigators, e.g., by limiting the types of
research that are subject to particular requirements of the rule.

V. Conclusion

EPA received relatively few comments on the proposed rule, and many
of the comments received did not address the amendments in the
proposal. For the reasons noted previously, the comments that did
address the proposal do not merit any change to the amendments as
proposed. Accordingly, EPA is finalizing the amendments as proposed for
the reasons stated herein and in the preamble to the proposed rule.

VI. Statutory and Executive Order Reviews

A. Executive Order 12866: Regulatory Planning and Review and Executive
Order 13563: Improving Regulation and Regulatory Review

Under Executive Order 12866 (58 FR 51735, October 4, 1993), this
action is a ``significant regulatory action,'' because the Office of
Management and Budget (OMB) determined that it would raise novel legal
or policy issues arising out of legal mandates, the President's
priorities, or the principles set forth in the Executive Order.
Accordingly, EPA submitted this action to OMB for review under
Executive Orders 12866 and 13563 (76 FR 3821, January 21, 2011). Any
changes made in response to OMB recommendations have been documented in
the docket for this rulemaking as required by the Executive Order.

B. Paperwork Reduction Act (PRA)

This action does not impose any new information collection burden
that would require additional review or approval by OMB. However, OMB
has previously approved the information collection requirements
contained in the existing regulations at 40 CFR part 26 under the
provisions of PRA (44 U.S.C. 3501 et seq.), and has assigned OMB
Control No. 2070-0169 (EPA ICR No. 2195). The OMB control numbers for
EPA's regulations in 40 CFR are listed in 40 CFR part 9.
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 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. Regulatory Flexibility Act (RFA)

RFA (5 U.S.C. 601 et seq.), generally requires an agency to prepare
a regulatory flexibility analysis of any rule subject to notice and
comment rulemaking requirements under the Administrative Procedure Act
(5 U.S.C. 551-553) or any other statute unless the agency certifies
that the rule will not have a significant economic impact on a
substantial number of small entities. Small entities include small
businesses,

[[Page 10542]]

small organizations, and small governmental jurisdictions.
For purposes of assessing the impacts of this rule on small
entities, small entity is defined as:
1. A small business as defined by the Small Business
Administration's (SBA) regulations at 13 CFR 121.201, which is based on
either the maximum number of employees or on the sales for small
businesses in each industry sector, as defined by a 6-digit NAICS code,
and for this rule is pesticide and other agricultural chemical
manufacturers (NAICS code 325320) who sponsor or conduct human research
with pesticides, or other entities (NAICS code 541710) that sponsor or
conduct human research with pesticides, and IRBs who review human
research with pesticides to ensure it meets applicable standards of
ethical conduct;
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; or
3. A small organization that is any not-for-profit enterprise which
is independently owned and operated and is not dominant in its field.
After considering the economic impacts of this final rule on small
entities, I certify that this action will not have a significant
economic impact on a substantial number of small entities. Because no
small entities have been identified that are directly regulated by
these amendments, EPA has not attempted to reduce the impact of this
final rule on small entities. Public comments were explicitly invited
on all aspects of the proposal and its impacts on small entities, but
no such comments were received.

D. Unfunded Mandates Reform Act (UMRA)

Title II of UMRA (2 U.S.C. 1531-1538) establishes requirements for
Federal agencies to assess the effects of their regulatory actions on
State, local, and tribal governments and the private sector. This rule
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. Thus, this rule is not
subject to the requirements of UMRA sections 202 or 205. This rule is
also not subject to the requirements of UMRA section 203, because it
contains no regulatory requirements that might significantly or
uniquely affect small governments. These amendments are unlikely to
affect State, local, and tribal governments at all, and are likely to
affect the private sector only trivially.

E. Executive Order 13132: Federalism

This action does not have federalism implications because it will
not 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 (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. Thus, Executive Order 13132 does not
apply to this action.

F. Executive Order 13175: Consultation and Coordination With Indian
Tribal Governments

This action does not have tribal implications as specified in
Executive Order 13175 (65 FR 67249, November 9, 2000). This action will
not 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. Executive Order 13045: Protection of Children From Environmental
Health Risks and Safety Risks

EPA interprets Executive Order 13045 (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
amendments.

H. Executive Order 13211: Actions Concerning Regulations That
Significantly Affect Energy Supply, Distribution, or Use

This action is not a ``significant regulatory action'' as defined
in Executive Order 13211 (66 FR 28355, May 22, 2001), because it is not
likely to have a significant adverse effect on the supply,
distribution, or use of energy.

I. National Technology Transfer and Advancement Act (NTTAA)

Section 12(d) of NTTAA (15 U.S.C. 272 note) directs EPA to use
voluntary consensus standards in its regulatory activities unless to do
so would be inconsistent with applicable law or otherwise impractical.
Voluntary consensus standards are technical standards (e.g., materials
specifications, test methods, sampling procedures, and business
practices) that are developed or adopted by voluntary consensus
standards bodies. NTTAA directs EPA to provide Congress, through OMB,
explanations when the Agency decides not to use available and
applicable voluntary consensus standards. This action does not involve
any technical standards. Therefore, EPA did not consider the use of any
voluntary consensus standards.

J. Executive Order 12898: Federal Actions To Address Environmental
Justice in Minority Populations and Low-Income Populations

Executive Order 12898 (59 FR 7629, February 16, 1994) establishes
Federal executive policy on environmental justice. Its main provision
directs Federal agencies, to the greatest extent practicable and
permitted by law, to make environmental justice part of their mission
by identifying and addressing, as appropriate, disproportionately high
and adverse human health or environmental effects of their programs,
policies, and activities on minority populations and low-income
populations in the United States.
EPA has determined that this final rule will not have
disproportionately high and adverse human health or environmental
effects on minority or low-income populations, because it does not
affect the level of protection provided to human health or the
environment. This rule does not entail special considerations of
environmental justice related issues. The strengthened protections for
human subjects participating in covered research established in the
2006 rule will not be altered by these amendments.

VII. Congressional Review Act

The Congressional Review Act (5 U.S.C. 801 et seq.), generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and the Comptroller General of the United
States. EPA will submit a

[[Page 10543]]

report containing this rule and other required information to the U.S.
Senate, the U.S. House of Representatives, and the Comptroller General
of the United States prior to publication of the rule in the Federal
Register. A major rule cannot take effect until 60 days after it is
published in the Federal Register. This action is not a ``major rule''
as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 26

Environmental protection, Administrative practice and procedures,
Human research, Pesticides and pests.

Dated: February 8, 2013.
Lisa P. Jackson,
Administrator.

Therefore, 40 CFR chapter I is amended as follows:

PART 26--[AMENDED]

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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).

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2. In Sec. 26.1101:
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a. Remove paragraphs (a), (c), and (g).
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b. Redesignate paragraph (b) as (c), (f) as (g), (e) as (f), and (d) as
(e).
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c. Add new paragraphs (a), (b), and (d).
The amendments 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 April 15, 2013
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, 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 or section 408 of FFDCA; 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 EPA Administrator retains final judgment as to whether a
particular activity is covered by this subpart.
* * * * *

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3. In Sec. 26.1102, revise paragraphs (a) and (c) and add new
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 the Federal Register issue of June 18,
1991 (56 FR 28003)) 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 appears in 40 CFR part 26, subpart A.

Sec. 26.1111 [Amended]

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4. In Sec. 26.1111, remove from paragraph (a)(4) the phrase ``or the
subject's legally authorized representative.''

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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.
* * * * *

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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

[[Page 10544]]

be given to the subject, in addition to a copy of the short form.

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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

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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.

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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 on or after
April 15, 2013 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]

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10. In Sec. 26.1302, remove the word ``shall.''

Sec. 26.1502 [Amended]

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11. In Sec. 26.1502:
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a. Remove in the first sentence of paragraph (a), the period after the
phrase ``during an inspection'' and add in its place a comma.
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b. Remove in the second sentence of paragraph (a), the phrase ``The
agency'' and add in its place ``EPA.''
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c. Remove in the last sentence of the introductory text of paragraph
(b), the phrase ``the Agency'' and add in its place ``EPA.''

Sec. 26.1505 [Amended]

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12. In Sec. 26.1505, remove from the last sentence, the citation
``Sec. 26.1502(c)'' and add in its place ``Sec. 26.1502(b)(4).''

Sec. 26.1507 [Amended]

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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]

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14. Redesignate Sec. Sec. 26.1601 through 26.1603 as Sec. Sec.
26.1603 through 26.1605.

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15. Add new Sec. Sec. 26.1601 and 26.1602 to subpart P 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 Sec. 26.1125.
(b) Reviews by EPA on or after April 15, 2013 and, to the extent
required by Sec. 26.1604, by the Human Studies Review Board of reports
of completed research subject to Sec. 26.1701.

Sec. 26.1602 Definitions.

The definitions in Sec. 26.1102 also apply to this subpart.

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16. In newly redesignated Sec. 26.1603:
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a. Remove paragraphs (a) and (e).
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b. Redesignate paragraphs (b) through (d) as (e) through (g).
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c. Add new paragraphs (a), (b), (c), (d), and (h).
The amendments 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 scientific validity and reliability of 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 EPA Administrator will also consider the process laid
out and the attendant discussion for evaluating that type of study as
provided in Recommendation 4-1 of 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 subject
to this subpart, the EPA Administrator may recommend additional
conditions which, in the judgment of the EPA

[[Page 10545]]

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.

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17. In newly redesignated Sec. 26.1604, revise 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.
* * * * *

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18. Add Sec. Sec. 26.1606 and 26.1607 to subpart P 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
required 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.

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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

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20. Revise Sec. Sec. 26.1701 through 26.1705 to read as follows:
* * * * *
Sec.
26.1701 To what does this subpart apply?
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.
26.1705 Prohibition of reliance on unethical human research with
non-pregnant, non-nursing adults initiated after April 7, 2006.
* * * * *

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 also apply to
this subpart.

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.

(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.

(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

[[Page 10546]]

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]

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21. In Sec. 26.1706, remove in paragraph (d) the word ``publishes''
and add in its place the phrase ``has published.''

[FR Doc. 2013-03456 Filed 2-13-13; 8:45 am]
BILLING CODE 6560-50-P