2195.04_Attachment A

Monday,
February 6, 2006

Part II

Environmental
Protection Agency

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40 CFR Parts 9 and 26
Protections for Subjects in Human
Research; Final Rule

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Federal Register / Vol. 71, No. 24 / Monday, February 6, 2006 / Rules and Regulations

ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Parts 9 and 26
[EPA–HQ–OPP–2003–0132; FRL–7759–8]
RIN 2070–AD57

Protections for Subjects in Human
Research
Environmental Protection
Agency (EPA).
ACTION: Final rule.

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AGENCY:

SUMMARY: With this final rule, EPA bans
research for pesticides involving
intentional exposure of human subjects,
when the subjects are pregnant women
or children. The rule further strengthens
existing protections for subjects in
research conducted or supported by
EPA, by prohibiting such research if it
would involve intentional exposure of
human subjects who are pregnant
women or children. The rule also
extends new protections to adult
subjects in research for pesticides
conducted by others who intend to
submit the research to EPA, when it
involves intentional exposure of human
subjects who are non-pregnant adults,
and creates a new, independent Human
Studies Review Board to advise the
Agency on the ethical and scientific
issues arising in such research. This
final rule focuses on third-party
intentional dosing human studies for
pesticides and sets the stage for further
Agency actions. In addition, in order to
display the OMB control number for the
information collection requirements
contained in this final rule, EPA is
amending the table of OMB approval
numbers for EPA regulations that
appears in 40 CFR part 9.
DATES: This rule is effective on April 7,
2006.
ADDRESSES: EPA has established a
docket for this action under docket
identification (ID) number EPA–HQ–
OPP–2003–0132. All documents in the
docket are listed in the index for the
docket. Although listed in the docket
index, some information is not publicly
available, i.e., Confidential Business
Information (CBI) or other information
whose disclosure is restricted by statute.
Certain other material, such as
copyrighted material, is not available
through the electronic docket and will
be publicly available only in hard copy
form. Publicly available docket
materials are available either
electronically at http://
www.regulations.gov or in hard copy at
the Public Information and Records
Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1801 S. Bell St.,

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Arlington, VA. This Docket Facility is
open from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal
holidays. The Docket telephone number
is (703) 305–5805.
FOR FURTHER INFORMATION CONTACT:
William L. Jordan, Mailcode 7501C,
Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460; telephone number: (703)
305–1049; fax number: (703) 308–4776;
e-mail address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. What Does this Final Rule Do?
With this final rule EPA significantly
strengthens and expands the protections
for subjects of ‘‘third-party’’ human
research (i.e., research that is not
conducted or supported by EPA) by: (1)
Prohibiting new research involving
intentional exposure of pregnant women
or children, intended for submission to
EPA under the pesticide laws; (2)
extending the provisions of the Federal
Policy for the Protection of Human
Subjects of Research (the ‘‘Common
Rule’’) to other human research
involving intentional exposure of nonpregnant adults, intended for
submission to EPA under the pesticide
laws; (3) requiring submission to EPA of
protocols and related information about
covered human research before it is
initiated; and (4) establishing an
independent Human Studies Review
Board to review both proposals for new
research and reports of covered human
research on which EPA proposes to rely
under the pesticide laws.
The final rule also: (1) Categorically
prohibits any EPA research involving
intentional exposure of human subjects
who are pregnant women or children to
pesticides or any substances; and (2)
adapts regulations of the Department of
Health and Human Services providing
additional protections beyond those of
the Common Rule to pregnant women
and children as subjects in EPA
observational research—i.e., research
which does not involve intentional
exposure to any substance. (Research
conducted by EPA is referred to as
‘‘first-party’’ research, and ‘‘secondparty’’ research refers to research
supported by EPA but performed by
others.)
Finally, this rule forbids EPA to rely,
in its actions under the pesticide laws,
on intentional-exposure human research
that either involves pregnant women or
children or is otherwise considered
unethical, except in narrowly defined
circumstances. For example, if children
were at risk from unsafe exposure to a

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substance, the Agency would be
permitted to rely on otherwise
unacceptable research to justify setting
a more restrictive standard to protect
them.
B. Legal Authority
EPA is promulgating this final rule to
effectuate the express mandate of the
United States Congress as set forth in
section 201 of the Department of the
Interior, Environment, and Related
Agencies Appropriations Act, 2006,
Public Law No. 109–54 (Appropriations
Act), which provides appropriated
funds for EPA and other federal
departments and agencies. In addition,
today’s final rule is authorized under
provisions of the following statutes that
EPA administers: Section 3(a) of the
Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA), which
authorizes the Administrator 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’’); section 25(a) of FIFRA,
which authorizes the Administrator to
‘‘prescribe regulations to carry out the
purposes of [FIFRA],’’ and section
408(e)(1)(C) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), which
authorizes the Administrator to issue a
regulation establishing ‘‘general
procedures and requirements to
implement [Section 408].’’ In addition,
EPA’s expansion of its human subject
protection regulations to include
additional subparts supplementing
EPA’s codification of the Common Rule
regarding first- and second-party
research are authorized pursuant to 5
U.S.C. 301 and 42 U.S.C. 300v–1(b).
C. Does this Action Apply to Me?
You may be potentially affected by
this action if you conduct human
research on substances regulated by
EPA. Potentially affected entities may
include, but are not limited to, entities
that conduct or sponsor research
involving intentional exposure of
human subjects that may be submitted
to EPA under FIFRA or FFDCA.
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).

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This listing is not intended to be
exhaustive, but rather provides a guide
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) code has
been provided to assist you and others
in determining whether this action
might apply to certain entities. To
determine whether you or your business
may be affected by this action, you
should carefully examine the
applicability provisions of 40 CFR part
26. If you have any questions regarding
the applicability of this action to a
particular entity, consult the person
listed under FOR FURTHER INFORMATION
CONTACT.
D. How Can I Access Electronic Copies
of this Document and Other Related
Information?
You may access an electronic copy of
this Federal Register document and the
associated electronic docket at http://
www.regulations.gov, or you may access
this Federal Register document
electronically through the EPA Internet
under the ‘‘Federal Register’’ listings at
http://www.epa.gov/fedrgstr/. A
frequently updated electronic version of
the Code of Federal Regulations (CFR) is
available at http://www.gpoaccess.gov/
ecfr/ .
II. Background

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A. Summary of EPA Goals for this Final
Rule
EPA’s most important statutory
responsibility is to protect public health
and the environment by regulating air
and water pollutants, pesticides,
hazardous wastes, industrial chemicals,
and other environmental substances. To
meet this responsibility the Agency
considers a wide range of information
about each substance, including its
potential to cause harm—i.e., its
toxicity—and how and at what levels
people may be exposed to it—i.e., their
exposure. By linking information about
toxicity with estimates of exposure, EPA
can estimate the risk a substance poses
to exposed populations, and then decide
whether and how best to regulate
releases of the substance into the
environment.
EPA believes that in general it can
best protect public health by
considering all available, relevant,
scientifically sound information,
including information developed
through research with human subjects.
But at the same time, EPA wants to take
action to ensure that research conducted
by EPA or for EPA, submitted to EPA,
and relied on by EPA—especially

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research with human subjects—has been
conducted ethically.
B. The Role of Human Research in EPA
Risk Assessments
The Agency’s understanding of
potential risks to people is usually
based on many tests performed with
laboratory animals. These tests differ in
the kinds of animals used, the duration
of exposure, the age of test animals, and
the pathway of exposure–through food,
air, or the skin. When they are
considered together, the results of all
these studies provide a good general
understanding of a pesticide’s potential
effects.
Animal studies, however, are not the
only source of relevant information for
characterizing potential risks of a
substance. Epidemiological studies, for
example, provide valuable information
about the relationship between chemical
exposure and effects of concern.
Monitoring studies that measure
concentrations of a substance in air,
water, food, or on surfaces also provide
valuable insights into chemical
exposures. Sometimes, however, the
relationship between environmental
concentrations of a substance and
potential human exposure is unclear,
and can be understood only through
research involving human subjects. For
example, a farmer’s actual exposure to
a pesticide he or she is applying will
depend on his or her equipment, the
kind and quantity of pesticide he or she
uses, what protective clothing or
equipment he or she uses, and how
many hours he or she works each day.
To be able to take these factors into
account, workers will often wear
monitors in the field to measure
exposure levels in their routine work.
Research like this provides critical data
for defining protective standards for
pesticide handlers and applicators.
Without these and similar studies
characterizing the exposures received by
individuals in the normal course of their
work and daily life, the Agency would
not understand adequately either what
types of application equipment and
protective clothing to require for a
pesticide, or how soon harvesters or
other workers could safely enter
pesticide-treated areas.
Some human research, however,
involves intentional exposure of human
subjects—defined in this rule as
exposure they would not have
experienced had they not participated
in the research. One kind of research
involves exposing subjects to low doses
of a substance to measure how it is
absorbed, distributed, metabolized, and
excreted. Humans process some
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studies of this kind can provide
essential support for safety monitoring
programs, such as those which measure
the known metabolites of a substance in
the blood or urine of workers to estimate
their exposure to the substance.
Although EPA has not required or
encouraged it, some third parties have
occasionally conducted and submitted
to EPA reports of research involving
intentional exposure of human subjects
to a substance to identify or measure its
toxic effects. These studies occur in a
controlled laboratory or clinical setting.
Animal data alone can sometimes
provide an incomplete or misleading
picture of a substance’s safety or risks.
Sometimes human research shows
people to be more susceptible than
animals to the effects of a chemical, and
supports regulatory measures more
protective than could be justified by
animal data alone. This has been the
case, for example, for arsenic, certain air
pollutants, and the pesticide ingredients
methyl isothiocyanate (MITC) and
hexavalent chromium. Even when
human research does not show people
to be more sensitive than animals,
scientifically sound human data
developed under strict ethical standards
can strengthen the basis for EPA
regulatory actions.
C. Societal Concern over the Ethics of
Human Research
Scientific experimentation with
human beings has always been
controversial. The history of human
research contains well-known examples
of unethical behavior in the name of
science, which have led to reforms in
the way the government and others
carry out and oversee human research.
Through these reforms, the standards for
ethical human research have evolved to
become progressively more stringent
and protective of the subjects of the
research. In the United States the
‘‘Common Rule,’’ a regulation followed
by EPA and 17 federal departments and
agencies, 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. See
Unit V.
For several years EPA has been at the
center of an intense debate about the
acceptability of intentional dosing
human toxicity studies for pesticides,
and about what to do with human
studies that are ethically deficient. In
this debate some have argued that all
research involving intentional exposure
of human subjects to pesticides is
fundamentally unethical and should
never be conducted or accepted. Others,
while acknowledging the possibility of

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ethical human research with pesticides,
have argued that EPA should simply
refuse to consider data from ethically
problematic research in its regulatory
decisions. Those who hold this view
interpret Agency reliance on an
ethically flawed study as an
endorsement of the investigators’
behavior, and as encouragement to
others to engage in similarly unethical
research. Some also argue that EPA’s
reliance on ethically deficient human
data could directly benefit the wrongdoer. For example, if EPA based a
regulatory decision on a human study
that shows humans to be less sensitive
than animals, the result might be a less
stringent regulatory measure,
advantageous to the company that
conducted the study. If the key study
was unethical, the company could
benefit from its own misconduct.
On the other hand, human research
has contributed enormously to scientific
understanding of the risks posed by
many substances in the environment,
and to some of EPA’s past regulatory
actions. With this in mind, others argue
that the Agency should consider all
relevant and scientifically sound
information—not excluding ethically
deficient human data—because to do so
will lead to better decisions, based on
assessments that better reflect actual
risks. Holders of this view argue that the
ethical deficiencies of the research are
the responsibility of the researchers, not
of EPA. They further argue that EPA can
do no additional harm to the subjects of
the research by relying on scientifically
valid and relevant data from an ethically
deficient study, whereas EPA’s refusal
to rely on such data could do nothing
to benefit the subjects of the research.
Moreover, they assert that while the
Agency cannot undo what has already
happened, EPA can clearly express its
disapproval of past unethical conduct.
Holders of this view also stress the
importance of strengthening protections
for volunteers who participate in future
studies, while taking advantage of all
that past research can offer to benefit
society.
D. EPA’s Solicitation of Expert Advice
In response to public concerns over
human research with pesticides, EPA
convened an advisory committee under
the joint auspices of the EPA Science
Advisory Board (SAB) and the FIFRA
Scientific Advisory Panel (SAP) to
address issues of the scientific and
ethical acceptability of such research.
This committee, known as the Data from
Testing of Human Subjects
Subcommittee (DTHSS), met in
December 1998 and November 1999,
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2000. Their report is available in the
public docket for this rulemaking, and
on the web at: http://www.epa.gov/
science1/pdf/ec0017.pdf.
The DTHSS advisory committee
agreed unanimously on several broad
principles, including the following:
• Any policy adopted should reflect
the highest standards, and special
concern for the interests of vulnerable
populations.
• The threshold of justification for
intentional exposure of human subjects
to toxic substances should be very high.
• The justification cannot be to
facilitate commercial interests, but only
to safeguard public health.
• Not only the nature and magnitude
of risks and benefits but their
distribution must be considered in
assessing research protocols.
• Bad science is always unethical.
No clear consensus, however,
emerged from the committee on many
other points, including either the
scientific merit or the ethical
acceptability of studies to identify or
measure toxic effects of pesticides in
human subjects. A vigorous public
debate continued about the extent to
which EPA should accept, consider, or
rely on third-party intentional dosing
human studies for pesticides.
In December 2001, EPA asked the
advice of the National Academy of
Sciences (NAS) on the many difficult
scientific and ethical issues concerning
intentional human dosing studies. At
EPA’s request, the NAS convened a
committee to provide the requested
advice. The committee met publicly in
December 2002, and again in January
and March 2003. After long and
thoughtful consideration of the full
range of issues, the committee released
its final report, ‘‘Intentional Human
Dosing Studies for EPA Regulatory
Purposes: Scientific and Ethical Issues,’’
in February 2004. Their report is
available at: http://www.nap.edu/books/
0309091721/html/.
The NAS recommendations addressed
what standards should guide the
conduct of future human research and
whether or not EPA should rely on the
results of ethically deficient human
studies. The NAS Report concluded that
the answers to these questions should
start from the existing standards for the
ethical treatment of human research
embodied in the Common Rule. The
NAS Report then offered numerous
recommendations, supported by
detailed rationales, for how to apply the
principles of the Common Rule to the
particular issues confronting EPA. EPA
has relied heavily on the advice of this
committee in developing this rule. The
NAS Report discusses the full range of

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types of human studies available to EPA
and the full breadth of statutory
programs under which they might be
considered.
E. Balancing Conflicting Societal Goals
EPA’s mission is to make the best
possible regulatory decisions to protect
public health and the environment. EPA
does not want to ignore potentially
important information that might
benefit its assessments and decisionmaking. At the same time, the Agency’s
conduct should encourage high ethical
standards in research with human
subjects. If all research with human
subjects always met the highest
contemporary ethical standards, these
goals could all be pursued together. But
sometimes they conflict.
Two salient issues illustrate the
difficulty in striking an appropriate
balance between societal goals in
conflict. First, the Agency must decide
what standard to apply to assess the
ethical acceptability of research
performed before the new rule takes
effect. The choices are: To apply today’s
standards of ethical conduct to research
performed in the past, or to judge past
research against the ethical norms
prevailing when it was conducted.
Codes of ethical research conduct
regulate the behavior of investigators
before and during the research. It is
reasonable to expect investigators to
follow ethical codes that prevail when
they do their work; but EPA believes it
is unreasonable to expect them to
anticipate and follow standards that
may be developed after their work is
done. EPA believes that scientifically
meritorious research that adhered to
accepted high ethical standards when it
was conducted should not be set aside
because ethical standards have
subsequently changed. EPA also
believes that ethical standards are likely
to continue to change in the future and
that if and when they do, such a change
should not invalidate or make
unacceptable otherwise meritorious
research conducted now, in conformity
with high ethical standards of today.
Other parts of the U.S. government, and
other countries, have arrived at a similar
position.
In the final rule, EPA has
implemented the applicable
recommendation of the NAS, and will
accept scientificatiated before the rule
becomes effective unless there is clear
and convincing evidence that it was
fundamentally unethical or significantly
deficient with respect to the ethical
standards prevailing when the research
was conducted.
The second salient issue concerns
whether it is ever justified to rely on a

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report of scientifically sound research
judged to be unethical. To illustrate this
problem, assume that EPA received a
report of scientifically valid research
involving intentional exposure of
children, which is defined by this rule
as unacceptable. But assume this study
shows that the level of exposure to the
tested substance safe for children is 5
parts per billion (ppb), whereas all other
information available from animal
studies and ethical human studies
suggests that children would be safe if
exposed at levels up to 90 ppb. A
regulatory standard of 5 ppb based on
the unacceptable study would
adequately protect exposed children; a
standard which did not rely on the
unacceptable study would be set at 90
ppb, and would not adequately protect
exposed children.
In such a situation, what should the
Agency do? If EPA refused to rely on the
unethical research in this example, it
would set its standard at 90 ppb and
would not adequately protect exposed
children. Moreover, if the final rule
always prohibited reliance on data from
research involving intentional exposure
of children, even in this exceptional
case, using the data to justify a level at
5 ppb would be a plain violation of a
regulation that could be subject to legal
challenge.
The ethical and responsible course,
EPA believes, would be to rely on the
data to set a fully protective standard,
while strongly condemning unethical
research conduct and imposing
appropriate administrative sanctions.
Moreover, the number of people who
would benefit from EPA’s regulatory
intervention could be far greater than
the number of subjects involved in the
research. Thus EPA has retained the
proposed exception, to permit it to take
legally defensible action to protect
public health in this kind of exceptional
situation.
EPA expects a circumstance like this
example to arise only rarely, if at all.
But however rarely it might occur, any
decision to rely on unacceptable data,
should only be made with great care,
with full opportunity for public
discussion, and in reliance on expert
advice. As discussed further later, the
final rule both provides for the essential
public health protection exception,
narrowly defined, and meets all these
additional criteria.
III. EPA’s Proposed Human Studies
Rulemaking and General Public
Comments
Summary: This unit reviews the
general public comments on EPA’s
proposed rulemaking. The detailed

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comments are addressed in subsequent
units of this preamble.
An extensive review of the historical
development of ethical standards for the
conduct of human research and the
events leading up to the promulgation of
this final rule appeared in the preamble
to the proposed rule, available in the
public docket for this action.
Today’s final rule is the first to
emerge from the process which began
with publication of an Advance Notice
of Proposed Rulemaking in the Federal
Register on May 7, 2003 (68 FR 24410)
(FRL–7302–8). On February 8, 2005 (70
FR 6661) (FRL–7695–4), EPA published
and invited public comment on a
Federal Register notice announcing its
plan to establish a comprehensive
framework for deciding whether to
consider or rely on certain types of
research with human subjects.
On September 12, 2005 (70 FR 53838)
(FRL–7728–2), EPA published in the
Federal Register a notice of proposed
rulemaking to strengthen the protections
for people who participate as subjects in
human research. The Agency proposed
to ban intentional dosing human testing
for pesticides when the subjects are
pregnant women or children, to
formalize and further strengthen
existing protections for subjects in
human research conducted or supported
by EPA, and to extend new protections
to adult subjects in human research for
pesticides, involving intentional
exposure of human subjects and
conducted by others who intend to
submit the research to EPA. The
proposal also contained provisions to
establish an independent Human
Studies Review Board responsible for
reviewing proposals to conduct new,
intentional-exposure human research
under the pesticide laws and EPA
decisions to rely on the results of certain
types of completed human research in
its actions under the pesticides laws.
EPA received approximately 50,000
comments during the 90–day public
comment period. The vast majority of
the comments were submitted by
private individuals as part of e-mail and
letter-writing campaigns. The remaining
unique comments came from
individuals and organizations
representing a range of stakeholders
including pesticide companies, farm
groups and other pesticide users, and
environmental and public health
advocacy groups. EPA has reviewed,
summarized, and responded to these
comments in the Response to Comments
document available in the docket for
this rule. In addition, this unit
summarizes the major themes raised by
the comments on the proposal, and

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explains how EPA has addressed them
in the final rule.
Comment: All human research with
pesticides is fundamentally unethical.
Response: EPA agrees with the advice
it has received, as discussed in Unit II.,
from its advisory committees. The SAB/
SAP Data from Testing of Human
Subjects Subcommittee agreed that
although ethical human research with
pesticides was possible, the threshold of
justification should be set very high.
The NAS Committee likewise counseled
care, recommending many specific
conditions which should be satisfied,
but nonetheless acknowledged the
possibility of ethical research when
those conditions were met. On that basis
EPA has gone forward with this final
rule.
Comment: Comments objected to the
Agency’s rulemaking on the ground that
it would promote unethical research on
human subjects by pesticide companies.
Response: EPA expects its tougher
new rules will eliminate all unethical
research and will decrease the overall
number of future intentional dosing
studies conducted for pesticides. The
additional science and ethics reviews by
EPA and the Human Studies Review
Board should eliminate any proposed
unethical research.
Over the period 1996 to 2001, EPA
received approximately 33 intentional
dosing studies of all types annually.
These included studies measuring
worker exposure; the efficacy of insect
repellents; studies of absorption,
distribution and excretion that help EPA
assess exposure; and studies of systemic
toxicity. Of these 33, only 4 a year, on
average, involved intentional exposure
of human subjects to measure minor,
reversible systemic toxic effects.
(Systemic effects are those that occur
within the body, such as trembling,
nausea, or headaches resulting from
chemical changes in the nervous
system.) See the Economic Analysis,
Appendix B.
Since 1996 we have received about 26
intentional dosing, systemic toxicity
studies on humans. After this rule is
finalized, we expect that number to
decrease from an average of 3 a year to
as few as 0 or 1 per year. We expect that
number of non-toxicity intentional
dosing studies to remain about the
same.
Comment: The proposal was unclear.
Response: Many comments on the
proposed rule reflected confusion about
which provisions applied to EPA and
which to regulated third parties, and
about how the standards applying to the
conduct of new research by EPA or third
parties differed from the standards
applying to EPA decisions to consider

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completed research. These different
elements were mingled in some
subparts of the proposed rule,
contributing to this confusion. A
concerted effort has been made in the
final rule to eliminate these potential
causes of confusion, by sharpening the
focus of each subpart and grouping
subparts in three broad groups:
• Rules applying to EPA’s conduct
and support of new research with
human subjects.
• Rules applying to certain types of
new third-party research for pesticides
with human subjects.
• Rules applying to EPA in its
regulatory capacity.
Comment: Ethical standards can be
evaded simply by denying intent to
submit the results of the research to
EPA.
Response: The final rule, like the
proposal, extends the Common Rule
requirements only to third-party
research intended for submission to
EPA under the pesticide laws, FIFRA
and FFDCA. EPA believes this is
appropriate because there has not been
adequate consideration of the policy
consequences of extending the
provisions of the final rule to
investigators who have no intent to
provide their research results to EPA
and would otherwise have no reason to
be aware of these requirements.
EPA also disagrees that the approach
used in the final rule makes it easy to
evade ethical standards for research by
denying the intent to submit. Several
elements in the final rule interact to
ensure the application of appropriate
standards. First is the explicit
presumption in the rule that all research
submitted by a pesticide registrant was
intended for submission to EPA.
Specific, credible documentation would
have to be provided to rebut this
presumption; a denial of intent,
standing alone, could not serve as a
rebuttal.
Second, if a submitter successfully
rebutted the presumption of intent, it
would make little practical difference,
and would certainly not compel the
Agency to accept unethically conducted
research. Under the final rule, whether
or not it was intended for submission to
EPA when research was initiated, and
whether or not it was otherwise subject
to the requirements of subpart K: (1)
After the effective date of the rule, all
reports of human research submitted to
EPA under the pesticide laws are
required by subpart M to be
accompanied by documentation of
ethical conduct of the research, (2) all
completed post-rule intentionalexposure research, on which the Agency
intends to rely in actions under the

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pesticide laws, is required by subpart P
to be reviewed by the Human Studies
Review Board, and (3) all post-rule
intentional-exposure research
considered under the pesticide laws is
subject under subpart Q to the Common
Rule as the ethical standard of
acceptability.
Consequently, the likelihood that
unethical research will be used by EPA
in actions under its pesticide laws is
very small—only when it is determined
that the data are crucial to support more
protective public health actions would
the Agency consider such data.
Comment: Limitation to research
involving intentional exposure of
human subjects excludes many kinds of
studies.
Response: Most third-party human
research for pesticides conducted by or
for EPA, or intended for submission to
EPA, meets the rule’s definition of
research involving intentional exposure,
and thus will be subject to the
requirements of subpart K. But whether
or not research is subject to subpart K,
all reports of all post-rule human
research submitted to EPA are required
by subpart M to be accompanied by
documentation of ethical conduct.
Comment: Prohibitions of new
research involving intentional exposure
of pregnant women, fetuses, and
children are subject to exceptions.
Response: The rule provides for no
exceptions under any circumstances to
the bans on the conduct of new research
involving intentional exposure of
pregnant women, fetuses, and children
as subjects. The final rule has been
revised for clarity; the prohibitions have
been moved to subparts B (applying to
EPA) and L (applying to third parties,)
where they stand alone, and they have
been reworded to emphasize that they
apply notwithstanding any other
provisions anywhere in 40 CFR part 26.
Comment: The prohibition on
considering human subjects research
involving intentional exposure of
pregnant women, fetuses, and children
applies only to regulatory decisions, and
not to such non-regulatory agency
actions as risk assessments.
Response: The final rule has been
changed from the proposal to make this
prohibition applicable to all Agency
actions taken under the pesticide laws.
Comment: The proposed exception
permitting EPA to consider unethically
obtained data when to do so would be
‘‘crucial to protection of public health’’
undermines all other provisions of the
rule. Anything from a more accurate risk
assessment to increased agricultural
production could be interpreted as
‘‘crucial to protection of public health,’’

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and used to justify reliance on unethical
data.
Response: Such a broad interpretation
was never intended by the Agency, but
EPA acknowledges that its intentions
were not perfectly clear from the
language of the proposal. The final rule
retains a ‘‘public health exception,’’ but
it is reworded to make it very clear that
it could never be invoked to support a
less stringent regulatory outcome than
could be justified without consideration
of the unethical research.
Comment: Many provisions of the
Common Rule allow for exceptions to
its requirements at the discretion of the
Administrator or Institutional Review
Boards (IRBs); these exceptions should
not be allowed for third-party research.
Response: EPA agrees that some
exceptions in the Common Rule are not
appropriate for the kinds of third-party
human research covered by this rule. In
mirroring the core protections of the
Common Rule as they apply to third
parties in subpart K of the final rule,
EPA has eliminated or narrowed many
of these exceptions, as discussed in
detail in Unit VII.
IV. Reorganization of the Rule
Structure
Summary: To clarify the various
requirements in the proposal and how
they apply to first, second, and third
parties, the Agency has extensively
reorganized the final rule. The new
organization regroups the provisions of
the proposal into several new subparts.
In this final rule, EPA’s codification of
the Common Rule remains in force with
no changes except to designate it as
subpart A of part 26. Following today’s
action, the text of 40 CFR 26.101
through 26.124 remains identical to the
codifications of the Common Rule by
the other federal departments and
agencies that have promulgated it.
The remaining subparts in the final
rule, each discussed in a later unit of
this preamble, are grouped as follows:
• Subparts A through D apply to EPA
as an investigator or sponsor of new
research with human subjects, and to
second-party investigators whose
research EPA supports. Subpart A
contains the basic policy for human
research (the unchanged Common Rule).
Subpart B prohibits EPA human
subjects research on any substance
involving intentional exposure of
pregnant women, fetuses, or children.
Subparts C and D provide additional
protections for pregnant women,
fetuses, and children when they are
subjects of observational studies
conducted or supported by EPA.
• Subparts K and L apply to third
parties as investigators or sponsors of

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new research involving intentional
exposure of human subjects and
intended for submission to EPA under
the pesticide laws. Subpart K
establishes the basic protections for
non-pregnant adult subjects in covered
third-party research, corresponding in
substance to subpart A. Subpart L
prohibits covered third-party human
subjects research for pesticides
involving intentional exposure of
pregnant women or children.

• Subpart M applies to all third
parties who submit reports of any
research with human subjects to EPA
under the pesticide laws, whether or not
the research is covered by subpart K,
and requires concurrent submission of
information documenting the ethical
conduct of such research.
• Subparts O—Q apply to EPA in its
regulatory capacity. Subpart O identifies
potential actions for noncompliance
with subparts A through L. Subpart P
addresses the establishment and

operation of the Human Studies Review
Board, and subpart Q defines the ethical
standards EPA will use to decide
whether to rely on data from human
research in EPA actions.
Because this reorganization causes
extensive changes in the numbering of
the provisions of the final rule, EPA
provides the following table to make it
easier to follow how the reorganization
affects the location of specific
provisions.

TABLE 1.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO EPA AS AN INVESTIGATOR OR
SPONSOR OF RESEARCH WITH HUMAN SUBJECTS
Location in Final Rule

Location in Proposed Rule
Title/Description

Subpart

Section

Subpart

Section

A

§§ 26.201 thru
26.124

Basic Policy for Protection of Subjects in Human Research
Conducted or Supported by EPA

A

§§ 26.101 thru
26.124

B

§§ 26.201 thru
26.203

Prohibition of Human Subjects Research Conducted or
Supported by EPA Involving Intentional Exposure of
Pregnant Women, Fetuses, or Children

B and D

§§ 26.220 and
26.420

B

§ 26.201

To what does this subpart apply?

n/a

n/a

B

§ 26.202(a)

Definition of research involving intentional exposure of a
human subject

A

§ 26.102(k)

B

§ 26.202(b)

Definition of child

D

§ 26.402(a)

B

§ 26.203

Prohibition of EPA human subjects research involving intentional exposure of pregnant women, fetuses, or children

B and D

§§ 26.220 and
26.420

C

§§ 26.301 thru
26.305

Additional Protections for Pregnant Women or Fetuses Involved as Subjects in Observational Research Conducted or Supported by EPA

B

§§ 26.201 thru
26.206

D

§§ 26.401 thru
26.406

Additional Protections for Children Involved as Subjects in
Observational Research Conducted or Supported by
EPA

D

§ 26.401 thru
26.408

TABLE 2.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO THIRD PARTIES AS INVESTIGATORS OR
SPONSORS OF RESEARCH WITH HUMAN SUBJECTS
Location in Final Rule

Location in Proposed Rule
Title/Description

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Subpart

Section

Subpart

Section

K

§§ 26.1101
thru 26.1125

Basic Ethical Requirements for Third-Party Human Subjects
Research for Pesticides Involving Intentional Exposure of
Non-Pregnant Adults

A

§§ 26.101 thru
26.124

K

§ 26.1101(a)

To what does this subpart apply?

A

§ 26.101(j)

K

§ 26.1101(b)

Exemption of research involving only the collection or study
of existing data . . .

A

§ 26.101(b)(4)

K

§ 26.1101(c)

Administrator retains final judgment as to whether a particular activity is covered by this subpart

A

§ 26.101(c)

K

§ 26.1101(d),
(e), and (f)

Relation to other Federal, State, Tribal, Local, or foreign
laws or regulations

A

§ 26.101(e), (f),
and (g)

K

§ 26.1101(g)

For purposes of determining a person’s intent under paragraph (a) of this section . . .

A

§ 26.101(k)

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TABLE 2.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO THIRD PARTIES AS INVESTIGATORS OR
SPONSORS OF RESEARCH WITH HUMAN SUBJECTS—Continued
Location in Final Rule

Location in Proposed Rule
Title/Description

Subpart

Section

Subpart

Section

K

§§ 26.1102(a)
thru
26.1102(h)

Definitions

A

§§ 26.102(a) thru
26.102(i)

K

§ 26.1102(i)

Definition of research involving intentional exposure . . .

A

§ 26.102(k)

K

§ 26.1102(j)

Definition of person

n/a

n/a

K

§§ 26.1107
thru 26.1117

IRB and informed consent requirements

A

§§ 26.107 thru
26.117

K

§ 26.1123

Early termination of research

A

§ 26.123(a)

K

§ 26.1125

Prior submission to EPA of proposed human research

A

§ 26.124(b)

L

§§ 1201 thru
26.1203

Prohibition of Third-Party Human Subjects Research for
Pesticides Involving Intentional Exposure of Pregnant
Women, Fetuses, or Children

B and D

§§ 26.220 and
26.420

M

§§ 1301 thru
26.1303

Requirements for Submission of Information on the Ethical
Conduct of Completed Human Research

A

§ 26.124(c)

TABLE 3.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO EPA IN ITS REGULATORY CAPACITY
Location in Final Rule

Location in Proposed Rule
Title/Description

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Subpart

Section

Subpart

Section

O

§§ 26.1501 thru
26.1503

Administrative Actions for Noncompliance

E

§§ 26.501 thru
26.506

P

§§26.1601 thru
26.1603

Review of Proposed and Completed Human Research

A

§ 26.124(b)

P

§ 26.1601(c)

Determination of Equivalence of Foreign Ethical Standards

A

§ 26.101(h)

P

§ 26.1603

Operation of the Human Studies Review Board

A

§ 26.124(b)(5)

Q

§§ 26.1701 thru
26.1703

Ethical Standards for Assessing Whether to Rely on the
Results of Human Subjects Research in EPA Actions

B, D, and F

§§ 26.221, 26.421,
26.601, 26.602,
and 26.603

Q

§§ 26.1701 and
26.1702

Applicability and Definitions

n/a

n/a

Q

§ 26.1703

Prohibition of reliance on research involving intentional exposure of pregnant women, fetuses, or children

B and D

§§ 26.221 and
26.421

Q

§ 26.1704

Prohibition of reliance on unethical human research conducted before the effective date of the final rule

F

§ 26.601

Q

§ 26.1705

Prohibition of reliance on unethical human research conducted after the effective date of the final rule

F

§ 26.602

Q

§ 26.1706

Criteria and procedures for decisions to protect public
health by relying on otherwise unacceptable research

F

§ 26.603

V. Subpart A—Basic Ethical Protections
for Subjects of Human Research
Conducted or Supported by EPA
Summary: This unit describes the
basic ethical protections that apply to
human research conducted or supported
by EPA. Unit V.A. discusses the
comprehensive system of ethical
protections created by the ‘‘Basic

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Federal Policy for Protection of Human
Research Subjects,’’ generally referred to
as the Common Rule. The Common Rule
applies to all human research conducted
or supported by EPA and 17 other
federal departments and agencies. Unit
V.B. discusses the proposed rule, Unit
V.C. discusses public comments, and
Unit V.D. discusses the final rule.

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A. The Common Rule
The Common Rule defines the core
protections for human subjects of
research, and it is important to
understand just what those protections
are.
First, the Common Rule requires that
research with human subjects be
overseen by a qualified, independent

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Federal Register / Vol. 71, No. 24 / Monday, February 6, 2006 / Rules and Regulations
IRB meeting specific requirements laid
out in the rule governing membership,
procedures, decision-making,
recordkeeping, and avoidance of
conflicts of interest. The IRB is vested
with responsibility to review proposed
research, and with authority to approve
or disapprove it. The IRB is also
responsible for overseeing the conduct
of approved research, and investigators
are required to report any unanticipated
events to the responsible IRB. IRB
members must be trained, and must
remain current with extensive guidance
promulgated by the Office for Human
Research Protections in HHS.
Under the Common Rule an IRB may
approve proposed human subjects
research only when it concludes that all
of the following conditions are satisfied:
• Risks to subjects have been
minimized.
• Risks to subjects are reasonable in
relation to anticipated benefits, if any, to
subjects, and the importance of the
knowledge that may reasonably be
expected to result.
• Selection of subjects is equitable.
• Informed consent will be sought
from each prospective subject or the
subject’s legally authorized
representative.
• Informed consent will be
appropriately documented.
• The research plan makes adequate
provision for monitoring the data
collected to ensure the safety of
subjects.
• There are adequate provisions to
protect the privacy of subjects and to
maintain the confidentiality of data.
• Additional safeguards have been
included in the study to protect the
rights and welfare of subjects who are
likely to be vulnerable to coercion or
undue influence, such as children,
prisoners, pregnant women, mentally
disabled persons, or economically or
educationally disadvantaged persons.
The Common Rule also requires each
IRB to maintain records of everything it
reviews, of its discussion of
controversial issues, and of its decisions
and their rationale.
The second major element in the
Common Rule is its requirement that no
investigator involve a human being as a
subject in research without the informed
consent of the subject or the subject’s
legally authorized representative. The
Common Rule further specifically
requires that:
• An investigator shall 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.

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• The information given to the subject
must be in language understandable to
the subject.
• No informed consent, 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.
The Common Rule defines the
following mandatory elements in
informed consent:
• A statement that the study involves
research, an explanation of the purposes
of the research and the expected
duration of the subject’s participation, a
description of the procedures to be
followed, and identification of any
procedures which are experimental.
• A description of any reasonably
foreseeable risks or discomforts to the
subject.
• A description of any benefits to the
subject or to others which may
reasonably be expected from the
research.
A disclosure of appropriate
alternative procedures or courses of
treatment, if any, that might be
advantageous to the subject.
• A statement describing the extent, if
any, to which confidentiality of records
identifying the subject will be
maintained.
• For research involving more than
minimal risk, an explanation as to
whether any compensation and any
medical treatments are available if
injury occurs and, if so, what they
consist of, or where further information
may be obtained.
• An explanation of whom to contact
for answers to pertinent questions about
the research and research subjects’
rights, and whom to contact in the event
of a research-related injury to the
subject.
• A statement that participation is
voluntary, refusal to participate will
involve no penalty or loss of benefits to
which the subject is otherwise entitled,
and that the subject may discontinue
participation at any time without
penalty or loss of benefits to which the
subject is otherwise entitled.
The Common Rule specifies
additional elements of informed consent
that are sometimes required, and defines
standards for documenting informed
consent by use of a written consent form
approved by the IRB and signed by the
subject. The Common Rule requires that
a copy be given to the person signing
the form.
The Common Rule extends these core
protections to all human subjects of
covered research, including those in

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6145

vulnerable populations. It is to this base
of core protections for all subjects that
‘‘additional protections’’ for pregnant
women, fetuses, and children as
subjects of observational research
conducted or supported by EPA, as
contained in subparts C and D of this
final rule, are added. Vulnerable
populations for which no ‘‘additional
protections’’ are provided by rule are
not left defenseless or exploited; they
are covered by these core protections of
the Common Rule, including its
requirement that IRBs ensure, on a caseby-case basis, that additional safeguards
are employed in any study involving
vulnerable populations to protect their
rights and welfare.
In addition to these substantive
protections for research subjects, the
Common Rule as it applies to research
conducted or supported by EPA or any
other signatory department or agency
also contains many administrative
provisions intended to accommodate
the wide range of circumstances in all
the departments and agencies to which
it applies. Among others, these
administrative provisions include:
• Authority for the agency head to
extend coverage of the rule to research
‘‘otherwise subject to regulation’’
(§ 26.101(a)) and to determine what is
within its scope (§ 26.101(c) and (d)).
• Provision that only certain sections
apply to third-party research subject to
regulation (§ 26.101(a)(2)).
• A list of six kinds of human
research exempted from coverage by the
rule (§ 26.101(b)).
• Provision for approving research
conducted under foreign standards that
‘‘afford protections that are at least
equivalent to those provided in’’ the
Common Rule (§ 26.101(h)).
• A grant of discretion to the agency
head to waive provisions of the rule,
with public notice in the Federal
Register and to the DHHS Office for
Human Research Protections
(§ 26.101(i)).
• A grant of discretion to IRBs to
waive or alter requirements for informed
consent (§ 26.116(c) and (d)) or
documentation of informed consent
(§ 26.117(c)).
B. The Proposed Rule
The September 12 proposal to extend
EPA’s Common Rule to third-party
research involved extending all the
provisions of subpart A, §§26.101
through 26.124, to covered third-party
research. It also would have altered the
shared text of the Common Rule by
adding:
• A new paragraph defining the scope
of third-party research to which it
applied (proposed § 26.101(j)).

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• A new paragraph defining how a
party’s intent to submit research to EPA
would be determined (proposed
§ 26.101(k)).
• A new definition of research
involving intentional exposure of a
human subject (proposed § 26.102(k)).
• A new requirement for prior
submission to EPA of proposals for
covered third-party research (proposed
§ 26.124(b)).
• A new requirement for submission
to EPA of documentation of the ethical
conduct of completed research
(proposed § 26.124(c)).
As noted in the preamble to the
proposal, HHS requested EPA not to
make any alterations in the text of the
shared Common Rule, and to codify the
extension of the Common Rule
standards to third-party research in the
final rule in a way that left subpart A—
the Common Rule—intact and
unchanged. EPA agreed that the
Common Rule should not be altered,
and committed to making this change in
the final rule.
C. Public Comment
Comment: The proposed extension of
the entire Common Rule, including its
provisions for administrative waivers of
many requirements, alarmed many
commenters. These administrative
provisions were perceived as loopholes
which could be exploited to undermine
the whole purpose of extending the
Common Rule.
Response: Such exploitation of these
provisions was never the Agency’s
intent, and EPA agrees with the
commenters who argued that many of
these administrative provisions were
not appropriate in a rule applying to
third-party research. Thus, while
subpart K in the final rule does extend
all the substantive core protections of
the Common Rule to non-pregnant adult
subjects of covered research, it also
eliminates or narrows the exceptions in
the Common Rule. Unit VII. discusses
each change from the Common Rule to
subpart K in detail.

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D. The Final Rule
In the final rule subpart A is the
unaltered Common Rule, exactly as
promulgated in 1991 except for its
designation as ‘‘Subpart A.’’ It applies to
all research with human subjects
conducted or supported by EPA.
VI. Subpart K—General Provisions
Applying to Third Party, Intentional
Exposure Human Research under the
Pesticide Laws
Summary: Subpart K extends the
basic protections of the Common Rule to
subjects in certain research conducted

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or supported by third parties. It applies
to third-party human research involving
intentional exposure of non-pregnant
adult subjects and that is intended to be
submitted to EPA under the pesticide
laws. In addition to the basic procedures
and protections contained in the
Common Rule, it also requires
researchers who propose to conduct
new research covered by the rule to
submit protocols and other materials for
science and ethics review by both EPA
and a newly created Human Studies
Review Board (HSRB). Unit VI.A.
summarizes EPA’s proposal, Unit VI.B.
discusses public comment, and Unit
VI.C. discusses the provisions of the
final rule.
A. EPA’s Proposed Rule
EPA’s proposal added to the ‘‘Scope’’
section of the Common Rule additional
paragraphs, proposed § 26.101(j) and (k),
to make the provisions of the Common
Rule applicable to certain third-party
human research. Thus, the Agency’s
proposal would have extended the
Common Rule requirements to third
parties, without substantive or editorial
modification.
The scope of the third-party human
research covered by the proposal was
defined as:
[A]ll research involving intentional
exposure of a human subject if, at any time
prior to initiating such research, any person
who conducted or supported such research
intended:
(1) To submit results of the research to EPA
for consideration in connection with any
regulatory action that may be performed by
EPA under the Federal Insecticide,
Fungicide, and Rodenticide Act (7 U.S.C. 136
et seq.) or section 408 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 346a); or
(2) To hold the results of the research for
later inspection by EPA under the Federal
Insecticide, Fungicide, and Rodenticide Act
(7 U.S.C. 136 et seq.) or section 408 of the
Federal Food, Drug, and Cosmetic Act (21
U.S.C. 346a).

In effect, this provision would have
included all intentional-exposure
human research conducted with the
intent to submit the results to the
Agency under the pesticide laws. The
proposal also established a rebuttable
presumption that any information
submitted by a person regulated under
the pesticide laws was generated with
the intent to submit it to EPA.
In § 26.102(k), the proposal defined
‘‘research involving intentional
exposure of a human subject’’ to mean
‘‘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.’’ The preamble to the proposed

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rule explained that this term did not
include a study that ‘‘monitored
agricultural workers (such as
professional fruit thinners or harvesters
or other workers) who perform their
usual work in areas that have been
treated with pesticides at rates and
using methods registered and approved
by EPA’’ (70 FR 53846). The preamble
also explained that intentional exposure
studies did not include ‘‘most
occupational exposure studies, and
studies involving use of registered
pesticides for approved uses according
to label directions’’ (70 FR 53845).
In addition, the proposed rule
included a new section, proposed
§ 26.124, that would have required any
person proposing to conduct a new
human study covered by the rule to
submit the protocol and other materials
for a science and ethics review by EPA.
The same proposed section also created
a new independent panel of experts,
called the Human Studies Review
Board, to review all proposed new
research covered by the rule. The HSRB
would also review all completed human
research that EPA intended to rely on
under the pesticide laws.
B. Public Comments
The major public comments
applicable to subpart K of the final rule
are discussed in Unit III.
C. The Final Rule
The final rule establishes new
requirements for third-party research in
a separate subpart K, and the rule text
defining the scope of the types of thirdparty research covered by the proposed
rule remains unchanged in the final
rule. The Agency, however, has decided
that the types of research captured by
the definition of ‘‘research involving
intentional exposure of a human
subject’’ is broader than suggested by
the preamble to the proposal. Although
the text of the definition remains the
same, EPA thinks it is important to
clarify that the term covers any research
on a substance, unless the subjects of
the research retain complete control
over whether, when, and how they are
exposed to the substance. Thus, if the
researcher decides a particular
compound will be studied in the
research and determines the manner in
which subjects will be exposed, the
research falls within the scope of
‘‘research involving intentional
exposure.’’
The substantive requirements
applicable to covered third-party
research are similar to the requirements
contained in the Common Rule. In most
cases the text is identical, and the
sections employ a parallel numbering

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system. The sections in subpart K are
designated as §§ 26.1101 through
26.1125 and correspond to the sections
of the Common Rule designated
§§ 26.1xx. For example, § 26.1107 in
subpart K corresponds to § 26.107 of the
Common Rule.
EPA also made a number of minor
modifications to the text of the Common
Rule in order to reflect the applicability
of subpart K to a particular subset of
human subjects research studies
involving intentional exposure of nonpregnant adults intended for submission
under the pesticide laws. These
modifications are discussed in
paragraph 1 below.
1. Modifications to the text of the
Common Rule in subpart K. In a number
of its provisions the Common Rule
refers to itself as a ‘‘policy.’’ Throughout
subpart K, EPA has replaced the word
‘‘policy’’ with ‘‘subpart,’’ to remove any
doubt about whether the provisions of
subpart K create binding requirements.
Throughout subpart K, EPA replaced
references to ‘‘department or agency
head’’ with ‘‘the Administrator.’’
Section 26.1102 includes a definition
stating that Administrator refers to the
Administrator of EPA or any officer or
employee to whom authority has been
delegated.
Section 26.101(b) of the Common
Rule exempts research in six categories
from the requirements of the Common
Rule. These exemptions generally cover:
(i) Research on educational practices
conducted in an educational setting.
(ii) Research involving surveys,
educational tests, observation, or
interviews that involve no collection of
sensitive personal information on
identifiable individuals.
(iii) Research involving surveys,
educational tests, observation, or
interviews that involve public officials
or candidates for public office.
(iv) Research involving the collection
or study of existing data, documents,
specimens, etc. from publicly available
sources or sources that do not disclose
the identity of individual subjects.
(v) Research examining the delivery of
public benefit programs.
(vi) Research involving taste and food
quality evaluation and consumer
acceptance.
Subpart K, however, covers only
third-party research for pesticides
involving intentional exposure of nonpregnant adults. Because five of these
exemptions describe types of research
that either could not possibly or should
not involve ‘‘intentional exposure’’ to a
pesticide, EPA deleted them from
subpart K. Because the fourth category,
above, could encompass the
examination of results from research

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involving intentional exposure, the
Agency did retain exception number 4
in subpart K. See § 26.1101(b) of the
regulatory text.
Section 26.101(d) of the Common
Rule states that, without prior notice, an
agency head may extend the
requirements of the Common Rule to
specific research activities or classes of
research. As a legal and policy matter,
EPA believes that the public should
receive notice of and an opportunity for
public comment on any extension of
these requirements to additional
categories of third-party research.
Accordingly, subpart K does not contain
a provision comparable to § 26.101(d).
Section 26.101(f) of the Common Rule
indicates that State and local laws may
contain additional requirements
governing the conduct of human
research and that the Common Rule
does not supersede those requirements.
Recognizing that Native American
governmental entities also have legal
authority to regulate the conduct of
human research, EPA has added Tribal
authority to the list of legal sources that
may establish additional requirements
beyond those in the final rule. See
§ 26.1101(e) of the regulatory text.
Section 26.101(h) of the Common
Rule authorizes the head of an agency
to allow human research conducted in
a foreign country to proceed in
accordance with the requirements of
that country, even if foreign authorities
require behavior that does not fully
comply with the Common Rule, so long
as the agency head determines that the
requirements of the foreign country
provide protections ‘‘at least equivalent
to those [of the Common Rule.]’’ This
section further provides that when an
agency head makes such a decision, he
must publish a notice of the action in
the Federal Register. In promulgating
subpart K, EPA retained a comparable
provision, but with several changes.
First, EPA moved this provision to
subpart P of the final rule, which
addresses EPA’s decisions on the
acceptability of proposed research,
where it appears as § 26.1601(c).
Second, EPA did not adopt the Common
Rule’s requirement to publish a Federal
Register Notice announcing such a
decision on proposed third-party
research. The Agency concluded that
such a procedure was redundant with
the HSRB process, which will involve
both a transparent presentation of EPA’s
positions regarding proposed research
and public meetings about such
positions and an opportunity for the
public to comment on them.
Section 26.101(i) contains language
allowing the Administrator to waive any
of the requirements of the Common

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Rule. While every other federal
Common Rule agency and department
has such discretion, and while such
discretion seems appropriate for firstand second-party research, EPA has
never exercised this authority under the
Common Rule and sees no need for such
discretion under subpart K.
Accordingly, subpart K does not contain
a provision comparable to § 26.101(i).
The definitions in the Common Rule
include the term research subject to
regulation; see § 26.102(e). Subpart K
omits this definition because the types
of third-party research covered by the
rule are specified by the paragraphs in
§ 26.1101 delineating the scope of
subpart K.
Section 26.102(j) contains a definition
of the term certification. Because this
definition actually establishes a
substantive obligation to submit
documentation of IRB approval, the
substantive requirement appears in
§ 26.1125 as one of the items that must
be submitted to EPA in connection with
review of proposed research. See
§ 26.1125(f) of the regulatory text.
EPA added a new definition of person
in § 26.1102(j) of the final rule to clarify
that the requirements of subpart K (as
well as subparts L and M) do not apply
to first-party and second-party human
research by other federal departments
and agencies that are subject to the
Common Rule. Having operated under
the Common Rule for many years, these
agencies and departments are very
familiar with its meaning and
application and have well developed
procedures for assuring compliance.
Therefore, EPA sees no reason either to
promulgate requirements that duplicate
regulations already in force, or to
impose on these agencies the new
requirements of subpart K concerning
submission of proposals for future
research for EPA and HSRB review. Of
course, the Agency will, on request,
work with other agencies intending to
submit the results of human research to
EPA to ensure that the results may be
considered under subpart Q.
Several sections of the Common
Rule—§§ 26.107(a), 26.111(a)(3),
26.111(b), and 26.116(b)(1)—refer to
additional measures required when
research involves pregnant women,
children, or other special populations as
subjects. Subpart L, however, prohibits
third-party research involving
intentional exposure of human subjects
who are pregnant women (and therefore
their fetuses) or children. Thus subpart
K covers only third-party research
involving intentional exposure of nonpregnant adults. To be consistent with
this scope, EPA removed from subpart

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K all references to pregnant women,
fetuses, newborns, or children.
The first sentence of § 26.107 of the
Common Rule states:
Each IRB shall have at least five members,
with varying backgrounds to promote
complete and adequate review of research
activities commonly conducted by the
institution.

This provision reflects the assumption
that IRBs are always associated with an
‘‘institution.’’ It also arguably would
excuse an IRB from having adequate
expertise to assess studies beyond those
‘‘commonly conducted’’ at the
institution. EPA believes that IRBs
should acquire whatever expertise they
need to evaluate the types of studies
they agree to review. Accordingly, EPA
has revised that sentence to read:

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Each IRB shall have at least five members,
with varying backgrounds to promote
complete and adequate review of research
activities which are presented for its
approval.

Section 26.108(a) of the Common Rule
contains a cross-reference to certain
earlier sections of the Common Rule.
For greater clarity, and consistent with
FDA’s approach in its similar rules. EPA
simply repeated the substantive
requirements of the referenced sections
in § 26.1108(a) of subpart K. This led to
redesignation of some paragraphs.
Section 26.109(c) of the Common Rule
includes a reference to § 26.117(c),
which gives IRBs the authority, under
certain circumstances, to waive the
requirement for written documentation
of informed consent. Since EPA has not
included in subpart K a paragraph
comparable to § 26.117(c) of the
Common Rule, the Agency has deleted
the cross-reference in § 26.1109(c) of
subpart K.
Section 26.114 of the Common Rule
contains a provision designed to
facilitate cooperative research among
multiple investigators in different
institutions. This section authorizes the
head of an agency to accept a joint
review or review by a single IRB to
avoid duplication of effort. Rather than
use the text of the Common Rule
provision, EPA has adopted in § 26.1114
a similar but clearer provision from FDA
regulation; see 21 CFR 56.114.
Section 26.115(a)(5) of the Common
Rule cites another provision of the
Common Rule that specifies the
information about the members of an
IRB which the IRB is required to
provide in its records. In the parallel
section of subpart K, § 26.1115(a)(5),
EPA followed the approach FDA used in
its regulations and repeated the
substantive provisions of the referenced
sections.
Sections 26.116(c) and (d) of the
Common Rule authorize an IRB to waive

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or alter the requirement for informed
consent in certain circumstances for
research conducted or supported by
EPA. EPA deleted these paragraphs from
subpart K because of the central
importance of informed consent to
ensuring ethical treatment of subjects in
human research. In addition, EPA
concluded that the types of human
research covered by subpart K—research
involving intentional exposure of nonpregnant adults intended for submission
under the pesticide laws—would not
meet any of the Common Rule criteria
for waiving or altering the informed
consent procedures.
EPA added a new paragraph to
§ 26.1116 to clarify that the informed
consent materials for research covered
by subpart K must include ‘‘the identity
of the pesticide and the nature of its
pesticidal function.’’ While implicit in
the requirements of § 26.1116(a)(1),
which is derived from § 26.116(a)(1) of
the Common Rule, the Agency thought
that the final rule should make this
obligation explicit.
In a provision that parallels the
waiver authority discussed above,
§ 26.117(c) of the Common Rule
authorizes an IRB to waive the
requirement for an investigator to obtain
a signed consent form from each subject
for research conducted or supported by
EPA. Because of the importance of being
able to demonstrate that each subject
was fully informed and freely
volunteered to participate in the types
of research covered by subpart K, EPA
decided not to adopt this Common Rule
provision in subpart K. The Agency also
made minor editorial changes to
§ 26.1117(a) and (b) to reflect the
deletion of paragraph (c).
Section 26.101(a)(2) identifies the
sections of the Common Rule which
apply to ‘‘research that is neither
conducted nor supported by a Federal
department of agency but is subject to
regulation as defined in § 26.102(e).’’
These sections include §§ 26.107
through 26.117, but not § 26.103 or
§§ 26.118 through 26.124. Sections
26.118 through 26.124 generally apply
to procedures associated only with firstparty and second-party research, but
which would not be relevant to thirdparty research. Consistent with the
thrust of § 26.101(a)(2) and in order to
reduce confusion, EPA has not created
parallel sections for § 26.103 or, with
two exceptions, any of the sections after
§ 26.117.
The first of these exceptions is to
include in subparts K and P of the final
rule two passages parallel to § 26.123 of
the Common Rule. Section 26.1123,
which corresponds to § 26.123(a) in
subpart A, authorizes the Administrator

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to suspend or terminate research if EPA
determines that a sponsor, IRB, or
investigator has materially failed to
comply with the terms of subpart K.
(FDA’s regulations contain a similar
provision at 21 CFR 56.113.) In
addition, EPA has included the
substance of § 26.123(b)—authorizing
EPA to consider an investigator’s record
in past ethical (or unethical) human
research when reviewing proposals for
new research—in § 26.1601(b) of
subpart P, which governs EPA’s review
of proposed new research.
The second exception is to include in
subpart P of the final rule a § 26.1601,
parallel to § 26.124 of subpart A. This
provides that, in its review of proposed
new research, EPA may, on a case-bycase basis, impose additional conditions
applicable to the conduct of a study that
are necessary for the protection of
human subjects.
2. Revisions to the requirements for
information concerning proposed
research. In reorganizing the final rule,
EPA has moved the substantive content
of proposed § 26.125, which would have
required third parties to submit
proposals for new human research for
EPA review, to § 26.1125 of subpart K.
In addition, EPA has revised this section
in the final rule in two ways. A new
§ 26.1125(d) adds ‘‘a description of the
circumstances and methods for
presenting information to potential
human subjects for the purpose of
obtaining their informed consent’’ to the
list of what information must be
included with a submitted proposal for
new research, and § 26.1125(f) adds an
explicit requirement for documentation
of IRB approvals.
VII. Intentional Exposure Research:
Subparts B and L—Prohibitions of
Human Research Involving Intentional
Exposure of Pregnant Women, Fetuses,
and Children
Summary: Subpart B of the final rule
categorically prohibits EPA from
conducting or supporting human
subjects research on a substance that
involves intentional exposure of
pregnant women, fetuses, and children
to the substance. See 40 CFR 26.203 of
the regulatory text.
Subpart L of the final rule prohibits
human subjects research for pesticides
conducted or supported by third parties
that involves intentional exposure of
pregnant women, fetuses, or children.
See 40 CFR 26.1203 of the regulatory
text.
Unit VII.A. summarizes EPA’s
proposal, Unit VII.B. discusses public
comments, and Unit VII.C. discusses the
provisions of the final rule.

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A. The Proposed Rule
The September 12 proposal
contained, in § 26.220 of proposed
subpart B, a clear prohibition of any
future EPA research involving
intentional dosing of pregnant women,
fetuses or certain newborns. Section
26.420 of proposed subpart D contained
an equally clear prohibition of any
future EPA research involving
intentional dosing of children.
The same sections of the proposal—
§ 26.220 in subpart B and § 26.420 in
subpart D—also prohibited any new
third-party research intended for
submission to EPA under the pesticide
laws, and involving intentional dosing
of pregnant women, fetuses, or children.
The proposed prohibition would, as a
practical matter, have applied to any
research conducted by pesticide
companies or by investigators working
on their behalf.

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B. Public Comments
Almost without exception, comments
on the prohibitions contained in the
proposed rule drew no distinction
between third-party research and firstand second-party research. Therefore,
unless otherwise indicated, the
following discussion applies both to the
proposed prohibitions against human
subjects research conducted or
supported by EPA that involves
intentional exposure of pregnant
women, fetuses, or children and to the
prohibitions against such research by
third parties who intend to submit the
results to EPA under the pesticide laws.
In addition, comments generally made
the same recommendations regarding
the prohibition on research involving
intentional exposure of children as for
the prohibition on research involving
intentional exposure of pregnant women
and fetuses. Again, unless otherwise
indicated, the discussion below refers to
both sets of prohibitions.
Comment: Some commenters argued
that the proposed prohibitions were too
narrow and should be expanded in
order that all potentially affected test
subjects received protection.
Specifically, these comments
recommended that: (1) The prohibition
on research with children should not be
limited to research involving intentional
exposure, but should cover all types of
human research (including scientific
observation of public behavior of
children); (2) the prohibition on
research with pregnant women should
be similarly broad; and (3) additional
groups should be protected under the
ban on intentional exposure research,
including prisoners, all women of
childbearing age, the elderly, and

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people with chronic diseases or
developmental disabilities.
Response: EPA believes that
‘‘observational research,’’ i.e., research
that does not involve intentional
exposure of human subjects, often
provides a great deal of valuable
scientific information that can be
critical for effective environmental and
public health regulation. To adopt the
commenters’ approach would mean, for
example, that EPA could not collect,
through research involving little or no
risk to the subjects, information on the
amount of time that children spend
outdoors, the types of food consumed by
pregnant women, or the possible
correlation between air pollution and
asthma in newborns. Therefore, EPA has
decided not to accept the comments
recommending expansion of the
prohibitions to cover all types of human
research.
EPA agrees with the commenters who
point out that other groups deserve
special consideration if they are to be
included in research as test subjects.
The Common Rule and EPA’s extension
of it to certain types of third-party
research already direct IRBs to pay
particular attention to the issues
involved with research on several of
these groups. See § 26.111(b) and
§ 26.1111(b) of the regulatory text. EPA
believes that the approach created by
the final rule—which requires both EPA
and HSRB review of all future thirdparty research covered by the rule—will
successfully identify those studies that
may proceed ethically and those for
which it would not be ethical to involve
individuals from the identified groups.
Comment: Some commenters argued
that the proposed prohibitions were too
broad and that certain kinds of research
should be excluded from the bans on
conduct of future research involving
intentional exposure of human subjects.
Specifically, these comments
recommended exclusion of: (1)
Pharmaceutical studies, particularly
products for control of head and body
lice; (2) nutrition studies with
micronutrients that may also be
pesticides; (3) research on the efficacy of
insect repellents; (4) research involving
only use of registered pesticides for
approved uses, or ‘‘product-in-use’’
studies; and (5) research on the efficacy
of swimming pool and spa sanitizers
and disinfectants;
Response: For a variety of reasons,
EPA is not persuaded by these
comments to modify the scope of its
proposed prohibitions.
EPA notes that it does not conduct or
support pharmaceutical studies and
nutritional studies with any human
subjects, and therefore there is no need

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to modify the proposed prohibitions for
first- and second-party research.
Further, EPA did not intend its
proposed prohibitions to apply to third
parties when conducting
pharmaceutical or micronutrient
research, and believes that such thirdparty research generally would fall
outside the scope of the prohibitions
because they would not meet the ‘‘intent
to submit’’ criterion in § 26.1201. In fact,
EPA thinks it would be contrary to the
public interest to ban research of the
effects on pregnant women and children
of drugs, like streptomycin, or
micronutrients, like copper or iodine,
simply because these compounds also
have approved uses as pesticides. Given
that it is unlikely an investigator would
undertake such research for submission
to EPA in support of a pesticide action,
these types of studies would not be
prohibited.
EPA believes that there is no need to
perform research on the efficacy of
insect repellents with pregnant women
or children. The efficacy of a repellent
depends primarily on the properties of
the pesticide formulation and does not
vary with the age of the person to whom
it is applied. Therefore, studies using
non-pregnant adults should provide
adequate information to assess how well
insect repellents work, and there is no
reason to exclude this type of research
from the prohibition.
Similarly, EPA does not believe that
comments have presented a compelling
argument for recommending the Agency
exclude from the prohibitions ‘‘productin-use’’ research on pesticides. The
Agency agrees with comments that such
product-in-use research will generally
pose relatively little risk to test subjects,
because the exposures occurring during
the research would correspond to
exposures authorized by the Agency
under its pesticide regulatory program—
exposures that EPA has found cause no
unreasonable adverse effects on human
health or the environment. But these
comments contain no satisfactory
explanation of why it is necessary to
conduct such product-in-use research
with pregnant women, fetuses, or
children. Like research on insect
repellents, the Agency believes that
general product-in-use research with
non-pregnant adults should provide
sufficient information to meet legitimate
scientific needs.
Finally, research on the efficacy of
antimicrobial agents used in swimming
pools, spas, and hot tubs raises unusual
and difficult issues. The Agency issues
experimental use permits for these
studies to determine whether, under
typical use conditions, the antimicrobial
can successfully control the additional

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microbial load introduced by bathers.
The Agency, however, does not approve
such field research until the Agency can
conclude that both the experimental use
is likely to be effective and the levels of
the antimicrobial in water will pose no
risk to the bathers.
EPA, however, does not regard such
studies as ‘‘research with human
subjects’’ under the definitions in the
Common Rule at §§ 26.102 and 26.1102,
and therefore does not believe they are
subject to the prohibitions or any other
provisions in part 26. The definitions of
‘‘research’’ and ‘‘human subject’’ make
clear that the phrase ‘‘research with a
human subject’’ applies to a systematic
investigation in which an investigator
collects information through an
intervention or interaction with an
individual for the purpose of developing
generalizable knowledge about humans.
In the case of these antimicrobial
efficacy studies, the research does not
involve interactions with, or collection
of information on, identifiable
individuals for the purpose of
producing generalizable knowledge.
Comment: A number of comments
objected to what they perceived to be
‘‘loopholes’’ in the proposed rule’s
prohibition on research involving
intentional exposure of children.
Specifically, they argued that: (1)
Proposed § 26.401(a)(1) permitted EPA
to waive the prohibition when research
was conducted outside the United
States; (2) proposed § 26.401(a)(2)
permitted EPA to waive any provision
of proposed subpart D, including the
prohibition; and (3) proposed § 26.408,
which authorized an IRB to waive the
requirement for assent from children
lacking the capacity to give it, and to
waive the requirement for permission
from abusive or neglectful parents,
meant that EPA intended to allow
research on mentally retarded, abused,
or neglected orphans.
Response: Many commenters
misinterpreted EPA’s proposed
language. Contrary to public comments,
none of the alleged ‘‘loopholes’’ ever
existed, because the prohibition in
proposed § 26.420 stated
‘‘Notwithstanding any other provision
of this part, under no circumstances
shall EPA or a person when covered by
§ 26.101(j) conduct or support research
involving intentional dosing of any
child.’’ The words, ‘‘Notwithstanding
any other provision of this part,’’ mean
that the provisions in proposed § 26.420
override all other provisions of the
entire regulation, including §§ 26.401
and 26.408. Even though those two
sections would have given EPA
authority to waive certain requirements,
they would not have authorized any

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departure from the ban in proposed
§ 26.420.
Nonetheless, in order to remove any
doubt about the scope of the
prohibitions, EPA has made several
changes in the final rule. The
prohibitions appear in separate subparts
so that there is less chance someone will
misread the provisions intended to
confer flexibility in the approach to
observational research as applying to
research involving intentional exposure.
In subpart D, which addresses
observational research with children
conducted or supported by EPA, EPA
has removed or revised the text of
§§ 26.401 and 26.408 to make clear that
they do not create an opportunity to
relax the protections for children.
C. The Final Rule
After careful consideration of public
comments—particularly the thousands
of comments expressing strong
opposition to EPA’s ever conducting
human subjects research that involves
intentional exposure of pregnant
women, fetuses, or children, the Agency
has retained in the final rule the
proposed prohibitions, essentially
without change. Subpart B contains the
proposed prohibitions against EPA
conducting or supporting new research
involving intentional exposure of
pregnant women, fetuses, and children.
This prohibition applies to EPA’s firstand second-party research with any
substance, and is not restricted to
pesticides.
Subpart L of the final rule contains a
parallel prohibition of new third-party
human subjects research for pesticides
involving intentional exposure of
pregnant women, fetuses, or children.
Subpart L applies to research conducted
or supported by any person who intends
to provide the results of the research to
EPA under FIFRA or the FFDCA. The
final rule retains the text from the
proposal establishing how EPA will
determine a person’s intent for purposes
of applying the prohibition.
The Agency recognized that the
wording of the proposed prohibitions
and other requirements could be
interpreted to apply to studies, which
do not constitute ‘‘research’’ with
‘‘human subjects,’’ as these terms are
defined in the Common Rule, but in
which humans who are not subjects of
the research may be incidentally
exposed. The Agency did not intend, for
example, that the proposal would affect
animal research on a pesticide simply
because a person might be intentionally
exposed to a test material as a
consequence of working as a lab
technician. Accordingly, EPA has
revised the rule text in subparts B, C, L,

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and Q to clarify that the prohibitions
and other provisions apply only to
research with human subjects and not to
other types of research.
The Agency hopes that the
reorganization of the final rule gives
greater prominence to these
prohibitions, and clarifies EPA’s intent
that there be no exceptions to or
loopholes in these prohibitions. Both
subparts B and L begin by expressly
stating the universe of research
activities to which they apply. To
further reinforce the point that the bans
on these types of testing are not subject
to any exceptions, the prohibitory
provisions use the introductory phrase
‘‘Notwithstanding any other provision
of this part, under no circumstances
. . . .’’ This language means that this
provision is to be enforced over all other
provisions of every other subpart of part
26.
VIII. Observational Research: Subparts
C and D—Additional Protections for
Pregnant Women, Fetuses, and
Children Involved as Subjects in
Observational Research Conducted or
Supported by EPA
Summary: This unit discusses
protections additional to the core
protections provided by the Common
Rule (subpart A), which are established
by the final rule for pregnant women
and fetuses (subpart C) and children
(subpart D) when they are subjects in
observational research conducted or
supported by EPA. The final rule
defines observational research as
research not involving intentional
exposure. The provisions of the final
rule are similar to regulations
promulgated by HHS to govern studies
with these populations when conducted
or supported by HHS. Unit VIII.A.
summarizes the proposal, Unit VIII.B.
discusses public comment, and Unit
VIII.C. describes the position taken in
the final rule.
A. The Proposed Rule
Most of the provisions of proposed
subparts B and D would have defined
additional protections for individuals
from vulnerable populations when they
were subjects in observational research
conducted or supported by EPA—i.e.,
studies that do not involve intentional
exposure. Proposed subpart B contained
protections for pregnant women,
fetuses, and certain newborns, and
proposed subpart D contained
protections for children. The protections
in both proposed subparts were in
addition to the basic protections created
by the Common Rule, 40 CFR part, 26
subpart A. Because the HHS regulations
affording additional protections for

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pregnant women and fetuses and for
children had been in existence for over
20 years and enjoyed widespread
acceptance by the research ethics
community, EPA proposed to adopt the
HHS rules without substantive change,
except as noted below.
1. Proposed subpart B. EPA proposed
to adopt by reference much of the
content of subpart B of the HHS rule, 45
CFR part 46, with only a few changes.
Thus, EPA proposed to adopt several
sections from the HHS rule:
• In proposed § 26.201, EPA adapted
the text of 45 CFR 46.201, thereby
defining the scope of the subpart—
research conducted or supported by
EPA that involved research with
pregnant women, fetuses, or certain
newborns.
• Proposed § 26.202 cross referenced
several paragraphs of 45 CFR 46.202
defining such terms as delivery, fetus,
neonate, and pregnancy.
• Proposed § 26.203 cross referenced
the requirement of 45 CFR 46.203 that
assigns to IRBs the primary
responsibility for ensuring that
investigators follow the requirements of
the subpart.
• Proposed § 26.204 cross referenced
the requirements of 45 CFR 46.204
defining the findings an IRB must make
(in additional to those required by the
Common Rule at § 26.111) before
approving proposed research with
pregnant women or fetuses. (Because of
the prohibition in proposed § 26.220,
the provisions in proposed §§ 26.204
and 26.205 would have applied only to
EPA’s observational research.) In
summary, these include findings that:
Adequate preliminary research exists to
characterize potential risk, the risks to
pregnant women and fetuses have been
minimized, either the risks are minimal
or the research holds out the prospect of
direct benefit, and appropriate informed
consent is obtained, in some cases from
both the father and the pregnant
woman.
• Proposed § 26.205 cross referenced
the requirements of 45 CFR 46.205
defining the findings an IRB must make
before approving observational research
with certain newborns, including,
where applicable, that the observational
research has the prospect of improving
the chances of survival of neonates of
uncertain viability or that the
observational research will develop
important biomedical knowledge which
could not otherwise be obtained.
• Proposed § 26.206 cross referenced
the requirements of 45 CFR 46.206
concerning observational research
involving, after delivery, the placenta,
the dead fetus, or fetal material.

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The major substantive change EPA
made to the HHS rule in proposed
subpart B was the choice not to propose
adopting the provisions in 45 CFR
46.207, which provide a special
procedure for approving in exceptional
cases observational research which does
not meet the standards of 45 CFR 46.204
or 46.205. EPA considered such a
provision both inappropriate and
unnecessary for observational research
with environmental substances.
2. Proposed subpart D. EPA proposed
to adopt much of the content of subpart
D of the HHS rule, 45 CFR part 46,
specifically:
• In proposed § 26.401, EPA adopted
the text of 45 CFR 46.401, thereby
defining the scope of the subpart—
research conducted or supported by
EPA involving children as subjects. The
proposed rule text contained the same
exceptions that appear in the HHS rule.
• Proposed § 26.402 contained the
same definitions that appear in the HHS
rule in 45 CFR 46.402, except that EPA
proposed to define a child as a person
younger than 18 years old, in contrast to
the HHS definition, which relies on
local law to determine when a person
becomes an adult.
• Proposed § 26.403 cross referenced
the requirement of 45 CFR 46.403 that
assigns to IRBs the primary
responsibility for ensuring that
investigators follow the requirements of
the subpart.
• Proposed § 26.404 adapted,
essentially verbatim, the text of the HHS
regulation in 46 CFR 46.404 that
authorizes IRBs to approve
observational research with children
(which also meets the criteria in
§ 26.111), which involves ‘‘no more than
minimal risk’’ only if there are adequate
procedures, as specified in § 26.408, for
soliciting the assent of the children and
the permission of their parents or
guardians. (Because of the prohibition
in proposed § 26.420, the provisions in
proposed §§ 26.404, 26.405, and 26.408
would have applied only to EPA’s
observational research.)
• Proposed § 26.405 adopted,
essentially verbatim, the text of the HHS
regulation in 46 CFR 46.405 that
authorizes IRBs to approve
observational research with children
(which also meets the criteria in
§ 26.111), which involves ‘‘greater than
minimal risk’’ only if the IRB finds the
observational research offered the
prospect of direct benefit to the
individual subjects or would otherwise
contribute to their well-being, and there
are adequate procedures, as specified in
§ 26.408, for soliciting the assent of the
children and the permission of their
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• Proposed § 26.408 adopted,
essentially verbatim, the text of the HHS
regulation in 45 CFR 46.408 establishing
special requirements for obtaining
permission by parents or guardians and
for assent by children. Among other
provisions this section provided that in
some cases an IRB could determine that
a child was not capable of assent, in
light of their age, maturity, or
psychological state. If so, the inability of
the investigator to obtain assent could
not be a basis for excluding a child from
research that held out the prospect of
benefit to the child. The proposal also
allowed an IRB to waive assent on the
same grounds that it could waive
informed consent by adults (see
§ 26.116(d)). This proposed section also
granted to IRBs discretion to determine
that, in some cases, it would not be
reasonable to require the permission of
a child’s parent or guardian because, for
example, the adult abused or neglected
the child. In such instances, this section
authorizes the IRB to approve an
alternative mechanism of obtaining
permission from an adult who would
better represent the child’s interests.
As noted above, most of the proposed
rule text came directly from the existing
HHS regulations establishing additional
protections. The Agency did propose a
few revisions. In addition to minor
editorial changes necessary to reflect
that the proposed rule would be
implemented by EPA, the most notable
substantive changes were: (1) Defining a
child as a person under the age of 18
years, (2) choosing not to propose
adopting the provisions in 45 CFR
46.406 and 46.407, and (3) choosing not
to propose adopting the provisions in 45
CFR 46.409.
In 45 CFR 46.406 and 46.407, HHS
establishes special standards and
procedures for approving in exceptional
cases research which does not meet the
standards of 45 CFR 46.404 or 46.405—
i.e., research which poses more than
minimal risk to the children in the
study but which offers no prospect of
direct benefit to them. EPA considers
such provisions both inappropriate and
unnecessary for research with
environmental substances, particularly
observational studies. Consistent with
the choice not to adopt those two
sections, EPA chose to omit 45 CFR
46.409 of the HHS rule as well, since it
specifies measures which are required
only when the children in a study
approved under the authority of 45 CFR
46.406 or 46.407 were wards of the
state.
B. Public Comment
Most comments on proposed subparts
B and D addressed the proposed

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prohibitions on research involving
intentional exposure of pregnant
women, fetuses, or children. These
comments are addressed in Unit VIII.
This unit covers the public comments
which addressed the adoption of
additional protections for pregnant
women and children as subjects in
observational research conducted or
supported by EPA.
Comment: Some commenters
supported EPA’s proposal to adopt only
some of the provisions of the HHS
regulations in 45 CFR part 46, subparts
B and D that create additional
protections for pregnant women,
fetuses, and children in observational
research. Other comments
recommended the Agency adopt these
HHS regulations in their entirety. By
doing so, EPA and HHS would follow
consistent approaches. These comments
also noted HHS has operated under
these regulations for over 20 years
without significant debate over their
ethical adequacy.
Response: The Agency agrees there is
considerable value in employing
consistent approaches in similar areas of
research. Consistency makes it easier for
affected researchers to comply and
helps to build a broader consensus on
what constitutes ethical behavior.
Accordingly, EPA is adopting large parts
of the HHS regulations from 45 CFR part
46, subparts B and D essentially
verbatim. The Agency, however, is not
promulgating all of these HHS rules
because, in EPA’s judgment, the omitted
provisions would never apply to
observational research. Specifically,
EPA has not adopted the following
sections from the HHS rules: 45 CFR
46.205, 46.207, 46.406, 46.407, and
46.409. These sections would apply
only when proposed research would
present more than a minimal risk to the
subjects and would have no prospect for
direct benefit to the subjects. EPA
simply cannot conceive of observational
research that could not meet such
criteria, and in the unlikely event that
an investigator proposed such research,
EPA would not expect to approve it.
Comment: Some comments objected
to the inclusion in the proposed rule of
provisions that allowed observational
research if an IRB judged the potential
risks to subjects as ‘‘minimal.’’ These
comments claimed that the concept of
‘‘minimal risk’’ was not adequately
defined and potentially subject to abuse.
These comments recommended that no
observational research be allowed
unless there was ‘‘no risk’’ to subjects.
(Many of these comments further argued
that no human research was totally risk
free and therefore no human research
should be allowed.)

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Response: The Common Rule and
subpart D of the final rule define
minimal risk as ‘‘the probability and
magnitude of harm or discomfort
anticipated in the research are not
greater in and of themselves than those
ordinarily encountered in daily life or
during the performance of routine
physical or psychological examinations
or tests.’’ 40 CFR 26.402. The Agency
agrees that this definition leaves room
for the exercise of expert judgment by a
person reviewing a proposed protocol,
and that different people may disagree
on whether a particular research
technique poses minimal risk.
Nonetheless, this definition has been
part of the Common Rule since 1991,
and this provision has been in the HHS
regulations since 1983. Based on its long
history of application and the benefits of
consistency with HHS, EPA has decided
to retain proposed § 26.404 without
change. In addition, EPA thinks the
prospects for abuse are extremely small
since all research allowed using these
criteria would need approval both from
a local IRB and from EPA’s Human
Subjects Research Review Official
(HSRRO).
Comment: Some comments objected
to EPA’s proposal to adopt 45 CFR
46.405, which would allow an IRB to
approve observational research with
children if the IRB found the risks to
children were ‘‘greater than minimal,’’
but presented ‘‘the prospect of direct
benefits to the individual subjects.’’
These comments argued that
observational research would never
meet such criteria.
Response: EPA rarely expects
observational research to pose ‘‘greater
than minimal risk.’’ By its very nature,
observational research leaves all
decisions regarding exposure to the
subjects. Thus, an investigator
ordinarily just measures and records
information about exposure and effects
that the subjects, in their own
discretion, choose to experience. EPA,
nonetheless, believes its final rule
should include a provision comparable
to 45 CFR 46.405. Although unlikely,
EPA thinks some measurement
techniques used in observational
research could theoretically involve
more than minimal risk to subjects and
therefore would fail to meet the criteria
for approval under § 26.304 of the final
rule. Consistent with the HHS approach
in 45 CFR 46.205, EPA believes that, if
such risks exist, the research should not
be allowed unless an IRB finds that the
‘‘greater than minimal risks’’ were
justified by the prospect of direct
benefits to the subjects. Because EPA
does not want to prevent potentially
valuable research that requires non-

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standard measurement techniques, EPA
has adopted in § 26.305 of its final rule
the content of the provision of the HHS
regulations.
Comment: Although most comments
agreed with EPA’s proposal to define
child as a person younger than 18 years
old, some comments recommended
using the text in the HHS rule, which
defers to the legal standards defining
children and adults in the local
jurisdictions where the research is
conducted. These comments pointed
out that EPA’s proposed definition
could lead to the exclusion of an
emancipated minor, typically an older
teenager who has married. Excluding
these potential subjects could deny
them the benefits of participating in the
research simply because of their age.
Other comments favored raising the age
to 21 years old because the human body,
particularly the brain, continues to
mature after the age of 17 years and
research might adversely affect 18–21
year olds during this developmental
period of potentially increased
sensitivity.
Response: EPA is not persuaded that
the potential increased sensitivity of
people between the ages of 18 and 20
years to some effects warrants defining
a child as a person under 21 years old.
The Agency notes that such sensitivity
is not likely to exist for all chemicals.
If, however, a proposal to perform
observational research did raise
concerns about an increased sensitivity
of subjects, those concerns can be
addressed on a case-by-case basis by the
IRB and EPA’s HSRRO. It is not
necessary, in EPA’s view, to deal with
these theoretical concerns by redefining
who is a child.
While EPA sees benefit to using a
definition consistent with HHS, the
Agency is concerned about the added
complexity for investigators who are
conducting research in multiple
jurisdictions. In addition, EPA questions
whether youngsters no older than 15
years, as an adult is defined in some
states, are sufficiently mature to make
decisions about whether to volunteer to
participate in human research. In light
of these concerns and the broad support
for EPA’s proposal, EPA has decided to
retain the proposed definition of child
as a person younger than 18 years old.
Comment: Some comments found
unclear the provisions in proposed
subpart D allowing the waiver, under
narrow conditions, of the requirements
for permission of parents and assent of
children to participate in observational
research conducted or supported by
EPA. Other comments objected to these
proposed provisions asserting that
children should never become subjects

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in research without their parent’s
permission and without their own
assent. Still other commenters asserted
that the rule should not allow parents to
permit their children’s participation in
human research unless the children will
benefit directly from doing so.
Response: EPA’s final rule has
retained the proposed rule text, with
only minor changes. EPA believes that
these provisions give the Agency
needed flexibility to protect the interests
of the child when either the child or the
parent(s) cannot. For example, the
proposal would allow waiver of assent
when the child is too young or
otherwise unable to make responsible
choices, and where the child’s refusal to
assent would cause his or her exclusion
from research that provides a direct
benefit. The proposal also allows waiver
of parental permission from a parent
who abuses or neglects their children;
clearly such parents do not have
adequate concern for the child’s welfare
to make decisions about whether the
child should participate in research.
(This provision strengthening the
protections for children was widely
misinterpreted as indicating EPA’s
intention to authorize or conduct
research involving intentional exposure
of mentally retarded, abused, and
neglected children.)
To clarify the operation of the
provision allowing waiver of parental
permission, EPA has modified the text
to make clear that any alternative
procedure must be ‘‘equivalent’’ to the
process of parental permission. By
‘‘equivalent’’ EPA means that the child’s
participation must be approved by an
adult who by position or relationship
puts the child’s well being foremost and
who will exercise sufficient diligence to
make a considered and informed
decision. Otherwise, EPA has decided
not to accept the changes recommended
by the commenters. EPA relies on the
facts that the concepts in this provision
comport with the generally accepted
legal principles defining the scope of
parental authority and that HHS has
operated successfully under these
provisions for over 20 years. Finally, as
noted above, EPA sees considerable
benefit from using an approach
consistent with that of HHS.
C. The Final Rule
Subpart C of the Agency’s final rule
retains most of the rule text appearing
in proposed subpart B. The most
significant changes from the proposal
are the isolation in subparts B and L of
the prohibition of new research
proposed at § 26.220, and removal to
subpart Q of the restriction on EPA
reliance on completed research

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proposed at § 26.221. To make the
applicability of the remaining
provisions of subpart C as clear as
possible, EPA has revised the titles of
the subpart and of § 26.301, and
reworded the text to emphasize
repeatedly that these provisions apply
only to observational research, and only
to research conducted or supported by
EPA. In the final rule observational
research is defined in § 26.302 as
research that does not involve
intentional exposure of research
subjects. In addition, EPA has deleted
from the final rule proposed § 26.205
(which referenced 45 CFR 46.205)
because its provisions would never
apply to the kinds of observational
research that this subpart permits.
Subpart D of the Agency’s final rule
retains most of the rule text appearing
in proposed subpart D. The most
significant change from the proposal is
the isolation in subparts B and L of the
prohibition of new research proposed at
§ 26.420, and the removal to subpart Q
of the restriction on EPA reliance on
completed research proposed at
§ 26.421. To make the applicability of
the remaining provisions of subpart D as
clear as possible, EPA has revised the
titles of the subpart and some of its
sections, and reworded the text to
emphasize repeatedly that these
provisions apply only to observational
research, not involving any intentional
exposure to any substance, and only to
research conducted or supported by
EPA.
In addition, EPA has made the
following revisions in subpart D to the
proposed rule text:
• In § 26.401(a)(2), EPA clarified that
the authority to waive requirements
related only to the sections of subpart D
and did not confer broad authority on
the Agency to waive any requirement in
any other subpart.
• In § 26.402(a) and (f), EPA added
definitions of Administrator and
observational research.
• In § 26.403, the text from 45 CFR
46.403 of the HHS regulation is
incorporated explicitly, rather than by
reference as was done in the proposal.
• In § 26.405, EPA reordered the text
to make its applicability clearer. The
revision was not intended to make a
substantive change.
• In § 26.406(c), EPA has revised the
text to clarify that if an IRB determines
that it is not appropriate to require the
permission of the parent or guardian for
a child to participate in a study, the IRB
must approve an equivalent, alternative
procedure for obtaining permission from
another adult who will appropriately
represent the interests of the child.

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IX. Additional Protections Pertaining to
Research Involving Prisoners Involved
as Subjects
Summary: Research with prisoners
conducted or supported by EPA is
subject to basic ethical requirements in
the Common Rule; the parallel
requirements in subpart K of the final
rule apply to the conduct of research by
third parties involving intentional
dosing of prisoners, if the research is
intended to be submitted under the
pesticide laws. The Agency has not
reached a final position on either the
need or the most appropriate form for
any additional protections for prisoners
beyond these basic requirements. The
Agency may, in a future action, issue a
final rule to address the aspects of its
September 12, 2005, proposal that relate
to establishing standards for the ethical
protections of imprisoned subjects of
research. Unit IX.A. summarizes EPA’s
proposal and Unit IX.B. explains EPA’s
decision not to adopt additional
protections for prisoners in this final
rule.
A. The Proposed Rule
In its September 12, 2005, proposal,
EPA noted that HHS has promulgated
regulations that provide additional
protections for prisoners in research
conducted or supported by HHS,
codified at 45 CFR part 46, subpart C.
The proposal explained that EPA had
decided not to propose adoption of the
HHS subpart C rules for a number of
reasons, among them that HHS and its
advisory committee, the Secretary’s
Advisory Committee on Human
Research Protections (SACHRP), were
actively considering revisions to the
HHS subpart C, unchanged since its
adoption in 1978.
In addition, the proposal noted that
EPA has never conducted or supported
any human studies with prisoner
subjects, and has no intention to do so
in the future. It also noted that some
third-party research with prisoner
subjects was submitted to the Agency
some 30 or more years ago; since HHS
adopted subpart C, this type of research
has essentially disappeared, and none
has been submitted to EPA for many
years. Finally, the proposal noted if
either EPA or third parties should
consider performing studies with
prisoner subjects, such research would
be subject to the requirements of the
Common Rule and EPA’s final rule.
B. The Final Rule
All provisions of the Common Rule
would apply to any EPA research with
imprisoned subjects. In particular, any
such research would be subject to the

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Common Rule requirements for IRB
review and approval and written
informed consent. Sections 26.111(a)(3)
and 26.111(b) require an IRB to
determine that selection of research
subjects is equitable and free from
coercion or undue influence, and note
that particular attention to these aspects
of subject selection is needed when
prisoners are involved. Implicit in other
sections, e.g., §§ 26.102(i), 26.116, and
26.117, is the concept that research
must treat each subject involved
ethically, taking into account their
particular circumstances.
In addition, the prohibitions in
subpart B and the additional protections
in subparts C and D would also apply
to imprisoned pregnant women or
children under the age of 18 years if
EPA were to conduct observational
research with subjects from those
populations.
EPA does not expect third parties to
submit to EPA any new studies on
prisoners. In the unlikely event that a
third party wished to conduct or
sponsor research involving intentional
exposure of prisoners for submission
under the pesticide laws, it would be
covered under subparts K and L. Unless
prohibited by subpart L, such research
would have to meet the requirements of
subpart K, which parallel the provisions
of the Common Rule. In addition, an
investigator would also be required to
submit for EPA and HSRB review a
proposal describing in detail how the
study would be carried out in an ethical
manner. Should such a study proposal
involve prisoners, it would receive
extremely close review, and EPA almost
certainly would not approve it, absent a
compelling justification.
The Agency has concluded that the
requirements of this final rule should
provide adequate protections for
prisoners, especially since there are not
likely to be any such studies.
Nonetheless, the Agency is still
considering the recommendation from
public comments to prohibit both EPA
and third-parties to conduct certain
types of research with prisoners. EPA
may, at a later date, adopt such a
provision, if it determines that such a
measure is needed and cannot be
effectuated under existing regulations.
In addition, EPA will continue to
monitor the work of the SACHRP
committee on prisoner protections, and
will reconsider adopting additional
protections for prisoners as subjects of
research when its recommendations are
known.

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X. Subpart M—Requirements for
Submission of Information on the
Ethical Conduct of Completed Human
Research
Summary: Subpart M of the final rule
requires third parties who submit the
results of completed human research to
EPA for consideration under the
pesticide laws to document the ethical
conduct of that research. Subpart M
specifies the range of information
required, including documentation of
any IRB reviews, documentation of
informed consent by subjects, and other
information required to support thirdparty proposals to conduct new human
research for pesticides involving
intentional exposure of non-pregnant
adults. The final rule directs submitters
to provide this information about
completed research to the extent it is
available, and if any of it is not
available, to describe the efforts made to
obtain it. Unit X.A. describes the
proposed rule, Unit X.B. addresses the
major public comments, and Unit X.C.
discusses the final rule.
A. The Proposed Rule
In the September 12 proposal,
§ 26.124(c) required ‘‘any person who
submits to EPA data derived from
human research covered by this
subpart’’ to provide information
documenting compliance with the
requirements of the subpart. The
required information included records
required of the IRBs that approved the
research; copies of sample informed
consent documents; and copies of
correspondence between EPA and the
investigator or sponsor about the
proposed protocol.
In addition, although the proposal
contained no provision directed at data
submitters requiring documentation of
ethical conduct of completed research,
the proposal indicated that EPA would
not rely on the results of research
conducted after the effective date of the
final rule unless the Agency had
‘‘adequate information to determine the
research was conducted in a manner
that substantially complied’’ with the
requirements of the rule.
B. Public Comments
EPA received no major public
comments on the proposed provisions
addressing the content of reports of
completed human research.
C. The Final Rule
EPA has created a new subpart M that
requires people who submit data from
completed human research to EPA to
accompany that submission with
information documenting the ethical
conduct of the research. The final rule

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requires that reports on completed
human research contain essentially the
same range of information concerning
the ethical conduct of the research as
would have been required by the
proposal.
The final rule, however, differs from
the proposal in several respects. First,
the final rule clarifies that it applies
only to reports of completed human
research submitted after the effective
date of the final rule.
Second, EPA has broadened the scope
of the proposed requirement to apply to
reports on all types of human research
submitted to the Agency for
consideration under the pesticide laws,
FIFRA and FFDCA. This provision of
the final rule is broader than the
proposal in two ways: It applies to all
persons who submit data, whether or
not they developed the data with the
intent to provide it to EPA; and it
applies to all types of human research,
not only to research involving
intentional exposure of human subjects.
The Agency decided to extend the scope
of this reporting requirement because it
expects to make ethical assessments of
all human research it receives under the
pesticide laws, irrespective of who did
it, who submitted it, or what type of
human research was involved.
Obtaining the information specified by
subpart M as part of the initial
submission will improve the efficiency
and quality of such ethical assessments.
Under FIFRA sections 3(c)(2)(A) and
3(c)(2)(B), EPA has the authority to
require information necessary to
support both applications for new
registration and for continued
registration of a pesticide. Since the
Agency regards information about the
ethical conduct of human research as
relevant to the assessment of the
acceptability of such research, the
Agency concludes that the reporting
provision is consistent with these
sections of FIFRA.
Finally, the Agency made two
changes to minimize the burden of
reporting information on the ethical
conduct of completed research. First,
the final rule provides that information
need not be resubmitted if it has
previously been provided to the Agency,
for example as part of the submission
required for protocol review under
§ 26.1125. Second, recognizing that not
all of the information specified by
subpart M may be available to the data
submitter in some cases—for example, if
the research were conducted in the past,
or if the submitter did not conduct the
study, § 26.1303 states that the specified
information should be provided ‘‘to the
extent available’’ and asks the submitter
to describe the efforts made to obtain

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information which he or she was unable
to provide.
XI. Subpart O—Administrative Actions
for Noncompliance
Summary: Subpart O contains
provisions, adapted from similar
regulations issued by FDA, that describe
the range of administrative actions EPA
could take to address noncompliance by
third parties with the requirements of
part 26. These actions include:
Withdrawal or suspension of a research
institution’s Federal wide assurance;
disqualification of an institution or an
IRB; debarment; and public censure.
This subpart describes procedures EPA
would follow in reaching a decision to
take any of these administrative actions.
Other than the addition of a new section
explaining the scope of research to
which these actions could be applied,
the final rule is unchanged from the
proposal.

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A. The Proposed Rule
In proposed subpart E the Agency
identified a number of specific
administrative actions that could be
taken, as circumstances warrant, against
any person or organization that failed to
comply with requirements of the rule.
These actions included: (1) Withdrawal
or suspension of a research institution’s
FWA; (2) disqualification of a research
institution or its IRB; (3) debarment of
an entity from receiving federal funds
for research; or (4) public censure—
presenting for public review an
objective analysis of the ethical
deficiencies of any human research
relied upon by EPA for regulatory
decision-making under any statutory
authority. The provisions in proposed
§§ 26.501 through 26.504 and § 26.506
closely follow FDA’s existing
regulations in 21 CFR 56.120 through
56.124.
B. Public Comment
EPA received only a few public
comments on this subpart, most
supporting the appropriate use of the
actions identified in proposed subpart E
to promote compliance. EPA also agreed
with several commenters that refusal to
rely on completed research provided the
strongest incentives for investigators to
follow the new requirements. Other
major comments, discussed below,
addressed the operation of EPA’s
compliance oversight program.
Comment: One comment complained
that the proposal gives EPA discretion
not to impose any of these sanctions at
all, even for the most egregiously
unethical research, and argued that only
mandatory sanctions could effectively
deter unethical human research.

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Another commenter recommended that
EPA explain what types of actions it
would apply to different types of
violations.
Response: EPA generally believes that
enforcement programs work best when
they employ a system of graduated
penalties that increase as the gravity of
the violation increases. Such an
approach requires the exercise of
discretion, but that discretion should
not operate entirely free from
constraints. Accordingly, the Agency
intends to establish policies to guide its
exercise of discretion about the
imposition of the sanctions. Although
EPA does not regard such policies or
penalty structure as appropriate for
inclusion in this rulemaking, the
Agency does intend to explain in
guidance how it will encourage
compliance with the new requirements
in the final rule.
Comment: Several comments urged
EPA to adopt procedures similar to
those of FDA by which it would decide
whether to disqualify an institution for
violating the requirement of the final
rule.
Response: EPA agrees it should have
a procedure for deciding whether to
disqualify an IRB or institution, and that
it may be appropriate to establish such
procedures through rulemaking. EPA
will further consider adopting
procedures similar to those used by
FDA and promulgated in 21 CFR part
16, but has decided not to adopt them
at this time.
C. The Final Rule
Subpart O of the final rule is
substantively unchanged from subpart E
of the proposal. EPA has added a new
§ 26.1501 entitled ‘‘To what does this
subpart apply?’’ which clarifies that
EPA will consider using the
administrative actions identified in the
subpart only to address instances of
non-compliance with the requirements
of the new rule occurring after the new
rule takes effect. Thus, actions debarring
an institution from receiving federal
funds for research or disqualifying an
institution from performing research
covered by subpart K could not be taken
on the basis of events that happened
before the final rule becomes effective.
The Agency notes, however, that actions
which violate the requirements of
FIFRA section 12(a)(2)(P) would be
subject to civil or criminal penalties if
they happened at any time after that
provision became law in 1972. The
Agency also made minor wording
changes in § 26.1502 of the final rule to
reflect FIFRA terminology and
enforcement practices.

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EPA recognizes the importance of an
effective program to ensure compliance
with the requirements of the final rule.
The office of the Agency’s Human
Subjects Research Review Official
(HSRRO) will have responsibility for
ensuring compliance with the new rule.
The HSRRO will also have
responsibility for managing the
development of any new guidelines
needed to explain or implement the
provisions of the final rule.
The Agency thinks that one of the
most important ways to encourage and
monitor compliance is through the
review of proposals for new research
before it is conducted, as required by
the final rule at § 26.1125. Once such
studies are initiated, EPA’s Office of
Enforcement and Compliance
Assurance, through its laboratory audit
program, can monitor facilities that
conduct human research covered by the
rule.
EPA inspectors conduct inspections
and audit studies under EPA’s good
laboratory practice (GLP) regulations. As
stated in the GLP regulations (40 CFR
160.15), EPA will not consider reliable
for purposes of supporting an
application for a research or marketing
permit any data developed by a testing
facility or sponsor that refuses to permit
such inspection. In addition, the
recordkeeping provisions of FIFRA
which cover records of any tests
conducted on human beings and records
containing research data relating to
registered pesticides including all test
reports submitted to the Agency in
support of registration or in support of
a tolerance petition also apply to studies
conducted under this rule.
Finally, the close examination of
reports on completed research
represents another important part of the
compliance program. EPA will train
scientists who conduct, approve, or
review human research about the
provisions of the final rule so they can
identify possible violations. Throughout
all of these efforts, the Agency hopes to
work with the HHS Office for Human
Research Protections and FDA, to
ensure that sponsors, investigators, and
IRBs understand and fulfill their
responsibilities under the final rule.
XII. Subpart P—Review of Proposed
and Completed Human Studies
Summary: This subpart of the final
rule provides that EPA will review all
proposals by third parties to conduct
research covered by subpart K, i.e., all
research involving the intentional
exposure of human subjects, if the
research is intended for submission to
EPA under the pesticide laws. The
subpart also requires EPA to establish

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an independent group of experts,
referred to as the Human Studies
Review Board (HSRB), to assist EPA in
evaluating such proposals. In addition,
the subpart requires that EPA review
reports submitted by third parties on
completed human research and, if EPA
decides to rely on information from
such research in an action under the
pesticide laws, to submit the results of
its assessment of the research to the
HSRB. The HSRB would perform
science and ethics reviews of proposals
from third parties to conduct specified
types of human research and of the
results of specified types of human
research if EPA intended to rely on the
information in its decision-making
under the pesticide laws. Further, when
HSRB review is not required by the final
rule, EPA would nonetheless retain
discretion to ask the HSRB to review
studies or to offer advice on other
issues.
Finally, although not required by the
final rule, EPA has decided to establish
the HSRB under the authority of the
Federal Advisory Committee Act. By
operating as a federal advisory
committee, the HSRB will be required to
use procedures that ensure transparency
in its operation and that afford
opportunities for the public to express
their views on issues being considered
by the HSRB.
A. The Proposed Rule
Proposed § 26.124 would have
required third parties to submit to EPA
detailed information concerning any
proposed new research covered by the
new rule at least 90 days before
initiating of the research. The proposal
would also have established a HSRB to
address in an integrated fashion the
scientific and ethical issues raised by
human research covered by the
proposal. Specifically, the Agency
proposed to convene a small group of
appropriately qualified experts and to
enlist their support in reviewing
covered research proposals, i.e., thirdparty research involving intentional
exposure of human subjects, when the
results of such research are intended to
be submitted to EPA under the pesticide
laws.
The same section also provided that
EPA would review the results of
completed research covered by the rule.
This section of the proposal also stated
that, after completing its initial staff
assessment of a research proposal or a
completed study if EPA intended to rely
on the results in its decision-making
under the pesticide laws, the Agency
would send its review and supporting
materials concerning the study to the
HSRB for further review and comment.

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EPA’s proposal did not specify any
details of how the HSRB would
function, other than to state that the
members would not be EPA employees,
would meet the conflict of interest
standards applying to special
government employees, and would have
expertise appropriate for the review of
human research. The Agency invited
public comment on whether the final
rule should specify the functions of the
HSRB. The preamble also indicated that,
as recommended by the NAS, EPA
intended to reexamine the functions of
the HSRB after 5 years.
B. Public Comment
EPA received a great many public
comments on its proposal to require
submission of proposed protocols and
other information relating to proposed
new human research and to submit its
assessments of the proposed new
human research to a new HSRB for
further review. The Agency’s Response
to Comments document, in the docket
for this action, provides a full response
to these comments. EPA agrees with
comments that stressed the importance
of having the HSRB use the substantive
standards contained in EPA’s final rule
when reviewing the ethics of proposed
and completed human research. As an
entity intended to help the Agency
make ethical and scientific judgments,
the HSRB will use the provisions of this
final rule in the formulation of their
advice. The major issues raised by the
comments are discussed below under
three headings: HSRB procedures; HSRB
membership and qualifications; and the
scope of research subject to HSRB
review.
1. HSRB procedures. The Agency
notes that most, if not all, comments on
the HSRB implicitly accepted EPA’s
proposal that HSRB review of proposed
new research would occur following its
review and approval by a local IRB and
after EPA developed its review.
Comment: Many comments addressed
whether EPA should charter the HSRB
under the Federal Advisory Committee
Act (FACA). Environmental and public
health advocacy groups favored this
approach because it would assure the
use of procedures that provided
opportunities for public comment and
transparency. Others, primarily
commenters affiliated with the pesticide
industry, objected on the grounds that a
FACA-chartered HSRB would be
inefficient, and the ensuing delays
would affect Agency decision-making,
particularly about new products. These
comments recommended either staffing
the HSRB only with EPA employees or
relying on the HHS Office for Human
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kinds of reviews described in the
proposed rule. Industry commenters
also expressed concern that a FACA
process might lead to public disclosure
of CBI.
Response: EPA has decided to charter
the HSRB under FACA. While operating
under the requirements for advisory
committees adds some procedural steps
to the review process, it is not apparent,
given the intensity of public concern
about the use of data from human
research, that a FACA process would
necessarily take longer than a process
involving internal EPA review. More
important, in EPA’s view, the benefits of
the transparency and opportunities for
public participation outweigh any
potential delays. Given the difficult
nature of the issues, EPA sees
significant advantages in ensuring that
all the considerations influencing the
Agency’s final position have been
publicly identified, carefully weighed,
and commented on by independent
experts.
The Agency recognizes the need to
manage aggressively to ensure both the
HSRB’s and its own review processes
operate efficiently. As part of its
commitment to effective management,
the Agency intends to acknowledge
receipt of new research proposals and to
respond promptly with a projected
timeline for completing EPA and HSRB
review. In addition, upon completion of
its internal reviews, EPA will send
copies to the submitter of the protocol
and the schedule for HSRB review. EPA
expects that it will continue to meet the
statutory deadlines for reaching
decisions on new applications for
pesticide registrations, even if HSRB
review is required.
Finally, the Agency notes that under
FIFRA and FACA, EPA follows
procedures designed to protect CBI from
disclosure. Whenever EPA provides CBI
to a federal advisory committee, that
information is not placed in a public
docket or discussed in a public meeting,
and special steps are taken to maintain
its confidentiality.
Comment: Many comments asked
EPA to clarify in the final rule the
procedures that the HSRB would use. In
particular, many suggested that the rule
require that the HSRB meetings afford
an opportunity for public comment.
Response: The Agency believes that,
at this early stage, the HSRB should
have the flexibility to adopt procedures
which best allow it to meet its
responsibilities. Since the HSRB will
function as a federal advisory
committee, FACA will dictate many of
its procedures, including key
procedures relating to transparency and
public participation. Since these were

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the areas of greatest concern for most
commenters, EPA believes that its
decision to establish the HSRB under
FACA adequately addresses these
comments.
Comment: Some comments
complained that the proposed rule did
not vest the HSRB with authority to
disapprove proposed new research or
EPA decisions to rely on the results of
completed human studies. Other
comments supported giving the HSRB
only an advisory role.
Response: EPA believes the HSRB
should have an advisory role. The
decision to disapprove proposed new
research or to decide whether or not to
rely on the results of completed studies
is inherently governmental. The Agency
cannot legally confer authority to make
such decisions on an advisory
committee. The Agency notes, however,
that it expects to give considerable
weight to the advice of the HSRB.
2. HSRB membership and
qualifications.
Comment: Many comments
emphasized that the HSRB must be
independent, that its members must
have no conflicts of interest, including
any financial relationships with the
pesticide industry.
Response: EPA agrees. Chartering the
HSRB as a federal advisory committee to
provide expert advice means that all
candidates for membership on the HSRB
must meet the federal requirements
governing conflicts of interest. Although
other requirements relating to the
operation of the HSRB as an advisory
committee are not specified in the final
rule, EPA did retain in the final rule a
requirement that members have no
conflicts of interest. Specifically, the
final rule provides that HSRB members
must ‘‘meet the ethics and other
requirements for special government
employees.’’ See § 26.1603(a) of the
regulatory text.
Comment: Several comments stressed
the importance of having HSRB
members with sufficient expertise in the
substantive disciplines raised by the
types of human research covered under
the rule. They specifically identified the
disciplines of clinical toxicology,
research ethics and the Common Rule,
and public health. Comments also noted
that the Agency might need to
supplement the HSRB to obtain
expertise to address particular types of
research covered by the rule.
Response: EPA generally agrees with
the comment and on January 3, 2006,
issued a Federal Register Notice
inviting nominations of experts to serve
on the HSRB (71 FR 116). The Notice
described the following areas of
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biostatistics, and human risk
assessment. Under FACA, EPA has the
authority to appoint consultants to the
HSRB who can provide additional
expertise when needed.
Comment: Several comments
recommended that the members of the
HSRB include non-scientists who are
members of the community and who
could represent the views of special
populations that could be the focus of
proposed human research.
Response: EPA does not believe that
it is necessary to include non-expert
community members on the HSRB.
However, under FACA, the public,
including non-expert community
representatives have opportunities to
provide both written and oral public
comment to the HSRB. In addition, the
HSRB has the flexibility under FACA to
ask representatives of community
groups to make presentations to the
committee on specific topics. EPA also
notes that, before a proposal reaches the
HSRB, an IRB will have reviewed and
approved it. Such IRBs are required by
the new rules (§ 26.1107), to include
people familiar with the concerns
arising in research with special
populations. Thus, EPA expects in most
cases that the concerns of communitybased representatives will be a part of
the information before the HSRB.
3. Scope of research subject to HSRB
review.
Comment: Some comments favored
expanding the scope of studies reviewed
by the HSRB to include all first-party
and second-party research, as well as
third-party research; all types of human
research, not only research involving
intentional exposure of human subjects;
studies performed with any substance
regulated by EPA, not only studies with
pesticides; and all human research
considered by EPA, not only the
completed studies on which EPA
intends to rely.
Response: EPA agrees that it may
sometimes be appropriate to obtain
HSRB review of some of these types of
studies. The final rule gives EPA
discretion to seek the advice of the
HSRB on additional types of studies
beyond those for which HSRB review is
required. For the reasons explained
earlier, however, the Agency has
decided not to expand the scope of
subpart K now, and therefore sees no
reason to expand the scope of required
EPA or HSRB review of proposed new
research. Similarly, the Agency has
decided not to extend without further
analysis and public discussion the
ethical framework in subpart Q to
decisions made under statutory
authorities other than FIFRA or FFDCA.
It would make no sense to require the

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HSRB to review human research that
fell outside the scope of the other
substantive provisions of the rule.
Finally, EPA has decided that it would
not be an efficient use of resources to
require HSRB review of human research
that the Agency had decided not to rely
on, typically because it falls short of
contemporary standards of scientific
validity. The Agency does not anticipate
that the HSRB would often disagree
with such conclusions, and therefore
EPA will use its discretion to determine
whether such scientific judgments
warrant HSRB review.
Comment: Many comments generally
supported the proposed review of new
research and completed research reports
by both EPA staff and the HSRB, at least
in some cases. A number of
commenters, however, suggested ways
to narrow the scope of the reviews
performed by the HSRB, including: (1)
By having the HSRB review only studies
intended to identify or measure toxic
effects, (2) by exempting from HSRB
review consumer acceptance studies,
insect repellent efficacy tests, or other
‘‘product-in-use’’ studies; (3) by
exempting from HSRB review proposals
to employ protocols for ‘‘routine’’
exposures or other studies that follow
established EPA guidelines; and (4) by
exempting from HSRB review the
results of research which the HSRB had
previously reviewed and approved as a
proposal, unless the investigator failed
to follow the approved protocol. Finally,
some comments recommended that the
HSRB be restricted to considering
ethical issues, but not scientific issues.
Response: EPA disagrees with the
comments suggesting a narrowed scope
for HSRB review. EPA agrees that each
of the categories described above may
contain at least some studies that
present no difficult scientific or ethical
issues. To the extent EPA’s review
indicates that a study presents no
difficult science or ethics issues, the
Agency would expect the HSRB to agree
and quickly conclude its review. But
any research involving intentional
exposure may present risks to
individual human subjects greater than
those they would receive in their
normal activities, and therefore warrants
careful examination, even if the purpose
of the study is not to identify or measure
toxic effects. Similarly, while EPA
anticipates that many consumer
acceptance tests, insect repellent
efficacy tests, and other ‘‘product-inuse’’ studies will raise no difficult
scientific or ethical issues, the Agency
has relatively little experience with
assessing explicitly the ethical attributes
of such research. Therefore the Agency
thinks it would be imprudent to exclude

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HSRB review of these studies. EPA
likewise recognizes that following
established guidelines may reduce the
chances of scientific deficiencies in a
study, but EPA’s guidelines do not
address the full range of potential
ethical issues that should be considered
on a case-by-case basis. Finally, EPA
believes that even if a study follows an
established protocol, unanticipated
scientific and ethical issues may arise
that will warrant expert advice.
C. The Final Rule
As a result of the reorganization of the
final rule, all provisions relating to EPA
and HSRB review of proposals for new,
third-party research or reports of
completed studies, or to the
establishment of the HSRB, now appear
in subpart P.
The final rule reflects one significant
change from the proposal. Under the
final rule, the HSRB will review all
research involving intentional exposure
conducted after the effective date of the
final rule, as well as all research
involving intentional exposure
performed before the rule takes effect, if
the purpose of the research was to
identify or measure a toxic effect. But
the final rule grants to the Agency
discretion to decide whether studies
performed before the effective date of
the final rule that do not measure
toxicity should undergo HSRB review.
After publishing the proposal, EPA
examined how the proposal would
affect its plans to complete tolerance
reassessment by August 2006, as
required by the 1996 FQPA
amendments to FFDCA. The Agency
reviewed the existing toxicity and
exposure databases for upcoming
tolerance reassessment decisions and
determined that as many as several
hundred studies relevant to the risk
assessments for these actions appeared
to meet the definition of ‘‘research
involving intentional exposure of
human subjects.’’ Only a relative few of
these intentional exposure studies
measure the toxicity of a pesticide; the
great majority of them measure the
levels of potential human exposure
resulting from pesticide use, the efficacy
of insect repellents, or the absorption,
distribution, metabolism, and excretion
of pesticides.
Since the enactment of the Food
Quality Protection Act in 1996 EPA has
relied on many of these non-toxicity,
intentional-exposure human studies in
its registration and reregistration
decisions. Moreover, the Agency has
afforded multiple opportunities for
public comment on several hundred
draft and final Reregistration Eligibility
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RED (IRED) documents, but has never
received any public comment on a RED
or IRED concerning the ethics of
intentional-exposure human studies
other than a toxicity study. Taking all of
these non-toxicity, intentional-exposure
studies to the HSRB would significantly
increase its workload and expand the
number of pending regulatory decisions
affected. Accordingly, EPA has decided
that while the final rule should require
the Agency to send to the HSRB all
completed toxicity studies on which it
intends to rely, it need not require all
non-toxicity studies in its existing
databases to undergo HSRB review.
Thus, under the final rule, the Agency
will retain the discretion to submit
additional types of old studies to the
HSRB, and will consider public
comments on its upcoming pesticide
actions for tolerance reassessment in
deciding which of the non-toxicity
studies raise significant ethical or
scientific issues warranting HSRB
review.
In addition, subpart P in the final rule
reflects a few other minor revisions to
the proposal. The provisions governing
Agency review of proposals for new
third-party research were placed in
subpart P in preference to subpart K, so
that subpart P would apply only to EPA,
and subpart K would apply only to
regulated third parties.
To help ensure effective
implementation of the final rule, EPA
has made several administrative
decisions affecting the HSRB. Most
important, the Agency has decided to
establish the HSRB as a separately
chartered advisory committee under the
Federal Advisory Committees Act
(FACA). FACA requires the HSRB, as a
federal advisory committee, to follow
certain basic procedures designed to
promote transparency and to ensure
public participation. These include
timely public notice of meetings, public
access to meetings, and opportunity for
the public to comment; public
availability of documents considered by
the HSRB and meeting minutes; and a
Federal officer or employee attending
each meeting. Of course, the HSRB will
be required to protect materials
designated as confidential from public
disclosure. Finally, EPA is also
committing to aggressive management of
the process to promote efficient use of
resources and timely decisions, and to
ensure affected stakeholders have
complete information about the status of
ongoing reviews.

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XIII. Subpart Q—Ethical Standards for
Assessing Whether to Rely on the
Results of Human Research in EPA
Regulatory Decisions
This unit discusses the ethical
standards EPA will use to guide its
decisions whether to rely in its actions
under the pesticide laws on the results
from completed human research. Unit
XIII.A. summarizes EPA’s proposal,
Unit XIII.B. discusses public comment,
and Unit XIII.C. describes the positions
taken in the final rule.
Summary: The final rule is
substantively unchanged from the
proposal, although the provisions have
been revised to make them clearer. One
new section (§ 26.1701) clarifies the
applicability of this subpart to EPA
decisions to rely on relevant,
scientifically valid ‘‘data from research
involving intentional exposure of
human subjects to a pesticide’’ in its
actions under the pesticide laws, FIFRA
and FFDCA. A second new section
(§ 26.1702) provides needed definitions
of terms. The remaining four sections in
the final rule together delineate the
framework within which EPA will
decide whether to rely on the results of
certain types of human research.
This framework rests on the basic
principle that EPA will not rely in its
actions on data derived from unethical
research. Section 26.1703 forbids EPA to
rely on data from any study involving
intentional exposure of pregnant
women, fetuses, or children. Section
26.1704 forbids EPA to rely on data
from ‘‘old’’ research—i.e., covered
studies initiated before the effective date
of the final rule—concluded to be
fundamentally unethical or significantly
deficient with respect to the ethical
standards prevailing when it was
conducted. Section 26.1705 forbids EPA
to rely on data from any ‘‘new’’
research—i.e., research initiated after
the effective date of the final rule—
unless EPA finds that the research
complied with the new requirements.
Finally, § 26.1706 creates a very narrow
exception to the Agency’s general
refusal to rely on unethical data, one
that allows reliance on unethical data
when it is crucial to supporting more
stringent regulatory measures to protect
public health.
A. The Proposed Rule
In proposed subpart F of 40 CFR part
26, EPA set out ethical standards for its
decisions to rely on or not to rely in its
regulatory decisions under FIFRA or
FFDCA on reports of completed
intentional-dosing research with human
subjects. For covered research initiated
after the effective date of the rule, EPA

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proposed to refuse to rely on data from
scientifically sound and relevant human
research unless EPA had adequate
information demonstrating that the
research complied with the Common
Rule. For covered research initiated
before the effective date of the rule, EPA
proposed to rely on data from
scientifically sound and relevant human
research unless there was clear evidence
to show the conduct of the research was
fundamentally unethical or was
significantly deficient relative to the
ethical standards prevailing when it was
conducted. EPA also proposed a formal
exception to these standards when to
rely on scientifically sound but ethically
deficient research would give crucial
support to a regulatory action more
protective of public health than could
be justified without relying on the
ethically deficient research.
B. Public Comments
EPA received many public comments
on proposed subpart F. The major issues
raised by the comments are grouped and
summarized below under these four
headings:
• Comments advocating a broader or
narrower scope for this subpart—a
change to the kinds of research and the
range of EPA decisions the framework
should cover.
• Comments questioning the
proposed framework itself, including
arguments to include standards for
scientific validity of human research,
and arguments that EPA should never
reject scientifically sound data for
ethical reasons.
• Comments on the substantive
ethical standard to be applied to ‘‘old’’
research initiated before this final rule
takes effect.
• Comments on the proposed ‘‘public
health exception’’ to the general refusal
to rely on unethical research.
The Agency notes that, although some
comments favored more specificity in
EPA’s final rule, many comments
expressed support for EPA’s proposal to
rely on the Common Rule as the ethical
benchmark for judging the acceptability
of research conducted after the effective
date of the final rule.
1. The scope of application of EPA’s
ethical framework.
Comment: Some comments advocated
expanding the application of the ethical
framework beyond research involving
intentional exposure of human subjects
to cover all types of human subjects
research considered by the Agency, or to
embrace consideration of human
subjects research conducted with
pesticides under EPA statutes other than
the pesticide laws, or to cover research
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human subjects to any environmental
substance, not only to pesticides.
Response: The Agency has decided
not to expand the application of the
ethical standards in this subpart to
encompass all types of human subjects
research relied on by EPA, to research
involving substances other than
pesticides, or to actions taken under
authorities other than the pesticide
laws. In the future, the Agency will
consider further actions to address these
and other issues beyond the scope of
this final rule.
The Agency believes an initial focus
on research involving intentional
exposure is warranted in that potential
risks to research subjects are generally
greater when exposure is intentional
than in other types of studies. It is
reasonable to scrutinize such research
closely to ensure that research subjects
are fully protected and the research is
ethical. EPA has not fully considered,
and public comments have not
thoughtfully addressed, what protective
measures would be appropriate for
research that does not involve
intentional exposure. Thus, the Agency
thinks it premature to conclude that all
of the provisions applying to research
involving intentional exposure should
apply more widely.
EPA thinks there has also been
inadequate consideration of the
consequences of expanding the scope of
the ethical framework to embrace
research with substances other than
pesticides. Most of the comments
favoring expansion of the rule beyond
pesticides came primarily from
stakeholders affiliated with the
pesticide industry, and EPA received
essentially no meaningful response to
its requests for comment from other
stakeholder interests, including those
likely to be affected by such an
expansion. Given the mandate of the
2006 Appropriations Act to address
research ‘‘for pesticides,’’ the final rule
retains the proposed focus on human
research for pesticides.
Finally, the Agency has decided to
retain the proposed applicability of the
framework to actions taken under the
pesticide laws. Although EPA
recognizes the theoretical possibility
that human research with a pesticide
may be considered under other statutes,
the Agency notes that the 2006
Appropriation Act does not require the
adoption of a broader scope than
decisions under FIFRA and FFDCA.
Also, the Agency has not received
meaningful public comment on whether
its authorities under other statutes
permit it to refuse to rely on relevant,
scientifically sound data which were
derived from an unethical study.

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Because of the questions about the
Agency’s legal authorities and the
absence of a clear mandate, EPA has
decided not to require the application of
the ethical framework to actions taken
under its other laws.
Comment: Other comments argued for
restricting the application of the ethical
framework to only certain kinds of
human research—to research intended
to identify or measure toxic effects, to
research conducted in a laboratory or
clinical setting, or to exclude research
involving only exposures that EPA had
already approved (e.g., studies of
registered pesticides used in accordance
with their approved labeling). Two
general reasons were offered for these
recommendations: (i) Public controversy
has focused exclusively on a narrower
set of studies than those falling within
the scope of proposed subpart F, and (ii)
there is so little risk from the types of
studies suggested for exclusion that no
additional measures would be needed to
protect subjects.
Response: Because EPA finds these
reasons unpersuasive, the Agency has
decided to retain, at this time, the scope
of the proposal for its final rule. Thus,
EPA is not narrowing the scope of its
framework in any of the ways
recommended above.
Although recent controversy has
focused on ‘‘intentional dosing, human
toxicity testing for pesticides’’ (see the
Appropriations Act discussed in Unit
XIV.A.), there has also been public
debate about other kinds of human
research, including product-in-use
studies using registered pesticides,
studies performed outside the laboratory
setting, and studies which do not
measure toxicity. To promote public
confidence in its operations and
judgments EPA must address this larger
universe of research. Second, EPA
thinks that it is important to examine
the risks of studies involving intentional
exposure of research subjects—even
when comparable exposures have
already been approved for the general
public under a pesticide registration.
While the risks experienced by the
research subjects and the general public
may not differ, the risks experienced by
the particular subjects may exceed what
they would otherwise receive, and
therefore researchers must provide each
potential subject a full explanation of
the potential for any additional risk they
might assume by volunteering for a
study. For its part, EPA should ensure
that, in their interactions with subjects,
the sponsors and investigators have
acted ethically.
2. The adequacy of the ethical
standards.

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Comment: Although nearly all
comments supported EPA’s application
of an explicit ethical standard in
deciding whether or not to rely on data
from completed human research, one
significant line of comment argued that
EPA should never refuse to rely on
relevant, scientifically sound research
even if it were conducted unethically.
This conclusion rested on three
arguments: (i) Rejecting scientifically
sound data would deprive decisionmakers of information that would serve
the mission of protecting public health;
(ii) applying a new standard of ethical
acceptability retroactively to completed
research would be unfair; and (iii)
refusing to rely on data from unethical
research could do nothing to remedy
any harm done to the subjects in the
research.
Response: While EPA sees some merit
in each of these arguments, the Agency
disagrees with the conclusion. EPA
believes that rejecting unethical data is
an appropriate and powerful means of
promoting compliance with ethical
standards, and that rejecting unethical
data generally meets public expectations
about conduct of the government.
First, EPA agrees that it is important
to consider all available information in
carrying out its mission to protect
public health. This is especially
important when reliable data show
humans to be more sensitive than
animals. Sometimes, however, data from
human research will show that humans
are less sensitive—or no more
sensitive—than animals, and that a less
restrictive regulatory measure may
provide adequate protection for public
health. This is important to know
because the Agency is interested in costefficient regulations. Finally, human
research often confirms a risk
assessment based on animal toxicity
data. Such confirmation increases
confidence in the Agency’s decisions.
Therefore, the Agency agrees that it is
always important to assess data from
available human research.
The Agency also agrees that it is
generally inappropriate to apply current
ethical standards to judge the
acceptability of research completed
before such standards were articulated.
Not only could that lead to declaring
unethical much completed research
which was considered ethical when it
was conducted, it would also set a
standard for ethical conduct—adherence
to standards not yet articulated—that
even the most ethically concerned
investigators and sponsors could never
meet. To avoid such an outcome EPA
will generally judge the ethical
acceptability of research initiated before
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the ethical standards prevailing when it
was performed.
The Agency also agrees that no
actions taken after research is completed
can undo any harm experienced by the
human subjects in the research. But this
point ignores the deterrent value of
government actions that ‘‘punish’’
unacceptable conduct. EPA believes that
by refusing to rely on unethical data it
creates a strong incentive for the
scientific community to conduct future
research ethically. If investigators and
sponsors understand that EPA will not
rely on the results of their research
unless it is performed ethically, they
will not wish to risk losing either their
direct investment in the research or any
benefit its use might bring to them.
Finally, EPA believes that the public
expects its government to apply a clear
standard of ethical acceptability in
deciding whether to rely on the results
of completed research. Such an
expectation, evident in thousands of
public comments on the proposed rule,
provides additional reason for
establishing an explicit ethical
framework for making these decisions,
and for refusing to rely on unethically
obtained data. (As discussed below,
EPA believes that in certain very limited
circumstances the ethical course of
conduct may require reliance on
ethically deficient research when to do
so is crucial to supporting more
stringent regulatory measures to protect
public health.)
Comment: Some comments, noting
that scientifically unsound research is
always unethical, argued that the
proposed framework should articulate
explicit standards of scientific validity.
Response: EPA agrees that its ethical
framework should exclude data which
are not scientifically sound, and thus
the final rule clarifies that subpart Q
applies only to ‘‘scientifically valid and
relevant data.’’ The Agency has not,
however, attempted to define a standard
for scientific validity and relevance,
because this is necessarily a case-bycase judgment. EPA has long had in
place policies and procedures to ensure
rigorous scientific review of research it
is considering, including procedures for
formal peer review of research and
assessments critical to Agency actions.
In addition, § 26.1603(b) of the final rule
provides that the HSRB ‘‘shall review
and comment on the scientific and
ethical aspects of research proposals
and reports of completed intentional
exposure research. . . .’’ Over time the
results of HSRB review of the scientific
aspects of both proposed and completed
human research will support
articulation of general principles for the

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scientifically sound and ethical conduct
of different types of human research.
3. The ethical standard for accepting
‘‘old’’ research. Opinions about research
conducted before the final rule varied
widely, and are summarized below
under these headings:
• The proposed standard is too weak;
the Common Rule should be applied to
all research, regardless of when it was
conducted;
• The rule should define such terms
as ‘‘standards prevailing when research
was conducted’’; ‘‘fundamentally
unethical’’; and ‘‘significantly
deficient.’’
• Rejection of any research involving
intentional exposure of pregnant
women, fetuses, or children is
inconsistent with ‘‘standards prevailing
when research was conducted.’’
• The standard of ‘‘clear evidence’’
should be different;
Comment: Many comments favored
application of the Common Rule to all
research, regardless of when it was
performed. These comments argued that
the standard in proposed § 26.601 was
unacceptably weak because it failed to
reflect contemporary ethical standards.
Response: EPA believes it would be
unreasonable to apply to completed
research ethical standards articulated
after the research was conducted. Thus,
the final rule retains the proposed
standard for judging the acceptability of
completed ‘‘old’’ research—i.e., research
initiated before the final rule becomes
effective.
First, for many years the prevailing
ethical standard in the U.S. has been the
Common Rule, and with respect to
biomedical research, the earlier DHHS
rules that form the basis for the
Common Rule. Consequently, as a
practical matter, the same standard of
ethical acceptability—the Common Rule
or its foreign equivalent—would apply
to research conducted since its
promulgation in 1991.
Thus, reference to ethical standards
prevailing at the time of the research
makes a practical difference only when
considering the acceptability of research
which meets today’s standards of
scientific validity but which was
conducted before today’s ethical
standards were articulated. Codes of
ethical research conduct require
investigators to do certain things in
certain ways before and during the
research. It is reasonable to expect
investigators to follow ethical codes that
prevail when they do their work; it is
unreasonable to expect them to
anticipate and follow standards
developed after their work is done. EPA
believes that scientifically meritorious
research which adhered to accepted

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ethical norms when it was conducted
should not be set aside because ethical
standards have subsequently changed.
EPA also believes that ethical standards
are likely to continue to change in the
future and that if and when they do,
such a change should not invalidate or
make unacceptable otherwise
meritorious research conducted now, in
conformity with the ethical standards of
today.
It is sometimes argued that to accept
‘‘old’’ research falling short of today’s
standards would encourage others to
conduct unethical research in the
future. EPA disagrees. With respect to
new research, the principal incentive to
conduct research ethically is the
prospect that the Agency might refuse to
rely on research that doesn’t comply
with contemporary ethical standards. A
refusal by EPA to rely on new human
research would carry serious economic
consequences for the investigator and
sponsor. Much third-party research is
conducted by private, for-profit
organizations in the hope that the
results will lead to financial benefits,
often through changes in government
regulation. For example, the current
controversy over pesticide studies
centers on research conducted by
pesticide companies who hoped to
demonstrate through human studies that
their products were safer than was
indicated by available animal studies,
and thus that their market could
expand—or at least need not shrink—
because of concerns about risk. An
Agency refusal to rely on data would
deprive the investigator and sponsor of
such potential financial benefits.
Importantly, under § 26.1705 of the final
rule, the Common Rule’s provisions will
guide EPA’s decisions about reliance on
the results of new research, i.e., studies
conducted after the rule takes effect.
The fact that EPA may apply a different
standard to ‘‘old’’ studies is irrelevant.
An investigator conducting a new,
covered study after these final rules take
effect would be very foolish to think
that the Agency will judge its ethical
acceptability by any standard other than
the Common Rule.
Comment: A number of comments
called for the rule to specify that certain
documents—the Nuremberg Code,
various editions of the Declaration of
Helsinki, the Belmont Report, and the
Common Rule, among others—would
serve as the point of reference in
identifying the ‘‘standards prevailing at
the time the research was conducted.’’
Other comments asked that the Agency
explain and give examples of the types
of ethical deficiencies that it would
deem ‘‘fundamentally unethical’’ or
‘‘significantly deficient’’ in the

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provision codified as § 26.1704 of the
final rule.
Response: In recent years, EPA has
reviewed numerous reports of
completed research on pesticides
involving intentional exposure of
human subjects. These studies have
been conducted over many years, in
many places, under a variety of ethical
policies and regulatory schemes; they
have addressed a wide range of research
questions, and they have presented a
wide spectrum of ethical shortcomings,
from minor flaws to more serious
deficiencies. Given these variations, the
Agency believes that its ethical
framework must retain sufficient
flexibility to judge each situation on its
merits, in the context of the time and
place the research was conducted.
While the historical documents cited in
the comments reflected widely shared
views about what constitutes ethical
conduct, they were not necessarily
universal or comprehensive in their
coverage. Certainly they are among the
standards which may have prevailed
when specific research was conducted,
and EPA will rely on them when they
are appropriate to the evaluation of a
particular study. But it adds nothing to
list them in the final rule.
EPA also thinks it unnecessary to
elaborate on the meaning of the
narrative standards ‘‘fundamentally
unethical,’’ ‘‘significantly deficient’’ or
‘‘substantial compliance.’’ The gravity of
a particular ethical lapse depends not
only on the details of the deficiency, but
also on the circumstances in which it
occurred. EPA agrees with the NAS that
each study requires case-by-case
evaluation. EPA expects these terms to
acquire greater clarity over time,
through HSRB and public review of
Agency decisions concerning reliance
on completed human research.
Comment: Some comments objected
to the proposed prohibition of EPA’s
reliance in its pesticide decisions on
data from human subjects research
involving intentional exposure of
pregnant women, fetuses, or children.
These comments argued that if such
research was not considered unethical
under the standards prevailing when it
was conducted EPA should accept and
consider it, and that exclusion of such
research could deprive EPA of
potentially valuable information.
Response: EPA agrees that existing
research involving intentional exposure
of pregnant women, fetuses, or children
may have been considered ethical
according to the standards prevailing
when the studies were conducted.
Nonetheless, in light of the provisions of
the 2006 Appropriations Act and the
thousands of public comments on the

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proposal condemning research of this
kind, the Agency believes it must
generally refuse to rely on such
research. The Agency knows of only a
very few existing studies involving
intentional exposure of pregnant women
or children. If it were determined that
reliance on any of them were crucial to
a decision that would impose a more
stringent regulatory restriction to protect
public health than could otherwise be
justified, the exception procedure
defined in § 26.1706 in the final rule
could be invoked.
Comment: Several comments
recommended revising the evidentiary
standard for accepting ‘‘old’’ studies.
Some suggested a change from ‘‘clear
evidence’’ to a less demanding test, such
as ‘‘any evidence.’’ Others
recommended adoption of the exact
wording of the NAS recommendation on
which EPA based the proposal,
changing ‘‘clear evidence’’ to ‘‘clear and
convincing evidence.’’
Response: It is conceivable that the
standard requiring ‘‘clear evidence’’
could lead the Agency to accept data
from research which it suspected but
could not prove had serious ethical
flaws. The Agency agrees this would be
unfortunate, but believes a change to a
standard of ‘‘any evidence’’ would
likely lead to even more unfortunate
outcomes. Because reliable information
about its conduct is often very limited,
in many cases it is difficult or
impossible to prove that older research
was ethical. An unsupported accusation
of unethical conduct should thus not in
itself be sufficient to force rejection of
completed research. Rejection of
research on the basis of weak or
suggestive evidence of unethical
conduct could deprive the Agency of
information important to sound
decisions. Because EPA can see no
benefit that would flow from changing
the standard to ‘‘any evidence,’’ EPA is
not accepting this recommendation.
On the other hand EPA agrees with
the comments urging a return to the
exact wording of the evidentiary test in
NAS Recommendation 5–7. Since the
Agency did not intend to alter the
standard, and since ‘‘clear and
convincing evidence’’ has an accepted
meaning under administrative law, EPA
has changed the final rule to read, in
pertinent part:
. . . EPA shall not rely on data from any
research initiated before April 7, 2006 if there
is clear and convincing evidence that the
conduct of that the research was
fundamentally unethical . . .

4. The exception allowing use of
unethical data to justify more stringent
regulatory restrictions to protect public
health.

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Comment: One group of comments
argued that the Agency should, without
exception, never rely on data derived
from unethical research because to do
otherwise would condone unethical
research. Many of these commenters
also misunderstood the proposed
exception as authorizing the conduct of
unethical future research.
Response: Although EPA thinks there
will rarely, if ever, be situations
requiring the use of this exception, EPA
can easily imagine a circumstance in
which ethical behavior could require
Agency decision-makers to rely on
unethical data. (See Unit II.) The
exception would be used when
scientifically sound but ethically flawed
data show that the Agency needs to take
a more protective action than could be
justified without considering the human
research. Invoking the exception would
allow EPA to protect the health of many
people—perhaps millions; a greater
public good than any benefits that
would flow from refusing to rely on the
data. In EPA’s moral calculus, the
greater good should and will guide the
choice whether to use unacceptable
data.
The Agency disagrees with the
argument that the final rule should
contain no exceptions to the basic
principle of refusing to rely on unethical
research, because an exception would
encourage the conduct of unethical
research. A public refusal by EPA to rely
on unethical data brings shame to the
investigator who acted unethically, and
in most cases also directly affects the
financial interests of the investigator,
sponsor, or both. Such a refusal serves
as an important deterrent to other
investigators, discouraging unethical
research in the future.
To further ensure that EPA’s
exceptional use of ethically flawed data
does not encourage unethical research
conduct, § 26.1706 expressly requires
the Agency to publish ‘‘a full
explanation of its decision to rely on
otherwise unacceptable data, including
a thorough discussion of the ethical
deficiencies of the study . . . .’’ In
addition, the Agency will have recourse
to any of the other measures identified
in subpart O to promote compliance
with standards of ethical research. EPA
believes the exception as defined in the
final rule, allowing for EPA
consideration of unethical research
under well defined and narrow
conditions and requiring a full public
discussion of its ethical deficiencies,
will not in any way encourage other
investigators to conduct unethical
research.
Comment: Some comments argued for
a broad interpretation of the concept of

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‘‘protection of public health,’’ such that
it would not be limited to cases
involving imposition of more stringent
regulatory restrictions. Some comments
suggested, for example, that a more
accurate assessment of risks to humans
should be interpreted as ‘‘protection of
public health.’’ Other comments called
upon EPA to clarify in the final rule that
‘‘protection of public health’’ does not
encompass the ability of American
agriculture to produce more crops at a
lower cost.
Response: EPA does not agree that the
public health exception should be
interpreted to permit reliance on
unethical research to support more
accurate risk assessments or more
efficient or lower cost agricultural
production. EPA’s ethical framework is
built on the principle that unethical
research should not be relied on in
Agency actions except in the most
extraordinary circumstances; such
interpretations would amount to
abandoning this principle altogether,
and could severely undermine
incentives for compliance with the new
requirements.
The Agency does agree, however, that
the proposal was unclear with respect to
what would constitute a ‘‘public health’’
benefit justifying invocation of the
exception. EPA has thus revised the
final rule to clarify that invoking the
public health exception would only
permit the Agency to ‘‘impose a more
stringent regulatory restriction that
would improve protection of public
health . . . .’’ See § 26.1706 of the
regulatory text.
C. The Final Rule
Subpart Q of the final rule
corresponds in substance to subpart F of
the proposal. In this final rule EPA has
moved the rule text to a new subpart,
and has rewritten the proposed
provisions to express the standards
more clearly.
Section 26.1701 of the final rule
describes the scope of subpart Q; it
applies to:
. . . EPA’s decisions whether to rely in its
actions under the Federal Insecticide,
Fungicide, and Rodenticide Act (7 U.S.C. 136
et seq.) or section 408 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 346a) on
scientifically valid and relevant data from
research involving intentional exposure of
human subjects.

The Agency has chosen to retain the
scope of the proposed rule because it
believes that the 2006 Appropriations
Act does not require this rule to address
a broader scope of issues, and because
there has not been adequate
consideration of the consequences of
adopting a more expansive scope.

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Section 26.1703 prohibits EPA’s
reliance on data from research involving
intentional exposures of pregnant
women, fetuses, or children. Derived
from proposed §§ 26.221 and 26.421,
this section states:
Except as provided in § 26.1706, in actions
within the scope of § 26.1701, EPA shall not
rely on data from any research involving
intentional exposure of any human subjects
who is a pregnant woman (and therefore her
fetus) or child.

This provision makes clear that the
Agency will not rely in its actions on
the results of research that EPA and
third parties are prohibited from
conducting under subparts B and L,
except under the narrow exception
provided by § 26.1706. To clarify that
this prohibition applies to EPA’s nonregulatory actions (such as issuance of
a risk assessment or a health advisory
level) as well as to its regulatory
decisions, EPA has changed the phrase
‘‘regulatory decision-making’’ in the
proposal to ‘‘actions’’ in the final rule.
Section 26.1704 defines the ethical
standard EPA will use to decide
whether to rely on the results of
research conducted with non-pregnant
adults before the effective date of the
rule. It provides:
Except as provided in § 26.1706, in actions
within the scope of § 26.1701, EPA shall not
rely on data from any research initiated
before April 7, 2006, 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. This
prohibition is in addition to the prohibition
in § 26.1703.

The above rule text is derived from
proposed § 26.601, and follows the
language of the NAS recommendation
5–7. In response to public comment, the
evidentiary standard for concluding
research was unethical has been
changed from ‘‘clear evidence’’ to ‘‘clear
and convincing evidence.’’ The Agency
made this change to minimize
confusion, to conform to the wording of
the NAS recommendation, and to use a
formulation of the evidentiary standard
that has an accepted legal meaning in
administrative law. For purposes of
clarity, the section also reaffirms that
the prohibition in § 26.1703 against
relying on research involving pregnant
women and children is unaffected by
this provision.
Section 26.1705 describes the ethical
standard EPA will use to decide
whether to rely on the results of human
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of the rule. It provides that the Agency
will not rely on data from such research:
Except as provided in § 26.1706, in actions
within the scope of § 26.1701, EPA shall not
rely on data from any research initiated after
April 7, 2006, unless EPA has adequate
information to determine that the research
was conducted in substantial compliance
with subparts A through M of this part, or if
conducted in a foreign country, under
procedures at least as protective as those in
subparts A through L. This prohibition is in
addition to the prohibition in § 26.1703.

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This rule text is based on proposed
§ 26.602. It has been revised to make
clear that EPA may accept and rely on
data from human research conducted in
a foreign country if EPA has adequate
information to determine the research
was ‘‘conducted . . . under procedures
at least as protective as those in subparts
A through L.’’ Allowing the use of
foreign research provided the research
meets ethical norms equivalent to those
of the Common Rule is consistent with
the Common Rule at § 26.101(h). Like
§ 26.1704, § 26.1705 reaffirms, for the
sake of clarity, that the prohibition in
§ 26.1703 against relying on research
involving pregnant women and children
is unaffected by this provision.
Finally § 26.1706 provides for an
exception to the general refusal to rely
on the results of unethical research.
This section defines the specific
circumstance in which the Agency will
use data from research judged
unacceptable under § 26.1703,
§ 26.1704, or § 26.1705, and the
procedures EPA must follow in reaching
that decision, as follows:

protection of public health’’ in the
proposal to ‘‘crucial to a decision that
would impose a more stringent
regulatory restriction that would
improve protection of public health’’ in
the final rule. This change reflects the
Agency’s intent to limit the exception to
a very narrow circumstance and to
prevent use of the exception in a way
that could benefit a person responsible
for the unethical conduct.
XIV. EPA’s 2006 Appropriations Act
and the Final Rule
This unit discusses how today’s final
rule meets the requirements of the
Department of the Interior,
Environment, and Related Agencies
Appropriations Act, 2006, Public Law
No. 109–54 (Appropriations Act), which
required EPA to promulgate a final rule
relating to intentional dosing human
toxicity studies for pesticides within
180 days of enactment of the Act, and
included various mandates concerning
the promulgated final rule.
A. Section 201 of EPA’s FY 2006
Appropriations Act
On August 2, 2005, the President
signed into law the Department of the
Interior, Environment, and Related
Agencies Appropriations Act, 2006,
Public Law No. 109–54 (Appropriations
Act), which provides appropriated
funds for EPA and other federal
departments and agencies. Section 201
of the Appropriations Act addresses
EPA activities regarding intentional
dosing human toxicity studies for
pesticides as follows:

EPA may rely on such data only if all the
conditions in paragraphs (a) through (d) of
this section are satisfied:
(a) EPA has obtained the views of the
Human Studies Review Board concerning the
proposal to rely on the otherwise
unacceptable data,
(b) EPA has provided an opportunity for
public comment on the proposal to rely on
the otherwise unacceptable data,
(c) EPA has determined that 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, and
(d) EPA publishes a full explanation of its
decision to rely on the otherwise
unacceptable data, including a thorough
discussion of the ethical deficiencies of the
study and the full rationale for finding that
the standard in paragraph (c) of this section
was met.

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.

The text of this section of the final
rule contains a number of minor
revisions to clarify the substantive and
procedural requirements. Most notably,
EPA changed the wording for the
substantive standard for using the
exception from ‘‘crucial to the

B. Compliance of the Final Rule with the
Appropriations Act
The first requirement of the
Appropriations Act is that EPA not
‘‘accept, consider or rely on third-party
intentional dosing human toxicity

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6163

studies for pesticides, or . . . conduct
intentional dosing human toxicity
studies for pesticides until the
Administrator issues a final rulemaking
on this subject.’’ EPA has not accepted,
considered, or relied on any third-party
intentional dosing human toxicity
studies in its actions under FIFRA and
FFDCA since September 2005. EPA has
further neither conducted nor supported
any intentional dosing human toxicity
study for pesticides during this
rulemaking period.
The second requirement of the
Appropriations Act is to ‘‘allow for a
period of not less than 90 days for
public comment on the Agency’s
proposed rule before issuing a final
rule.’’ A notice of proposed rulemaking
addressing both third-party intentional
dosing human toxicity studies for
pesticides and EPA’s conduct of
intentional dosing human studies was
published in the Federal Register on
September 12, 2005 (70 FR 53838); the
public comment period ended on
December 12, 2005.
EPA’s proposed rule addressed first-,
second-, and third-party human subjects
testing for pesticides. In particular, the
proposal defined the scope of thirdparty human research covered by the
proposal as:
[A]ll research involving intentional
exposure of a human subject if, at any time
prior to initiating such research, any person
who conducted or supported such research
intended:
(1) To submit results of the research to EPA
for consideration in connection with any
regulatory action that may be performed by
EPA under the Federal Insecticide,
Fungicide, and Rodenticide Act (7 U.S.C. 136
et seq.) or section 408 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 346a); or
(2) To hold the results of the research for
later inspection by EPA under the Federal
Insecticide, Fungicide, and Rodenticide Act
(7 U.S.C. 136 et seq.) or section 408 of the
Federal Food, Drug, and Cosmetic Act (21
U.S.C. 346a).

EPA used the act of submitting, or the
intent to submit, to the Agency under
FIFRA or FFDCA as a surrogate for the
Appropriations Act’s requirement that
EPA promulgate a rule addressing
‘‘third-party intentional dosing human
toxicity studies for pesticides.’’ The use,
sale, and distribution of pesticides are
exclusively regulated by EPA under
FIFRA and FFDCA. Moreover, as
discussed above, the ongoing
controversy over EPA’s use of human
research data in its risk assessments has
focused almost exclusively on the use of
such data in risk assessments under
FIFRA and FFDCA. Indeed, the
Congressional debate that resulted in
the passage of section 201 of the
Appropriations Act focused entirely on

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human subjects research related to
Agency actions under FIFRA and
FFDCA. Therefore, EPA believes that
interpreting the phrase ‘‘third-party
intentional dosing human toxicity
studies for pesticides’’ to require either
submission or intent to submit under
FIFRA or FFDCA reflects the intent of
the Congress as expressed in section 201
of the Appropriations Act.
The third requirement of the
Appropriations Act is that the final rule
‘‘not permit the use of pregnant women,
infants or children as subjects.’’ Today’s
final rule effectuates this mandate by:
(1) Categorically prohibiting EPA from
conducting or supporting research
involving intentional exposure to any
substance of human subjects who are
pregnant women or children (subpart B
of the final rule, § 26.203); and (2)
prohibiting third-party research for
pesticides involving intentional
exposure of human subjects who are
pregnant women or children (subpart L
of the final rule, § 26.1203).
The fourth requirement of the
Appropriations Act is that the final rule
‘‘shall be consistent with the principles
proposed in the 2004 report of the
National Academy of Sciences on
intentional human dosing.’’ Based on a
careful review of the NAS report, EPA
concludes that the underlying
principles intended by the NAS
committee to be reflected in its
recommendations are the three
‘‘fundamental ethical principles’’
identified by the National Commission
for the Protection of Human Subjects of
Biomedical and Behavioral Research
(National Commission) in its report,
Ethical Principles and Guidelines for
the Protection of Human Subjects of
Research (the ‘‘Belmont Report’’). These
three fundamental principles are respect
for persons, beneficence, and justice.
See NAS Report at pp. 49–50, 98, and
113–14.
The NAS committee makes the point
clearly that they did not propose new
principles:

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[T]he committee was not required to invent
the basic standards that govern human
research in the United States. These
standards are already embodied in the
Federal Policy for the Protection of Human
Subjects (the Common Rule.) NAS Report pp.
4, 33.

The NAS committee further stated
that the fundamental principles
articulated in the Belmont Report both
undergird and are made operational by
the procedural requirements of the
Common Rule. The following quotations
express this view:
Federal regulations incorporate the
obligation of beneficence by requiring IRBs to
ensure that risks are minimized to the extent

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possible, given the research question, and are
reasonable in relation to potential benefits to
the participant or to the importance of the
knowledge to be gained through the research
(40 CFR 26.111(a)(1)–(2)). NAS Report at 56.
[D]etermining whether the principle of
beneficence has been satisfied requires
balancing the anticipated risks to study
participants against the anticipated benefits
of the study to society. The risks to
participants must be reasonable in relation to
the societal benefit. In the words of the
Common Rule, the risks must be reasonable
in relation to the importance of the
knowledge that may reasonably be expected
to result (40 CFR 26.111 (a)(2)). NAS Report
at 107.
According to the Common Rule, IRBs
should not approve a research protocol
involving humans unless ‘‘selection of
subjects is equitable’’ (40 CFR 26.111(3)).
This requirement derives from the principle
of justice identified in the Belmont Report.
NAS Report at 114.
Voluntary, informed consent by research
participants . . . is a major element in the
system of protection of research participants.
The consent requirement expresses the
principle of respect for persons, including
respect for and promotion of autonomous
choices. The Common Rule stresses this
requirement, as do other codes of research
ethics, including the Nuremberg Code (1949),
the Declaration of Helsinki, and the Good
Clinical Practice guidelines. NAS Report at
120.

Accordingly, EPA concludes that the
‘‘principles proposed in the 2004 report
of the National Academy of Sciences on
intentional human dosing’’ are, in fact,
the three fundamental principles of
respect for persons, beneficence, and
justice articulated in the Belmont
Report, and that the Common Rule rests
on the foundation of those principles.
Today’s final rule extending the
substantive requirements of EPA’s
Common Rule to additional categories
of regulated third-party research is thus
consistent with those principles, as
required by the Appropriations Act.
The fifth requirement of the
Appropriations Act is that the final rule
‘‘shall be consistent with the principles
. . . of the Nuremberg Code with respect
to human experimentation.’’
The NAS report (p. 47) explains the
history of the Nuremberg Code as
follows:
Public policies regarding the ethical
treatment of humans in research began
forming in the late 1940’s, largely in response
to the atrocities committed by Nazi
investigators who were tried before the
Nuremberg Military Tribunal (United States
v. Karl Brandt, et al.) In 1946, the American
Medical Association adopted its first code of
research ethics, which ultimately influenced
the Nuremberg Tribunal’s standards for
ethical research, embodied in the ten ‘‘basic
principles’’ for human research now known
as the Nuremberg Code. [Footnotes and
references omitted]

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Before publishing the NPRM, EPA
carefully assessed whether the proposed
provisions were consistent with the 10
principles of the Nuremberg Code as a
guide, and concluded that it was
consistent with such principles. EPA
believes this final rule remains
consistent with the principles of the
Nuremberg Code. An analysis
explaining this conclusion is in the
docket for this action, and comments on
this issue have been addressed in our
Response to Comments document.
The sixth requirement of the
Appropriations Act is that the final rule
‘‘shall establish an independent Human
Subjects Review Board.’’ EPA believes
that the entity required by the
Appropriations Act is intended to be
substantially identical to the ‘‘Human
Studies Review Board’’ recommended
by Chapter 6 of the NAS Report.
Consistent with both the requirement of
the Appropriations Act and the
recommendations of the NAS, this final
rule establishes an independent HSRB.
The HSRB will review proposed human
subjects research after review by a local
IRB and EPA staff. This sequence is
consistent both with EPA’s current
practice for reviewing first- and secondparty human research proposals and
with the practice of FDA for reviewing
human research proposals. Although the
NAS Report recommended that the EPA
and HSRB reviews come before the IRB
review, EPA believes that HSRB review
after local IRB and EPA review will
better serve the purposes for which
HSRB review of proposed research is
intended.
The final requirement of the
Appropriations Act is that the final rule
‘‘shall be issued no later than 180 days
after enactment of this Act.’’ This
requirement was met when EPA
Administrator Stephen L. Johnson
signed the final rule before January 29,
2006, and it was made publicly
available.
XV. Effective Date of the Final Rule
EPA noted in the preamble to the
proposed rule that it considered the
expeditious application of the new
protections in the final rule to be in the
public interest. Accordingly the Agency
explained that it would provide no
longer period than is essential between
publication of the final rule and its
effective date. Since the final rule is
being promulgated under the authority
of FIFRA, EPA is subject to FIFRA
section 25(a)(4), 7 U.S.C. 136w(a)(4),
which provides that:
Simultaneously with the promulgation of
any rule or regulation under this Act, the
Administrator shall transmit a copy thereof
to the Secretary of the Senate and the Clerk

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of the House of Representatives. The rule or
regulation shall not become effective until
the passage of 60 calendar days after the rule
or regulation is so transmitted.

Therefore, EPA proposed that the
final rule would be effective 60 days
after its promulgation and transmittal to
Congress.
EPA received only one comment on
the effective date, arguing that the
requirements of the rule should not
apply retroactively. EPA agrees that the
provisions of the final rule should not
apply retroactively, and the final rule
contains no retroactive requirements.
Specifically, the final rule establishes
standards for the conduct by EPA and
by third parties, in the future, of certain
types of research. The Agency notes that
the actions to promote compliance
identified in subpart O of the final rule
would only be applied to those whose
actions, following the effective date of
the final rule, did not comply with
applicable requirements. Actions
occurring before the final rule takes
effect would not be subject to direct
sanctions under subpart O, such as civil
penalties or debarment. In addition, the
final rule establishes standards to guide
future Agency decisions about the
ethical acceptability of completed
research. While some of the research
that EPA will evaluate under the new
standards for ethical acceptability was
conducted prior to the effective date of
the final rule, such studies will be
judged by the ethical standards
prevailing when the research was
performed. Thus, even the standard of
acceptability is not ‘‘retroactive’’ in the
sense that conduct would be judged
using a standard created after the
conduct occurred.
The Agency has decided to make the
final rule effective 60 days after the date
of publication of its Notice of Final
Rulemaking in the Federal Register. As
required by FIFRA section 25(a)(4), the
Agency has previously transmitted
copies of the signed final rule to the
Secretary of the Senate and the Clerk of
the House of Representatives. Although
technically the rule could take effect a
few days earlier, EPA concluded that
allowing 60 days from the date of
publication of this Federal Register
document was appropriate.
Accordingly, this rule takes effect on
April 7, 2006.
The Agency notes that a number of
the provisions of the rule apply to
research ‘‘initiated’’ after the effective
date of this rule. For purposes of
research conducted or supported by
EPA, the Agency will consider that an
investigator has initiated a study once
the Agency’s HSRRO has approved the
protocol for the study. For purposes of

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research that is covered by subparts K
or L or by § 26.1705, a study was
‘‘initiated’’ when the first subject was
enrolled. If that date cannot be
determined, EPA will consider the
earliest date on which experimental
activity involved a subject to be the date
of initiation of the research.
XVI. FIFRA Review Procedures for the
Final Rule
FIFRA section 25(a)(2)(B) provides:
‘‘[a]t least 30 days prior to signing any
regulation in final form for publication
in the Federal Register, the
Administrator shall provide the
Secretary of Agriculture a copy of such
regulation.’’ This section also authorizes
the Secretary to waive the opportunity
to review and comment on final
regulations. FIFRA section 25(d)(1)
states that ‘‘[t]he Administrator shall
submit to an advisory panel for
comment [the] final form of regulations
issued under section 25(a) within the
same time periods as provided for the
comments of the Secretary of
Agriculture . . . .’’ This section also
authorizes the FIFRA Scientific
Advisory Panel to waive the
opportunity for review. Both, the FIFRA
Scientific Advisory Panel (SAP) and the
U.S. Department of Agriculture (USDA)
have waived the opportunity under
FIFRA to review the final rule.
In addition, FIFRA section 25(a)(3)
states that ‘‘[a]t such time as the
Administrator is required under
paragraph (2) to provide the Secretary of
Agriculture with . . . a copy of the final
form of regulations, the Administrator
shall also furnish a copy of such
regulations to the Committee on
Agriculture in the House of
Representatives, and the Committee on
Agriculture, Nutrition, and Forestry in
the United States Senate.’’ Because
USDA waived review under FIRFA
section 25(a)(2)(B), EPA is not required
to furnish a copy of the final regulations
to the specified committees 30 days
prior to signature of the final rule. The
Agency, nonetheless, provided copies of
the final rule to the Congressional
committees prior to its publication.
XVII. Statutory and Executive Order
Reviews
A. Executive Order 12866
Under Executive Order 12866,
entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993),
the Office of Management and Budget
(OMB) has determined that this final
rule is a ‘‘significant regulatory action’’
under section 3(f) of the Executive
Order because this action might raise
novel legal or policy issues.

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Accordingly, this action was submitted
to OMB for review under Executive
Order 12866 and any changes made
based on OMB recommendations have
been documented in the docket for this
rulemaking as required by section
6(a)(3)(E) of the Executive Order.
In addition, EPA prepared an
economic analysis of the potential costs
and benefits associated with this action.
This analysis is contained in a
document entitled ‘‘Economic Analysis
of the Human Studies Final Rule’’
(Economic Analysis). A copy of the
Economic Analysis is available in the
docket for this rulemaking and is briefly
summarized here.
The Economic Analysis describes the
benefits of the rulemaking in qualitative
terms. These benefits include greater
protections for test subjects, and a
corresponding reduction in their risks,
to the extent that affected third-party
researchers are not already following the
Common Rule. The benefits to sponsors
of third-party human research include a
better understanding of the standards
that EPA will apply in determining
whether to rely on the results of their
studies, and thus, the opportunity to
design and perform studies that are
more likely to meet EPA standards,
leading to more efficient Agency
reviews. The Agency believes the
general public will also benefit from this
action because the rule will strengthen
the protections for human subjects and
reinforce the Agency’s strong
commitment to base its decisions on
scientifically sound information.
The Economic Analysis also estimates
the costs of the final rule by focusing on
the costs to third parties of complying
with the new requirements and the costs
to EPA of implementing the new
requirements. In general, EPA believes
that most, if not all, recent third-party
research intended for submission to
EPA that involves intentional exposure
of human subjects already complies
with the Common Rule or an equivalent
foreign standard. For purposes of this
analysis, EPA assumed that current
practice was in full compliance with the
Common Rule.
After reviewing the history of EPA’s
consideration of research involving
human subjects in its various program
offices, EPA estimates that this action
will affect only a limited number of
third-party studies involving human
subjects each year. EPA also collected
data on the cost per study of compliance
with the Common Rule. These costs
include preparing documents to support
review by an IRB and the expense
associated with the IRB review. These
costs are very minor relative to the
overall cost of conducting the studies.

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For EPA, the costs are associated with
the review of protocols and the review
of completed human studies by EPA
staff and the Human Studies Review
Board.
As detailed in the Economic Analysis
prepared for this final rule, this action
is estimated to result in a total annual
incremental cost to third parties of
approximately $39,000, and an
estimated annual cost to EPA of
approximately $808,000.
B. Paperwork Reduction Act
The information collection
requirements contained in this final rule
have been approved by the Office of
Management and Budget (OMB) under
the Paperwork Reduction Act (PRA), 44
U.S.C. 3501 et seq., under OMB control
number 2070–0169. In accordance with
the procedures at 5 CFR 1320.11, EPA
sought comment on the Information
Collection Request (ICR) document that
was submitted to OMB in conjunction
with the proposed rule (identified under
EPA ICR No. 2195.01). Revised to reflect
the provisions in this final rule, the ICR
document (identified under EPA ICR
No. 2195.02) was prepared and
submitted to OMB and serves as the
basis for OMB’s approval. A copy of this
ICR document has been placed in the
docket for this rulemaking.
Under the PRA, an agency may not
conduct or sponsor, and a person is not
required to respond to an information
collection request unless it displays a
currently valid OMB control number.
The OMB control numbers for the EPA
regulations codified in Chapter 40 of the
CFR, after appearing in the preamble of
the final rule, are listed in 40 CFR part
9, displayed either by publication in the
Federal Register or by other appropriate
means, such as on the related collection
instrument or form, if applicable. The
display of OMB control numbers in
certain EPA regulations is consolidated
in 40 CFR part 9. For this ICR activity,
in addition to displaying the applicable
OMB control number in this unit, the
Agency is amending the table in 40 CFR
9.1 to list the OMB control number
assigned to this ICR activity. Due to the
technical nature of the table, EPA finds
that further notice and comment about
amending the table is unnecessary. As a
result, EPA finds that there is ‘‘good
cause’’ under section 553(b)(B) of the
Administrative Procedures Act (APA), 5
U.S.C. 553(b)(B), to amend this table
without further notice and comment.
EPA estimates that respondents may
submit to the Agency each year under
FIFRA or FFDCA, approximately 33
reports of research involving intentional
exposure of human subjects. The
Agency expects extremely limited

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submission of toxicity studies per year
(i.e., 0–4 studies), with the bulk of the
33 studies being composed of efficacy
and skin sensitization studies. (See also
the response to comment on this topic
that appears in Unit III.) EPA estimates
that it may receive approximately 29
reports each year of other types of
pesticide research involving human
subjects. EPA estimates that preparation
of the required information will require
about 32 hours per study, for a total
estimated annual burden for affected
entities of 1,984 hours, at an estimated
cost of $1,927 per study, or a total
estimated annual paperwork cost to
respondents of $84,647. This total
annual paperwork burden and cost
estimate includes activities related to
initial rule familiarization, as well as
activities that researchers already
perform and would continue to perform
even without the Agency’s rulemaking
in this area (i.e., developing a protocol
and maintaining records). The average
annual burden on EPA for reviewing
this information for each study
submission is estimated to be 80 hours
per study (in total 4,960 hours),
representing a paperwork related labor
cost of about $14,672 per response and
a total annual cost of $909,664.
In the context of the PRA, ‘‘burden’’
means the total time, effort, or financial
resources expended by persons to
generate, maintain, retain, or disclose or
provide information to or for a Federal
agency. This includes the time needed
to review instructions; develop, acquire,
install, and utilize technology and
systems for the purposes of collecting,
validating, and verifying information,
processing and maintaining
information, and disclosing and
providing information; adjust the
existing ways to comply with any
previously applicable instructions and
requirements; train personnel to be able
to respond to a collection of
information; search data sources;
complete and review the collection of
information; and transmit or otherwise
disclose the information.
The information collection activity
imposed by this final rule is planned to
ensure that sound and appropriate
scientific data are available to EPA
when making regulatory decisions, and
to protect the interests, rights and safety
of those individuals who are
participants in the type of research
activity that is the subject of this rule.
Specifically, this new information
collection activity consists of reporting
and recordkeeping requirements.
Whenever respondents intend to
conduct research for submission to EPA
under the pesticide laws that involves
intentional dosing of human subjects,

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they will be required to submit study
protocols to EPA and a cognizant local
IRB before such research is initiated so
that the scientific design and ethical
standards that will be employed during
the proposed study may be reviewed
and approved. Respondents will also be
required to submit information about
the ethical conduct of completed
research that involved intentional
dosing of human subjects when such
research is submitted to EPA.
FIFRA sections 3(c)(1)(F) and
3(c)(2)(B) authorize EPA to require
various data in support of a pesticide’s
continued registration or an application
for a new or amended pesticide
registration. FIFRA section 12(a)(2)(P)
forbids any person ‘‘to use any pesticide
in tests on human beings unless such
human beings (i) are fully informed of
the nature and purposes of the test and
of any physical and mental health
consequences which are reasonably
foreseeable therefrom, and (ii) freely
volunteer to participate in the test.’’
C. Regulatory Flexibility Act
Pursuant to section 605(b) of the
Regulatory Flexibility Act (RFA), 5
U.S.C. 601 et seq., after considering the
potential economic impacts of today’s
rule on small entities, the Agency
hereby certifies that this final rule will
not have a significant adverse economic
impact on a substantial number of small
entities. This determination is based on
the Agency’s economic analysis
performed for this rulemaking,
summarized in Unit XVI.A., and a copy
of which is available in the docket for
this rulemaking. The following is a brief
summary of the factual basis for this
certification.
Small entities include small
businesses, small organizations, and
small governmental jurisdictions. For
purposes of assessing the impacts of
today’s rule on small entities, small
entity is defined in accordance with the
RFA 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; and (3)
a small organization that is any not-forprofit enterprise which is independently
owned and operated and is not
dominant in its field.
Although we cannot predict whether
or how many small entities might
engage in the subject matter research in
the future, as estimated in the Economic
Analysis, the cost to researchers covered
by this rule is estimated to be $5,200 per
study. This is a trivially small portion
of the overall cost of performing such

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studies, each of which is estimated to
cost from $125,000 to $500,000. After
reviewing the history of EPA’s
consideration on human research in its
various program offices, EPA estimates
that this rule would affect only a limited
number of third-party human studies
each year. Because both the number of
affected studies is relatively small and
the estimated current costs of
compliance with the Common Rule are
low, the potential overall costs from this
rule to third parties are also estimated
to be small.
D. Unfunded Mandates Reform Act
Under Title II of the Unfunded
Mandates Reform Act of 1995 (UMRA)
(Public Law 104–4), EPA has
determined that this 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 one year. As
described in Unit XVI.A. the estimated
total costs associated with this action
are approximately $38,837 per year.
This cost represents the incremental
cost to researchers attributed to the
additional procedural requirements
contained in this final rule. Based on
historical submissions, EPA has
determined that State, local, and tribal
governments rarely perform human
research intended for submission to
EPA under FIFRA or FFDCA. In
addition, the final rule is not expected
to significantly or uniquely affect small
governments. Accordingly, this action is
not subject to the requirements of
sections 202 and 205 of UMRA.

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E. Executive Order 13132
Pursuant to Executive Order 13132,
entitled Federalism (64 FR 43255,
August 10, 1999), EPA has determined
that this rule 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 the
Order. As indicated earlier, instances
where a state performs human research
intended for submission to EPA under
FIFRA or FFDCA are rare. Therefore,
this final rule may seldom affect a state
government. Thus, Executive Order
13132 does not apply to this rule.
F. Executive Order 13175
As required by Executive Order
13175, entitled Consultation and
Coordination with Indian Tribal
Governments (59 FR 22951, November
6, 2000), EPA has determined that this

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final rule does not have tribal
implications because it will not have
substantial direct effects on tribal
governments, on the relationship
between the Federal government and
the Indian tribes, or on the distribution
of power and responsibilities between
the Federal government and Indian
tribes, as specified in the Order. As
indicated previously, instances where a
tribal government performs human
research intended for submission to
EPA under FIFRA or FFDCA are
extremely rare. Thus, Executive Order
13175 does not apply to this rule.
G. Executive Order 13045
Executive Order 13045, entitled
Protection of Children from
Environmental Health Risks and Safety
Risks (62 FR 19885, April 23, 1997) does
not apply to this rule because this action
is not designated as an ‘‘economically
significant’’ regulatory action as defined
by Executive Order 12866. Furthermore,
this final rule does not establish an
environmental standard that is intended
to have a negatively disproportionate
effect on children. To the contrary, this
action will provide added protections
for children with regard to the research
covered by the rule.
H. Executive Order 13211
This final rule is not subject to
Executive Order 13211, entitled Actions
Concerning Regulations that
Significantly Affect Energy Supply,
Distribution, or Use (66 FR 28355, May
22, 2001) because this rule does not
have any significant adverse effect on
the supply, distribution, or use of
energy.
I. National Technology Transfer and
Advancement Act
Section 12(d) of the National
Technology Transfer and Advancement
Act of 1995 (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
impractical. Voluntary consensus
standards are technical standards (e.g.,
materials specifications, test methods,
sampling procedures) that are
developed or adopted by voluntary
consensus standards bodies. NTTAA
directs EPA to provide Congress,
through OMB, with explanations when
the Agency decides not to use available
and applicable voluntary consensus
standards. This action does not require
specific methods or standards to
generate data. Therefore, this final rule
does not impose any technical standards
that would require Agency

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6167

consideration of voluntary consensus
standards.
J. Executive Order 12898
This final rule does not have an
adverse impact on the environmental
and health conditions in low-income
and minority communities. Therefore,
under Executive Order 12898, entitled
Federal Actions to Address
Environmental Justice in Minority
Populations and Low-Income
Populations (59 FR 7629, February 16,
1994), the Agency is not required to
consider environmental justice-related
issues. Although not directly impacting
environmental justice-related concerns,
the provisions of this rule will require
researchers to use procedures to ensure
equitable selection of test subjects in
covered human research.
XVIII. 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 that includes a copy
of the rule to each House of the
Congress and the Comptroller General of
the United States. EPA will submit a
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. This rule is not a
‘‘major rule’’ as defined by 5 U.S.C.
804(2).
List of Subjects in 40 CFR Part 9
Environmental protection, Reporting
and recordkeeping requirements.
List of Subjects in 40 CFR Part 26
Environmental protection, Human
research subjects, Reporting and
recordkeeping requirements.
Dated: January 26, 2006.
Stephen L. Johnson,
Administrator.

Therefore, 40 CFR chapter I is
amended as follows:
■ 1. Part 9 is amended as follows:
■

PART 9—[AMENDED]
a. The authority citation for part 9
continues to read as follows:

■

Authority: 7 U.S.C. 135 et seq., 136–136y;
15 U.S.C. 2001, 2003, 2005, 2006, 2601–2671,
21 U.S.C. 331j, 346a, 348; 31 U.S.C. 9701; 33
U.S.C. 1251 et seq., 1311, 1313d, 1314, 1318,
1321, 1326, 1330, 1342, 1344, 1345 (d) and
(e), 1361; E.O. 11735, 38 FR 21243, 3 CFR,
1971–1975 Comp. p. 973; 42 U.S.C. 241,
242b, 243, 246, 300f, 300g, 300g–1, 300g–2,
300g–3, 300g–4, 300g–5, 300g–6, 300j–1,
300j–2, 300j–3, 300j–4, 300j–9, 1857 et seq.,

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6901–6992k, 7401–7671q, 7542, 9601–9657,
11023, 11048.

b. In § 9.1 the table is amended by
adding the following new entries under
the new heading ‘‘Protection of Human
Subjects’’ to read as follows:
■

§ 9.1 OMB approvals under the Paperwork
Reduction Act.

*

*

*

*

*

40 CFR citation
*

OMB Control No.

*

*

*

*

.
Protection of Human Subjects

26.305 Protections applicable, after
delivery, to the placenta, the dead fetus,
or fetal material.

26.1303 Submission of information
pertaining to ethical conduct of
completed human research.

Subpart D—Observational Research:
Additional Protections for Children Involved
as Subjects in Observational Research
Conducted or Supported by EPA
26.401 To what does this subpart apply?
26.402 Definitions.
26.403 IRB duties.
26.404 Observational research not involving
greater than minimal risk.
26.405 Observational research involving
greater than minimal risk but presenting
the prospect of direct benefit to the
individual subjects.
26.406 Requirements for permission by
parents or guardians and for assent by
children.

Subpart N—[Reserved]

Subpart E—[Reserved]
26.1125 ..............
26.1303 ..............
*
*

*

*

*

2070–0169
2070–0169
*
*

*

Subpart F—[Reserved]
*

Subpart G—[Reserved]
Subpart H—[Reserved]

*

Subpart I—[Reserved]

PART 26—[AMENDED]

Subpart J—[Reserved]

2. Part 26 is amended as follows:
a. By revising the authority citation for
part 26 to read as follows:

■
■

Authority: 5 U.S.C. 301; 7 U.S.C.
136w(a)(1); 21 U.S.C. 346a(e)(1)(C); section
201 of Public Law No. 109–54; and 42 U.S.C.
300v–1(b).

b. By redesignating §§ 26.101 through
26.124 as subpart A and adding a new
subpart heading to read as follows:

■

Subpart A—Basic EPA Policy for
Protection of Subjects in Human
Research Conducted or Supported by
EPA
c. By adding new subparts B through
Q as follows:

■

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Subpart B—Prohibition of Research
Conducted or Supported by EPA Involving
Intentional Exposure of Human Subjects
who are Pregnant Women or Children
Sec.
26.201 To what does this subpart apply?
26.202 Definitions.
26.203 Prohibition of research conducted or
supported by EPA involving intentional
exposure of any human subject who is a
pregnant woman (and therefore her
fetus) or child.
Subpart C—Observational Research:
Additional Protections for Pregnant Women
and Fetuses Involved as Subjects in
Observational Research Conducted or
Supported by EPA
26.301 To what does this subpart apply?
26.302 Definitions.
26.303 Duties of IRBs in connection with
observational research involving
pregnant women and fetuses.
26.304 Additional protections for pregnant
women and fetuses involved in
observational research.

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Subpart K—Basic Ethical Requirements for
Third-Party Human Research for Pesticides
Involving Intentional Exposure of Nonpregnant Adults
26.1101 To what does this subpart apply?
26.1102 Definitions.
26.1103—26.1106 [Reserved]
26.1107 IRB membership.
26.1108 IRB functions and operations.
26.1109 IRB review of research.
26.1110 Expedited review procedures for
certain kinds of research involving no
more than minimal risk, and for minor
changes in approved research.
26.1111 Criteria for IRB approval of
research.
26.1112 Review by institution.
26.1113 Suspension or termination of IRB
approval of research.
26.1114 Cooperative research.
26.1115 IRB records.
26.1116 General requirements for informed
consent.
26.1117 Documentation of informed
consent.
26.1118—26.1122 [Reserved]
26.1123 Early termination of research.
26.1124 [Reserved]
26.1125 Prior submission of proposed
human research for EPA review.
Subpart L—Prohibition of Third-Party
Research for Pesticides Involving
Intentional Exposure of Human Subjects
who are Pregnant Women or Children
26.1201 To what does this subpart apply?
26.1202 Definitions.
26.1203 Prohibition of research involving
intentional exposure of any pregnant
woman, fetus, or child.
Subpart M—Requirements for Submission
of Information on the Ethical Conduct of
Completed Human Research
26.1301 To what does this subpart apply?
26.1302 Definitions.

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Subpart O—Administrative Actions for
Noncompliance
26.1501 To what does this subpart apply?
26.1502 Lesser administrative actions.
26.1503 Disqualification of an IRB or an
institution.
26.1504 Public disclosure of information
regarding revocation.
26.1505 Reinstatement of an IRB or an
institution.
26.1506 Debarment.
26.1507 Actions alternative or additional to
disqualification.
Subpart P—Review of Proposed and
Completed Human Research
26.1601 EPA review of proposed human
research.
26.1602 EPA review of completed human
research.
26.1603 Operation of the Human Studies
Review Board.
Subpart Q—Ethical Standards for
Assessing Whether to Rely on the Results
of Human Research in EPA Actions
26.1701 To what does this subpart apply?
26.1702 Definitions.
26.1703 Prohibition of reliance on research
involving intentional exposure of human
subjects who are pregnant women (and
therefore their fetuses) or children.
26.1704 Prohibition of reliance on unethical
human research with non-pregnant
adults conducted before April 7, 2006.
26.1705 Prohibition of reliance on unethical
human research with non-pregnant
adults conducted after April 7, 2006.
26.1706 Criteria and procedure for
decisions to protect public health by
relying on otherwise unacceptable
research.

Subpart B—Prohibition of Research
Conducted or Supported by EPA
Involving Intentional Exposure of
Human Subjects who are Pregnant
Women or Children.
§ 26.201

To what does this subpart apply?

(a) This subpart applies to all research
involving intentional exposure of any
human subject who is a pregnant
woman (and her fetus) or a child
conducted or supported by the
Environmental Protection Agency
(EPA). This includes research
conducted in EPA facilities by any
person and research conducted in any
facility by EPA employees.
(b) The requirements of this subpart
are in addition to those imposed under
the other subparts of this part.
§ 26.202

Definitions.

The definitions in § 26.102 shall be
applicable to this subpart as well. In
addition, the definitions at 45 CFR

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46.202(a) through (f) and at 45 CFR
46.202(h) are applicable to this subpart.
(a) Research involving intentional
exposure of a human subject means 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.
(b) A child is a person who has not
attained the age of 18 years.
§ 26.203 Prohibition of research
conducted or supported by EPA involving
intentional exposure of any human subject
who is a pregnant woman (and therefore
her fetus) or child.

Notwithstanding any other provision
of this part, under no circumstances
shall EPA conduct or support research
involving intentional exposure of any
human subject who is a pregnant
woman (and therefore her fetus) or
child.
Subpart C—Observational Research:
Additional Protections for Pregnant
Women and Fetuses Involved as
Subjects in Observational Research
Conducted or Supported by EPA
§ 26.301

To what does this subpart apply?

(a) Except as provided in paragraph
(b) of this section, this subpart applies
to all observational research involving
human subjects who are pregnant
women (and therefore their fetuses)
conducted or supported by the
Environmental Protection Agency
(EPA). This includes research
conducted in EPA facilities by any
person and research conducted in any
facility by EPA employees.
(b) The exemptions at § 26.101(b)(1)
through (b)(6) are applicable to this
subpart.
(c) The provisions of § 26.101(c)
through (i) are applicable to this
subpart. References to State or local
laws in this subpart and in § 26.101(f)
are intended to include the laws of
federally recognized American Indian
and Alaska Native Tribal Governments.
(d) The requirements of this subpart
are in addition to those imposed under
the other subparts of this part.

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§ 26.302

Definitions.

The definitions in §§ 26.102 and
26.202 shall be applicable to this
subpart as well. In addition,
observational research means any
human research that does not meet the
definition of research involving
intentional exposure of a human subject
in § 26.202(a).

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§ 26.303 Duties of IRBs in connection with
observational research involving pregnant
women and fetuses.

The provisions of 45 CFR 46.203 are
applicable to this section.
§ 26.304 Additional protections for
pregnant women and fetuses involved in
observational research.

The provisions of 45 CFR 46.204 are
applicable to this section.
§ 26.305 Protections applicable, after
delivery, to the placenta, the dead fetus, or
fetal material.

The provisions of 45 CFR 46.206 are
applicable to this section.
Subpart D—Observational Research:
Additional Protections for Children
Involved as Subjects in Observational
Research Conducted or Supported by
EPA
§ 26.401

To what does this subpart apply?

(a) This subpart applies to all
observational research involving
children as subjects, conducted or
supported by EPA. References to State
or local laws in this subpart and in
§ 26.101(f) are intended to include the
laws of federally recognized American
Indian and Alaska Native Tribal
Governments. This includes research
conducted in EPA facilities by any
person and research conducted in any
facility by EPA employees.
(b) Exemptions at § 26.101(b)(1) and
(b)(3) through (b)(6) are applicable to
this subpart. The exemption at
§ 26.101(b)(2) regarding educational
tests is also applicable to this subpart.
However, the exemption at
§ 26.101(b)(2) for research involving
survey or interview procedures or
observations of public behavior does not
apply to research covered by this
subpart, except for research involving
observation of public behavior when the
investigator(s) do not participate in the
activities being observed.
(c) The exceptions, additions, and
provisions for waiver as they appear in
§ 26.101(c) through (i) are applicable to
this subpart.
§ 26.402

Definitions.

The definitions in § 26.102 shall be
applicable to this subpart as well. In
addition, the following terms are
defined:
(a) For purposes of this subpart,
Administrator means the Administrator
of the Environmental Protection Agency
and any other officer or employee of the
Environmental Protection Agency to
whom authority has been delegated by
the Administrator.
(b) Assent means a child’s affirmative
agreement to participate in research.

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6169

Mere failure to object should not, absent
affirmative agreement, be construed as
assent.
(c) Permission means the agreement of
parent(s) or guardian to the
participation of their child or ward in
research.
(d) Parent means a child’s biological
or adoptive parent.
(e) Guardian means an individual
who is authorized under applicable
State, Tribal, or local law to consent on
behalf of a child to general medical care.
(f) Observational research means any
research with human subjects that does
not meet the definition of research
involving intentional exposure of a
human subject in § 26.202(a).
(g) Minimal risk means that the
probability and magnitude of harm or
discomfort anticipated in the research
are not greater in and of themselves than
those ordinarily encountered in daily
life or during the performance of routine
physical or psychological examinations
or tests.
§ 26.403

IRB duties.

In addition to other responsibilities
assigned to IRBs under this part, each
IRB shall review observational research
covered by this subpart and approve
only research that satisfies the
conditions of all applicable sections of
this subpart.
§ 26.404 Observational research not
involving greater than minimal risk.

EPA will conduct or fund
observational research in which the IRB
finds that no greater than minimal risk
to children is presented, only if the IRB
finds that adequate provisions are made
for soliciting the assent of the children
and the permission of their parents or
guardians, as set forth in § 26.406.
§ 26.405 Observational research involving
greater than minimal risk but presenting the
prospect of direct benefit to the individual
subjects.

If the IRB finds that an intervention or
procedure presents more than minimal
risk to children, EPA will not conduct
or fund observational research that
includes such an intervention or
procedure unless the IRB finds and
documents that:
(a) The intervention or procedure
holds out the prospect of direct benefit
to the individual subject or is likely to
contribute to the subject’s well-being;
(b) The risk is justified by the
anticipated benefit to the subjects;
(c) The relation of the anticipated
benefit to the risk is at least as favorable
to the subjects as that presented by
available alternative approaches; and
(d) Adequate provisions are made for
soliciting the assent of the children and

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permission of their parents or guardians,
as set forth in § 26.406.

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§ 26.406 Requirements for permission by
parents or guardians and for assent by
children.

(a) In addition to the determinations
required under other applicable sections
of this subpart, the IRB shall determine
that adequate provisions are made for
soliciting the assent of the children,
when in the judgment of the IRB the
children are capable of providing assent.
In determining whether children are
capable of assenting, the IRB shall take
into account the ages, maturity, and
psychological state of the children
involved. This judgment may be made
for all children to be involved in
research under a particular protocol, or
for each child, as the IRB deems
appropriate. If the IRB determines that
the capability of some or all of the
children is so limited that they cannot
reasonably be consulted or that the
intervention or procedure involved in
the observational research holds out a
prospect of direct benefit that is
important to the health or well-being of
the children and is available only in the
context of the research, the assent of the
children is not a necessary condition for
proceeding with the observational
research. Even where the IRB
determines that the subjects are capable
of assenting, the IRB may still waive the
assent requirement under circumstances
in which consent may be waived in
accord with § 26.116(d).
(b) In addition to the determinations
required under other applicable sections
of this subpart, the IRB shall determine,
in accordance with and to the extent
that consent is required by § 26.116, that
adequate provisions are made for
soliciting the permission of each child’s
parents or guardian. Where parental
permission is to be obtained, the IRB
may find that the permission of one
parent is sufficient for research to be
conducted under § 26.404 or § 26.405.
(c) In addition to the provisions for
waiver contained in § 26.116, if the IRB
determines that a research protocol is
designed for conditions or for a subject
population for which parental or
guardian permission is not a reasonable
requirement to protect the subjects (for
example, neglected or abused children),
it may replace the consent requirements
in subpart A of this part and paragraph
(b) of this section with provided an
appropriate, equivalent mechanism for
protecting the children who will
participate as subjects in the research is
substituted, and provided further that
the waiver is not inconsistent with
Federal, State, or local law. The choice
of an appropriate, equivalent

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mechanism would depend upon the
nature and purpose of the activities
described in the protocol, the risk and
anticipated benefit to the research
subjects, and their age, maturity, status,
and condition.
(d) Permission by parents or
guardians shall be documented in
accordance with and to the extent
required by § 26.117.
(e) When the IRB determines that
assent is required, it shall also
determine whether and how assent must
be documented.
Subpart E—[Reserved]
Subpart F—[Reserved]
Subpart G—[Reserved]
Subpart H—[Reserved]
Subpart I—[Reserved]
Subpart J—[Reserved]
Subpart K—Basic Ethical
Requirements for Third-Party Human
Research for Pesticides Involving
Intentional Exposure of Non-pregnant
Adults
§ 26.1101
apply?

To what does this subpart

(a) Except as provided in paragraph
(b) of this section, subpart K of this part
applies to all research initiated after
April 7, 2006 involving intentional
exposure of a human subject if, at any
time prior to initiating such research,
any person who conducted or supported
such research intended:
(1) 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 (7
U.S.C. 136 et seq.) or section 408 of the
Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 346a); or
(2) To hold the results of the research
for later inspection by EPA under the
Federal Insecticide, Fungicide, and
Rodenticide Act (7 U.S.C. 136 et seq.) or
section 408 of the Federal Food, Drug,
and Cosmetic Act 21 U.S.C. 346a).
(b) Unless otherwise required by the
Administrator, research is exempt from
this subpart if it involves only the
collection or study of existing data,
documents, records, pathological
specimens, or diagnostic specimens
from previously conducted studies, and
if these sources are publicly available or
if the information is recorded by the
investigator in such a manner that
subjects cannot be identified, directly or

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through identifiers linked to the
subjects.
(c) The Administrator retains final
judgment as to whether a particular
activity within the scope of paragraphs
(a) and (b) of this section is covered by
this subpart.
(d) Compliance with this subpart
requires compliance with pertinent
Federal laws or regulations which
provide additional protections for
human subjects.
(e) This subpart does not affect any
State or local laws or regulations which
may otherwise be applicable and which
provide additional protections for
human subjects. Reference to State or
local laws in this subpart is intended to
include the laws of federally recognized
American Indian and Alaska Native
Tribal Governments.
(f) This subpart does not affect any
foreign laws or regulations which may
otherwise be applicable and which
provide additional protections to human
subjects of research.
(g) For purposes of determining a
person’s intent under paragraph (a) of
this section, EPA may consider any
available information relevant to
determining the intent of a person who
conducts or supports research with
human subjects after the effective date
of the rule. EPA shall rebuttably
presume such intent existed 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 under
FIFRA or the FFDCA and, at the time
the research was initiated, the results of
the research would be relevant to EPA’s
exercise of its authority under FIFRA or
the FFDCA with respect to that class of
people, products, or activities.
§ 26.1102

Definitions.

(a) For purposes of this subpart,
Administrator means the Administrator
of the Environmental Protection Agency
(EPA) and any other officer or employee
of EPA to whom authority has been
delegated.
(b) Institution means any public or
private entity or agency (including
Federal, State, and other agencies).
(c) Legally authorized representative
means an individual or judicial or other
body authorized under applicable law to
consent on behalf of a prospective
subject to the subject’s participation in
the procedure(s) involved in the
research.
(d) Research means a systematic
investigation, including research,
development, testing and evaluation,

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designed to develop or contribute to
generalizable knowledge. Activities
which meet this definition constitute
research for purposes of this subpart,
whether or not they are considered
research for other purposes. For
example, some demonstration and
service programs may include research
activities.
(e) Human subject means a living
individual about whom an investigator
(whether professional or student)
conducting research obtains:
(1) Data through intervention or
interaction with the individual, or
(2) Identifiable private information.
(3) ‘‘Intervention’’ includes both
physical procedures by which data are
gathered (for example, venipuncture)
and manipulations of the subject or the
subject’s environment that are
performed for research purposes.
Interaction includes communication or
interpersonal contact between
investigator and subject. ‘‘Private
information’’ includes information
about behavior that occurs in a context
in which an individual can reasonably
expect that no observation or recording
is taking place, and information which
has been provided for specific purposes
by an individual and which the
individual can reasonably expect will
not be made public (for example, a
medical record). Private information
must be individually identifiable (i.e.,
the identity of the subject is or may
readily be ascertained by the
investigator or associated with the
information) in order for obtaining the
information to constitute research
involving human subjects.
(f) IRB means an institutional review
board established in accord with and for
the purposes expressed in this part.
(g) IRB approval means the
determination of the IRB that the
research has been reviewed and may be
conducted at an institution within the
constraints set forth by the IRB and by
other institutional and Federal
requirements.
(h) Minimal risk means that the
probability and magnitude of harm or
discomfort anticipated in the research
are not greater in and of themselves than
those ordinarily encountered in daily
life or during the performance of routine
physical or psychological examinations
or tests.
(i) Research involving intentional
exposure of a human subject means 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.

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(j) Person means any person, as that
term is defined in FIFRA section 2(s) (7
U.S.C. 136), except:
(1) A federal agency that is subject to
the provisions of the Federal Policy for
the Protection of Human Subjects of
Research, and
(2) A person when performing human
research supported by a federal agency
covered by paragraph (j)(1) of this
section.

continuing review of any project in
which the member has a conflicting
interest, except to provide information
requested by the IRB.
(f) An IRB may, in its discretion,
invite individuals with competence in
special areas to assist in the review of
issues which require expertise beyond
or in addition to that available on the
IRB. These individuals may not vote
with the IRB.

§§ 26.1103 through 26.1106 [Reserved]

§ 26.1108

§ 26.1107

IRB membership.

(a) Each IRB shall have at least five
members, with varying backgrounds to
promote complete and adequate review
of research activities which are
presented for its approval. The IRB shall
be sufficiently qualified through the
experience and expertise of its
members, and the diversity of the
members, including consideration of
race, gender, and cultural backgrounds
and sensitivity to such issues as
community attitudes, to promote respect
for its advice and counsel in
safeguarding the rights and welfare of
human subjects. In addition to
possessing the professional competence
necessary to review specific research
activities, the IRB shall be able to
ascertain the acceptability of proposed
research in terms of institutional
commitments and regulations,
applicable law, and standards of
professional conduct and practice. The
IRB shall therefore include persons
knowledgeable in these areas. If an IRB
regularly reviews research that involves
a vulnerable category of subjects, such
as prisoners or handicapped or mentally
disabled persons, consideration shall be
given to the inclusion of one or more
individuals who are knowledgeable
about and experienced in working with
these subjects.
(b) Every nondiscriminatory effort
will be made to ensure that no IRB
consists entirely of men or entirely of
women, including the institution’s
consideration of qualified persons of
both sexes, so long as no selection is
made to the IRB on the basis of gender.
No IRB may consist entirely of members
of one profession.
(c) Each IRB shall include at least one
member whose primary concerns are in
scientific areas and at least one member
whose primary concerns are in
nonscientific areas.
(d) Each IRB shall include at least one
member who is not otherwise affiliated
with the institution and who is not part
of the immediate family of a person who
is affiliated with the institution.
(e) No IRB may have a member
participate in the IRB’s initial or

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IRB functions and operations.

In order to fulfill the requirements of
this subpart each IRB shall:
(a) Follow written procedures:
(1) For conducting its initial and
continuing review of research and for
reporting its findings and actions to the
investigator and the institution;
(2) For determining which projects
require review more often than annually
and which projects need verification
from sources other than the investigator
that no material changes have occurred
since previous IRB review;
(3) For ensuring prompt reporting to
the IRB of proposed changes in research
activity; and
(4) For ensuring that changes in
approved research, during the period for
which IRB approval has already been
given, may not be initiated without IRB
review and approval except where
necessary to eliminate apparent
immediate hazards to the human
subjects.
(b) Follow written procedures for
ensuring prompt reporting to the IRB,
appropriate institutional officials, and
the Environmental Protection Agency
of:
(1) Any unanticipated problems
involving risks to human subjects or
others;
(2) Any instance of serious or
continuing noncompliance with this
subpart of the requirements or
determinations of the IRB; or
(3) Any suspension or termination of
IRB approval.
(c) Except when an expedited review
procedure is used (see § 26.1110),
review proposed research at convened
meetings at which a majority of the
members of the IRB are present,
including at least one member whose
primary concerns are in nonscientific
areas. In order for the research to be
approved, it shall receive the approval
of a majority of those members present
at the meeting.
§ 26.1109

IRB review of research.

(a) An IRB shall review and have
authority to approve, require
modifications in (to secure approval), or
disapprove all research activities
covered by this subpart.

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(b) An IRB shall require that
information given to subjects as part of
informed consent is in accordance with
§ 26.1116. The IRB may require that
information, in addition to that
specifically mentioned in § 26.1116 be
given to the subjects when, in the IRB’s
judgment, the information would
meaningfully add to the protection of
the rights and welfare of subjects.
(c) An IRB shall require
documentation of informed consent in
accordance with § 26.1117.
(d) An IRB shall notify investigators
and the institution in writing of its
decision to approve or disapprove the
proposed research activity, or of
modifications required to secure IRB
approval of the research activity. If the
IRB decides to disapprove a research
activity, it shall include in its written
notification a statement of the reasons
for its decision and give the investigator
an opportunity to respond in person or
in writing.
(e) An IRB shall conduct continuing
review of research covered by this
subpart at intervals appropriate to the
degree of risk, but not less than once per
year, and shall have authority to observe
or have a third party observe the
consent process and the research.

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§ 26.1110 Expedited review procedures for
certain kinds of research involving no more
than minimal risk, and for minor changes in
approved research.

(a) The Secretary, HHS, has
established, and published as a Notice
in the Federal Register, a list of
categories of research that may be
reviewed by the IRB through an
expedited review procedure. The list
will be amended, as appropriate after
consultation with other departments
and agencies, through periodic
republication by the Secretary, HHS, in
the Federal Register. A copy of the list
is available from the Office for Human
Research Protections, HHS, or any
successor office.
(b)(1) An IRB may use the expedited
review procedure to review either or
both of the following:
(i) Some or all of the research
appearing on the list and found by the
reviewer(s) to involve no more than
minimal risk,
(ii) Minor changes in previously
approved research during the period (of
1 year or less) for which approval is
authorized.
(2) Under an expedited review
procedure, the review may be carried
out by the IRB chairperson or by one or
more experienced reviewers designated
by the chairperson from among
members of the IRB. In reviewing the
research, the reviewers may exercise all

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of the authorities of the IRB except that
the reviewers may not disapprove the
research. A research activity may be
disapproved only after review in
accordance with the non-expedited
procedure set forth in § 26.1108(b).
(c) Each IRB which uses an expedited
review procedure shall adopt a method
for keeping all members advised of
research proposals which have been
approved under the procedure.
(d) The Administrator may restrict,
suspend, or terminate, an institution’s
or IRB’s use of the expedited review
procedure for research covered by this
subpart.
§ 26.1111 Criteria for IRB approval of
research.

(a) In order to approve research
covered by this subpart the IRB shall
determine that all of the following
requirements are satisfied:
(1) Risks to subjects are minimized:
(i) By using procedures which are
consistent with sound research design
and which do not unnecessarily expose
subjects to risk, and
(ii) Whenever appropriate, by using
procedures already being performed on
the subjects for diagnostic or treatment
purposes.
(2) Risks to subjects are reasonable in
relation to anticipated benefits, if any, to
subjects, and the importance of the
knowledge that may reasonably be
expected to result. In evaluating risks
and benefits, the IRB should consider
only those risks and benefits that may
result from the research (as
distinguished from risks and benefits
subjects would receive even if not
participating in the research). The IRB
should not consider possible long-range
effects of applying knowledge gained in
the research (for example, the possible
effects of the research on public policy)
as among those research risks that fall
within the purview of its responsibility.
(3) Selection of subjects is equitable.
In making this assessment the IRB
should take into account the purposes of
the research and the setting in which
the research will be conducted and
should be particularly cognizant of the
special problems of research involving
vulnerable populations, such as
prisoners, mentally disabled persons, or
economically or educationally
disadvantaged persons.
(4) Informed consent will be sought
from each prospective subject or the
subject’s legally authorized
representative, in accordance with, and
to the extent required by § 26.1116.
(5) Informed consent will be
appropriately documented, in
accordance with, and to the extent
required by § 26.1117.

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(6) When appropriate, the research
plan makes adequate provision for
monitoring the data collected to ensure
the safety of subjects.
(7) When appropriate, there are
adequate provisions to protect the
privacy of subjects and to maintain the
confidentiality of data.
(b) When some or all of the subjects
are likely to be vulnerable to coercion or
undue influence, such as prisoners,
mentally disabled persons, or
economically or educationally
disadvantaged persons, additional
safeguards have been included in the
study to protect the rights and welfare
of these subjects.
§ 26.1112

Review by institution.

Research covered by this subpart that
has been approved by an IRB may be
subject to further appropriate review
and approval or disapproval by officials
of the institution. However, those
officials may not approve the research if
it has not been approved by an IRB.
§ 26.1113 Suspension or termination of
IRB approval of research.

An IRB shall have authority to
suspend or terminate approval of
research that is not being conducted in
accordance with the IRB’s requirements
or that has been associated with
unexpected serious harm to subjects.
Any suspension or termination of
approval shall include a statement of
the reasons for the IRB’s action and
shall be reported promptly to the
investigator, appropriate institutional
officials, and the Administrator of EPA.
§ 26.1114

Cooperative research.

In complying with this subpart,
sponsors, investigators, or institutions
involved in multi-institutional studies
may use joint review, reliance upon the
review of another qualified IRB, or
similar arrangements aimed at
avoidance of duplication of effort.
§ 26.1115

IRB records.

(a) An IRB shall prepare and maintain
adequate documentation of IRB
activities, including the following:
(1) Copies of all research proposals
reviewed, scientific evaluations, if any,
that accompany the proposals, approved
sample consent documents, progress
reports submitted by investigators, and
reports of injuries to subjects.
(2) Minutes of IRB meetings which
shall be in sufficient detail to show
attendance at the meetings; actions
taken by the IRB; the vote on these
actions including the number of
members voting for, against, and
abstaining; the basis for requiring
changes in or disapproving research;
and a written summary of the

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discussion of controverted issues and
their resolution.
(3) Records of continuing review
activities.
(4) Copies of all correspondence
between the IRB and the investigators.
(5) A list of IRB members identified
by name; earned degrees; representative
capacity; indications of experience such
as board certifications, licenses, etc.,
sufficient to describe each member’s
chief anticipated contributions to IRB
deliberations; and any employment or
other relationship between each
member and the institution, for
example, full-time employee, a member
of governing panel or board,
stockholder, paid or unpaid consultant.
(6) Written procedures for the IRB in
the same detail as described in
§ 26.1108(a) and § 26.1108(b).
(7) Statements of significant new
findings provided to subjects, as
required by § 26.1116(b)(5).
(b) The records required by this
subpart shall be retained for at least 3
years, and records relating to research
which is conducted shall be retained for
at least 3 years after completion of the
research. All records shall be accessible
for inspection and copying by
authorized representatives of EPA at
reasonable times and in a reasonable
manner.

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§ 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 or the subject’s
legally authorized representative. An
investigator shall seek such consent
only under circumstances that provide
the prospective subject or the
representative sufficient opportunity to
consider whether or not to participate
and that minimize the possibility of
coercion or undue influence. The
information that is given to the subject
or the representative shall be in
language understandable to the subject
or the representative. No informed
consent, whether oral or written, may
include any exculpatory language
through which the subject or the
representative 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.
(a) Basic elements of informed
consent. In seeking informed consent
the following information shall be
provided to each subject:
(1) A statement that the study
involves research, an explanation of the

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purposes of the research and the
expected duration of the subject’s
participation, a description of the
procedures to be followed, and
identification of any procedures which
are experimental;
(2) A description of any reasonably
foreseeable risks or discomforts to the
subject;
(3) A description of any benefits to the
subject or to others which may
reasonably be expected from the
research;
(4) A disclosure of appropriate
alternative procedures or courses of
treatment, if any, that might be
advantageous to the subject;
(5) A statement describing the extent,
if any, to which confidentiality of
records identifying the subject will be
maintained;
(6) For research involving more than
minimal risk, an explanation as to
whether any compensation and an
explanation as to whether any medical
treatments are available if injury occurs
and, if so, what they consist of, or where
further information may be obtained;
(7) An explanation of whom to
contact for answers to pertinent
questions about the research and
research subjects’ rights, and whom to
contact in the event of a research-related
injury to the subject; and
(8) A statement that participation is
voluntary, refusal to participate will
involve no penalty or loss of benefits to
which the subject is otherwise entitled,
and the subject may discontinue
participation at any time without
penalty or loss of benefits to which the
subject is otherwise entitled.
(b) Additional elements of informed
consent. When appropriate, one or more
of the following elements of information
shall also be provided to each subject:
(1) A statement that the particular
treatment or procedure may involve
risks to the subject (or to the embryo or
fetus, if the subject may become
pregnant) which are currently
unforeseeable;
(2) Anticipated circumstances under
which the subject’s participation may be
terminated by the investigator without
regard to the subject’s consent;
(3) Any additional costs to the subject
that may result from participation in the
research;
(4) The consequences of a subject’s
decision to withdraw from the research
and procedures for orderly termination
of participation by the subject;
(5) A statement that significant new
findings developed during the course of
the research which may relate to the
subject’s willingness to continue
participation will be provided to the
subject; and

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(6) The approximate number of
subjects involved in the study.
(c) The informed consent
requirements in this subpart are not
intended to preempt any applicable
Federal, State, or local laws which
require additional information to be
disclosed in order for informed consent
to be legally effective.
(d) Nothing in this subpart is intended
to limit the authority of a physician to
provide emergency medical care, to the
extent the physician is permitted to do
so under applicable Federal, State, or
local law.
(e) If the research involves intentional
exposure of subjects to a pesticide, the
subjects of the research must be
informed of the identity of the pesticide
and the nature of its pesticidal function.
§ 26.1117
consent.

Documentation of informed

(a) Informed consent shall be
documented by the use of a written
consent form approved by the IRB and
signed by the subject or the subject’s
legally authorized representative. A
copy shall be given to the person
signing the form.
(b) The consent form may be either of
the following:
(1) A written consent document that
embodies the elements of informed
consent required by § 26.1116. This
form may be read to the subject or the
subject’s legally authorized
representative, but in any event, the
investigator shall give either the subject
or the representative 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 § 26.1116
have been presented orally to the
subject or the subject’s legally
authorized representative. When this
method is used, there shall be a witness
to the oral presentation. Also, the IRB
shall approve a written summary of
what is to be said to the subject or the
representative. Only the short form itself
is to be signed by the subject or the
representative. However, the witness
shall sign both the short form and a
copy of the summary, and the person
actually obtaining consent shall sign a
copy of the summary. A copy of the
summary shall be given to the subject or
the representative, in addition to a copy
of the short form.
§§ 26.1118 through 26.1122 [Reserved]
§ 26.1123

Early termination of research.

The Administrator may require that
any project covered by this subpart be
terminated or suspended when the

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Administrator finds that an IRB,
investigator, sponsor, or institution has
materially failed to comply with the
terms of this subpart.
§ 26.1124 [Reserved]
§ 26.1125 Prior submission of proposed
human research for EPA review.

Any person or institution who intends
to conduct or sponsor human research
covered by § 26.1101(a) shall, after
receiving approval from all appropriate
IRBs, submit to EPA prior to initiating
such research all information relevant to
the proposed research specified by
§ 26.1115(a), and the following
additional information, to the extent not
already included:
(a) A discussion of:
(1) The potential risks to human
subjects;
(2) The measures proposed to
minimize risks to the human subjects;
(3) The nature and magnitude of all
expected benefits of such research, and
to whom they would accrue;
(4) Alternative means of obtaining
information comparable to what would
be collected through the proposed
research; and
(5) The balance of risks and benefits
of the proposed research.
(b) All information for subjects and
written informed consent agreements as
originally provided to the IRB, and as
approved by the IRB.
(c) Information about how subjects
will be recruited, including any
advertisements proposed to be used.
(d) A description of the circumstances
and methods proposed for presenting
information to potential human subjects
for the purpose of obtaining their
informed consent.
(e) All correspondence between the
IRB and the investigators or sponsors.
(f) Official notification to the sponsor
or investigator, in accordance with the
requirements of this subpart, that
research involving human subjects has
been reviewed and approved by an IRB.
Subpart L—Prohibition of Third-Party
Research for Pesticides Involving
Intentional Exposure of Human
Subjects who are Pregnant Women or
Children

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§ 26.1201
apply?

To what does this subpart

Subpart L applies to any person who,
after April 7, 2006, conducts or supports
research with a human subject intended:
(1) For submission to EPA for
consideration in connection with any
action that may be performed by EPA
under the Federal Insecticide,
Fungicide, and Rodenticide Act (7
U.S.C. 136 et seq.) or section 408 of the

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Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 346a); or
(2) To be held for later inspection by
EPA under the Federal Insecticide,
Fungicide, and Rodenticide Act (7
U.S.C. 136 et seq.) or section 408 of the
Federal Food, Drug, and Cosmetic Act
21 U.S.C. 346a).
(b) For purposes of determining a
person’s intent under paragraph (a) of
this section, EPA may consider any
available information relevant to
determining the intent of a person who
conducts or supports research with
human subjects after the effective date
of the rule. EPA shall rebuttably
presume such intent existed 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 under
FIFRA or the FFDCA and, at the time
the research was initiated, the results of
the research would be relevant to EPA’s
exercise of its authority under FIFRA or
the FFDCA with respect to that class of
people, products, or activities.
§ 26.1202

Definitions.

The definitions in § 26.1102 shall be
applicable to this subpart as well. In
addition, the definitions at 45 CFR
46.202(a) through (f) and at 45 CFR
46.202(h) are applicable to this subpart.
In addition, a child is a person who has
not attained the age of 18 years.
§ § 26.1203 Prohibition of research
involving intentional exposure of any
pregnant woman, fetus, or child.

Notwithstanding any other provision
of this part, under no circumstances
shall a person conduct or sponsor
research covered by § 26.1201 that
involves intentional exposure of any
human subject who is a pregnant
woman (and therefore her fetus) or
child.
Subpart M—Requirements for
Submission of Information on the
Ethical Conduct of Completed Human
Research
§ 26.1301
apply?

To what does this subpart

This subpart applies to any person
who submits a report containing the
results of any human research if:
(a) The report is submitted after April
7, 2006, and
(b) The report is submitted for
consideration in connection with any
action that may be performed by EPA
under the Federal Insecticide,
Fungicide, and Rodenticide Act (7
U.S.C. 136 et seq.) or section 408 of the

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Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 346a).
§ 26.1302

Definitions.

The definitions in § 26.102 shall
apply to this subpart as well.
§ 26.1303 Submission of information
pertaining to ethical conduct of completed
human research.

Any person who submits to EPA data
derived from human research covered
by this subpart shall provide at the time
of submission information concerning
the ethical conduct of such research. To
the extent available to the submitter and
not previously provided to EPA, such
information should include:
(a) Copies of all of the records
relevant to the research specified by
§ 26.1115(a) to be prepared and
maintained by an IRB.
(b) Copies of all of the records
relevant to the information identified in
§ 26.1125(a) through (f).
(c) Copies of sample records used to
document informed consent as specified
by § 26.1117, but not identifying any
subjects of the research.
(d) If any of the information listed in
paragraphs (a) through (c) of this section
is not provided, the person shall
describe the efforts made to obtain the
information.
Subpart N—[Reserved]
Subpart O—Administrative Actions for
Noncompliance
§ 26.1501
apply?

To what does this subpart

This subpart applies to any human
research subject to subparts A through
L of this part. References to State or
local laws in this subpart are intended
to include the laws of federally
recognized American Indian and Alaska
Native Tribal Governments.
§ 26.1502

Lesser administrative actions.

(a) If apparent noncompliance with
the applicable regulations in subparts A
through L of this part concerning the
operation of an IRB is observed by an
officer or employee of EPA or of any
State duly designated by the
Administrator during an inspection.
EPA may send a letter describing the
noncompliance to the IRB and to the
parent institution. The agency will
require that the IRB or the parent
institution respond to this letter within
a reasonable time period specified by
EPA and describe the corrective actions
that will be taken by the IRB, the
institution, or both to achieve
compliance with these regulations.
(b) On the basis of the IRB’s or the
institution’s response, EPA may

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schedule a reinspection to confirm the
adequacy of corrective actions. In
addition, until the IRB or the parent
institution takes appropriate corrective
action, the Agency may:
(1) Withhold approval of new studies
subject to the requirements of this part
that are conducted at the institution or
reviewed by the IRB;
(2) Direct that no new subjects be
added to ongoing studies subject to this
part;
(3) Terminate ongoing studies subject
to this part when doing so would not
endanger the subjects; or
(4) When the apparent noncompliance
creates a significant threat to the rights
and welfare of human subjects, notify
relevant State and Federal regulatory
agencies and other parties with a direct
interest of the deficiencies in the
operation of the IRB.
(c) The parent institution is presumed
to be responsible for the operation of an
IRB, and EPA will ordinarily direct any
administrative action under this subpart
against the institution. However,
depending on the evidence of
responsibility for deficiencies,
determined during the investigation,
EPA may restrict its administrative
actions to the IRB or to a component of
the parent institution determined to be
responsible for formal designation of the
IRB.

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§ 26.1503 Disqualification of an IRB or an
institution.

(a) Whenever the IRB or the
institution has failed to take adequate
steps to correct the noncompliance
stated in the letter sent by the Agency
under § 26.1502(a) and the EPA
Administrator determines that this
noncompliance may justify the
disqualification of the IRB or of the
parent institution, the Administrator
may institute appropriate proceedings.
(b) The Administrator may disqualify
an IRB or the parent institution from
studies subject to this part if the
Administrator determines that:
(1) The IRB has refused or repeatedly
failed to comply with any of the
regulations set forth in this part, and
(2) The noncompliance adversely
affects the rights or welfare of the
human subjects of research.
(c) If the Administrator determines
that disqualification is appropriate, the
Administrator will issue an order that
explains the basis for the determination
and that prescribes any actions to be
taken with regard to ongoing human
research, covered by subparts A through
L of this part, conducted under the
review of the IRB. EPA will send notice
of the disqualification to the IRB and the
parent institution. Other parties with a

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direct interest, such as sponsors and
investigators, may also be sent a notice
of the disqualification. In addition, the
agency may elect to publish a notice of
its action in the Federal Register.
(d) EPA may refuse to consider in
support of a regulatory decision the data
from human research, covered by
subparts A through L of this part, that
was reviewed by an IRB or conducted at
an institution during the period of
disqualification, unless the IRB or the
parent institution is reinstated as
provided in § 26.1505, or unless such
research is deemed scientifically sound
and crucial to the protection of public
health, under the procedure defined in
§ 26.1706.
§ 26.1504 Public disclosure of information
regarding revocation.

A determination that EPA has
disqualified an institution from studies
subject to this part and the
administrative record regarding that
determination are disclosable to the
public under 40 CFR part 2.
§ 26.1505 Reinstatement of an IRB or an
institution.

An IRB or an institution may be
reinstated to conduct studies subject to
this part if the Administrator
determines, upon an evaluation of a
written submission from the IRB or
institution that explains the corrective
action that the institution or IRB has
taken or plans to take, that the IRB or
institution has provided adequate
assurance that it will operate in
compliance with the standards set forth
in this part. Notification of
reinstatement shall be provided to all
persons notified under § 26.1502(c).
§ 26.1506

Debarment.

If EPA determines that an institution
or investigator repeatedly has not
complied with or has committed an
egregious violation of the applicable
regulations in subparts A through L of
this part, EPA may recommend that
institution or investigator be declared
ineligible to participate in EPAsupported research (debarment).
Debarment will be initiated in
accordance with procedures specified at
40 CFR part 32.
§ 26.1507 Actions alternative or additional
to disqualification.

Disqualification of an IRB or of an
institution is independent of, and
neither in lieu of nor a precondition to,
other statutorily authorized proceedings
or actions. EPA may, at any time, on its
own initiative or through the
Department of Justice, institute any
appropriate judicial proceedings (civil
or criminal) and any other appropriate

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regulatory action, in addition to or in
lieu of, and before, at the time of, or
after, disqualification. The Agency may
also refer pertinent matters to another
Federal, State, or local government
agency for any action that that agency
determines to be appropriate.
Subpart P—Review of Proposed and
Completed Human Research
§ 26.1601 EPA review of proposed human
research.

(a) EPA shall review all protocols
submitted under § 26.1125 in a timely
manner. With respect to any research or
any class of research, the Administrator
may recommend additional conditions
which, in the judgment of the
Administrator, are necessary for the
protection of human subjects.
(b) In reviewing proposals covered by
this subpart, the Administrator may take
into account factors such as whether the
applicant has been subject to a
termination or suspension under
§ 26.123(a) or § 26.1123 and whether the
applicant or the person or persons who
would direct or has/have directed the
scientific and technical aspects of an
activity has/have, in the judgment of the
Administrator, materially failed to
discharge responsibility for the
protection of the rights and welfare of
human subjects (whether or not the
research was subject to Federal
regulation).
(c) When research covered by subpart
K takes place in foreign countries,
procedures normally followed in the
foreign countries to protect human
subjects may differ from those set forth
in subpart K. (An example is a foreign
institution which complies with
guidelines consistent with the World
Medical Assembly Declaration of
Helsinki, issued either by sovereign
states or by an organization whose
function for the protection of human
research subjects is internationally
recognized.) In these circumstances, if
the Administrator determines that the
procedures prescribed by the institution
afford protections that are at least
equivalent to those provided in subpart
K, the Administrator may approve the
substitution of the foreign procedures in
lieu of the procedural requirements
provided in subpart K.
(d) Following initial evaluation of the
protocol by Agency staff, EPA shall
submit the protocol and all supporting
materials, together with the staff
evaluation, to the Human Studies
Review Board.
(e) EPA shall notify the submitter of
the proposal of the results of the EPA
and Human Studies Review Board
reviews.

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Federal Register / Vol. 71, No. 24 / Monday, February 6, 2006 / Rules and Regulations

§ 26.1602 EPA review of completed human
research.

(a) When considering data under
FIFRA or FFDCA from research
involving intentional exposure of
humans, EPA shall review the material
submitted under § 26.1303 and other
available, relevant information and
document its conclusions regarding the
scientific and ethical conduct of the
research.
(b) EPA shall submit its review of data
from human research covered by
subpart Q, together with the available
supporting materials, to the Human
Studies Review Board if EPA decides to
rely on the data and:
(1) The data are derived from research
initiated after April 7, 2006, or
(2) The data are derived from research
initiated before April 7, 2006, and the
research was conducted for the purpose
of identifying or measuring a toxic
effect.
(c) In its discretion, EPA may submit
data from research not covered by
paragraph (b) of this section to the
Human Studies Review Board for their
review.
(d) EPA shall notify the submitter of
the research of the results of the EPA
and Human Studies Review Board
reviews.
§ 26.1603 Operation of the Human Studies
Review Board.

rmajette on PROD1PC67 with RULES2

EPA shall establish and operate a
Human Studies Review Board as
follows:
(a) Membership. The Human Studies
Review Board shall consist of members
who are not employed by EPA, who
meet the ethics and other requirements
for special government employees, and
who have expertise in fields appropriate
for the scientific and ethical review of
human research, including research
ethics, biostatistics, and human
toxicology.
(b) Responsibilities. The Human
Studies Review Board shall comment on
the scientific and ethical aspects of
research proposals and reports of
completed research with human
subjects submitted by EPA for its review
and, on request, advise EPA on ways to

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strengthen its programs for protection of
human subjects of research.
Subpart Q—Ethical Standards for
Assessing Whether to Rely on the
Results of Human Research in EPA
Actions
§ 26.1701
apply?

To what does this subpart

This subpart applies to EPA’s
decisions whether to rely in its actions
taken under the Federal Insecticide,
Fungicide, and Rodenticide Act (7
U.S.C. 136 et seq.) or section 408 of the
Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 346a) on scientifically valid
and relevant data from research
involving intentional exposure of
human subjects.
§ 26.1702

Definitions.

The definitions in § 26.1102 and
§ 26.1202 shall apply to this subpart as
well.
§ 26.1703 Prohibition of reliance on
research involving intentional exposure of
human subjects who are pregnant women
(and therefore their fetuses) or children.

Except as provided in § 26.1706, in
actions within the scope of § 26.1701,
EPA shall not rely on data from any
research involving intentional exposure
of any human subject who is a pregnant
woman (and therefore her fetus) or
child.
§ 26.1704 Prohibition of reliance on
unethical human research with nonpregnant adults conducted before April 7,
2006.

Except as provided in § 26.1706, in
actions within the scope of § 26.1701,
EPA shall not rely on data from any
research initiated before April 7, 2006,
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. This prohibition is in
addition to the prohibition in § 26.1703.

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§ 26.1705 Prohibition of reliance on
unethical human research with nonpregnant adults conducted after April 7,
2006.

Except as provided in § 26.1706, in
actions within the scope of § 26.1701,
EPA shall not rely on data from any
research initiated after April 7, 2006,
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. This prohibition is in addition to
the prohibition in § 26.1703.
§ 26.1706 Criteria and procedure for
decisions to protect public health by relying
on otherwise unacceptable research.

This section establishes the exclusive
criteria and procedure by which EPA
may decide to rely on data from
research that is not acceptable under the
standards in §§ 26.1703 through
26.1705. EPA may rely on such data
only if all the conditions in paragraphs
(a) through (d) of this section are
satisfied:
(a) EPA has obtained the views of the
Human Studies Review Board
concerning the proposal to rely on the
otherwise unacceptable data,
(b) EPA has provided an opportunity
for public comment on the proposal to
rely on the otherwise unacceptable data,
(c) EPA has determined that relying
on the data is crucial to a decision that
would impose a more stringent
regulatory restriction that would
improve protection of public health,
such as a limitation on the use of a
pesticide, than could be justified
without relying on the data, and
(d) EPA publishes a full explanation
of its decision to rely on the otherwise
unacceptable data, including a thorough
discussion of the ethical deficiencies of
the underlying research and the full
rationale for finding that the standard in
paragraph (c) of this section was met.
[FR Doc. 06–1045 Filed 2–3–06; 8:45 am]
BILLING CODE 6560–50–S

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