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Protections for Subjects in Human Research
Protections for Subjects in Human Research
[Federal Register: February 6, 2006 (Volume 71, Number 24)]
[Rules and Regulations]
[Page 6137-6176]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr06fe06-7]
[[Page 6138]]
----------------------------------------------------------------------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
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AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
----------------------------------------------------------------------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., 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)
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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 non-pregnant 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
``second-party'' 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 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
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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 firstand 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).
[[Page 6139]]
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
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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
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 research with human subjects--has been conducted ethically.
B. The Role of Human Research in EPA Risk Assessments
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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 substances differently from animals, and 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.
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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
[[Page 6140]]
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 wrong-doer.
For example, if EPA based a regulatory decision on a human study that
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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,
and completed its report in September 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
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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 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 decision-making. 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
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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
[[Page 6141]]
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
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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 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
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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, intentionalexposure 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 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,
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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
[[Page 6142]]
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
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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 intentional-exposure research, on which the Agency intends to
rely in actions under the 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
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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,'' 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
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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
[[Page 6143]]
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
Sec. Sec.
Basic Policy for
A
Sec. Sec.
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26.201 thru
26.124
Protection of
Subjects in Human
Research Conducted
or Supported by
EPA
-------------------------------------------------------------------------B
Sec. Sec.
Prohibition of
B and D
26.201 thru
Human Subjects
26.203
Research Conducted
or Supported by
EPA Involving
Intentional
Exposure of
Pregnant Women,
Fetuses, or
Children
-------------------------------------------------------------------------B
Sec.
26.201
To what does this
n/a
subpart apply?
-------------------------------------------------------------------------B
Sec.
26.202(a)
Definition of
A
research involving
intentional
exposure of a
human subject
-------------------------------------------------------------------------B
Sec.
26.202(b)
Definition of child D
-------------------------------------------------------------------------B
Sec.
26.203
Prohibition of EPA
B and D
human subjects
research involving
intentional
exposure of
pregnant women,
fetuses, or
children
-------------------------------------------------------------------------C
Sec. Sec.
Additional
B
26.301 thru
Protections for
26.305
Pregnant Women or
Fetuses Involved
as Subjects in
Observational
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26.101 thru
26.124
Sec. Sec.
26.220 and 26.420
n/a
Sec.
26.102(k)
Sec.
26.402(a)
Sec. Sec.
26.220 and 26.420
Sec. Sec.
26.201 thru
26.206
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Research Conducted
or Supported by
EPA
-------------------------------------------------------------------------D
Sec. Sec.
Additional
D
Sec.
26.401 thru
26.401 thru
Protections for
26.408
26.406
Children Involved
as Subjects in
Observational
Research Conducted
or Supported by
EPA
----------------------------------------------------------------------------------------------------------------
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 --------------------------------------Subpart
Section
Subpart
Section
---------------------------------------------------------------------------------------------------------------K
Sec. Sec.
Basic Ethical
A
Sec. Sec.
26.1101 thru
Requirements for
26.101 thru
26.1125
Third-Party Human
26.124
Subjects Research
for Pesticides
Involving
Intentional
Exposure of NonPregnant Adults
-------------------------------------------------------------------------K
Sec.
26.1101(a)
To what does this
A
Sec.
26.101(j)
subpart apply?
-------------------------------------------------------------------------K
Sec.
26.1101(b)
Exemption of
A
Sec.
research involving
26.101(b)(4)
only the
collection or
study of existing
data . . .
-------------------------------------------------------------------------K
Sec.
26.1101(c)
Administrator
A
Sec.
26.101(c)
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retains final
judgment as to
whether a
particular
activity is
covered by this
subpart
-------------------------------------------------------------------------K
Sec.
26.1101(d), Relation to other
A
(e), and (f)
Federal, State,
Tribal, Local, or
foreign laws or
regulations
-------------------------------------------------------------------------K
Sec.
26.1101(g)
For purposes of
A
determining a
person's intent
under paragraph
(a) of this
section . . .
--------------------------------------------------------------------------
Sec.
26.101(e),
(f), and (g)
Sec.
26.101(k)
[[Page 6144]]
K
Sec. Sec.
Definitions
A
26.1102(a) thru
26.1102(h)
-------------------------------------------------------------------------K
Sec.
26.1102(i)
Definition of
A
research involving
intentional
exposure . . .
-------------------------------------------------------------------------K
Sec.
26.1102(j)
Definition of
n/a
person
-------------------------------------------------------------------------K
Sec. Sec.
IRB and informed
A
26.1107 thru
consent
26.1117
requirements
-------------------------------------------------------------------------K
Sec.
26.1123
Early termination
A
of research
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Sec. Sec.
26.102(a) thru
26.102(i)
Sec.
26.102(k)
n/a
Sec. Sec.
26.107 thru
26.117
Sec.
26.123(a)
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K
Sec.
26.1125
Prior submission to A
Sec.
26.124(b)
EPA of proposed
human research
-------------------------------------------------------------------------L
Sec. Sec.
1201
Prohibition of
B and D
Sec. Sec.
thru 26.1203
Third-Party Human
26.220 and 26.420
Subjects Research
for Pesticides
Involving
Intentional
Exposure of
Pregnant Women,
Fetuses, or
Children
-------------------------------------------------------------------------M
Sec. Sec.
1301
Requirements for
A
Sec.
26.124(c)
thru 26.1303
Submission of
Information on the
Ethical Conduct of
Completed Human
Research
----------------------------------------------------------------------------------------------------------------
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 --------------------------------------Subpart
Section
Subpart
Section
---------------------------------------------------------------------------------------------------------------O
Sec. Sec.
Administrative
E
Sec. Sec.
26.1501 thru
Actions for
26.501 thru
26.1503
Noncompliance
26.506
-------------------------------------------------------------------------P
Sec. Sec. 26.160 Review of Proposed
A
Sec.
26.124(b)
1 thru 26.1603
and Completed
Human Research
-------------------------------------------------------------------------P
Sec.
26.1601(c)
Determination of
A
Sec.
26.101(h)
Equivalence of
Foreign Ethical
Standards
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P
Sec.
26.1603
Operation of the
A
Human Studies
Review Board
-------------------------------------------------------------------------Q
Sec. Sec.
Ethical Standards
B, D, and F
26.1701 thru
for Assessing
26.1703
Whether to Rely on
the Results of
Human Subjects
Research in EPA
Actions
-------------------------------------------------------------------------Q
Sec. Sec.
Applicability and
n/a
26.1701 and
Definitions
26.1702
-------------------------------------------------------------------------Q
Sec.
26.1703
Prohibition of
B and D
reliance on
research involving
intentional
exposure of
pregnant women,
fetuses, or
children
-------------------------------------------------------------------------Q
Sec.
26.1704
Prohibition of
F
reliance on
unethical human
research conducted
before the
effective date of
the final rule
-------------------------------------------------------------------------Q
Sec.
26.1705
Prohibition of
F
reliance on
unethical human
research conducted
after the
effective date of
the final rule
-------------------------------------------------------------------------Q
Sec.
26.1706
Criteria and
F
procedures for
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Sec.
26.124(b)(5)
Sec. Sec.
26.221, 26.421,
26.601, 26.602,
and 26.603
n/a
Sec. Sec.
26.221 and 26.421
Sec.
26.601
Sec.
26.602
Sec.
26.603
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decisions to
protect public
health by relying
on otherwise
unacceptable
research
---------------------------------------------------------------------------------------------------------------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 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.
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
[[Page 6145]]
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
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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.
? 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.
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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 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 case-by-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'' (Sec. 26.101(a))
and to determine what is within its scope (Sec. 26.101(c) and (d)).
? Provision that only certain sections apply to third-party
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research subject to regulation (Sec. 26.101(a)(2)).
? A list of six kinds of human research exempted from
coverage by the rule (Sec. 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 (Sec. 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 (Sec. 26.101(i)).
? A grant of discretion to IRBs to waive or alter
requirements for informed consent (Sec. 26.116(c) and (d)) or
documentation of informed consent (Sec. 26.117(c)).
B. The Proposed Rule
The September 12 proposal to extend EPA's Common Rule to thirdparty research involved extending all the provisions of subpart A,
Sec. Sec. 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 Sec. 26.101(j)).
[[Page 6146]]
? A new paragraph defining how a party's intent to submit
research to EPA would be determined (proposed Sec. 26.101(k)).
? A new definition of research involving intentional
exposure of a human subject (proposed Sec. 26.102(k)).
? A new requirement for prior submission to EPA of proposals
for covered third-party research (proposed Sec. 26.124(b)).
? A new requirement for submission to EPA of documentation
of the ethical conduct of completed research (proposed Sec. 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
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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.
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 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 Sec. 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:
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[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 intentionalexposure 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 Sec. 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 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
Sec. 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
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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 third-party 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
[[Page 6147]]
system. The sections in subpart K are designated as Sec. Sec. 26.1101
through 26.1125 and correspond to the sections of the Common Rule
designated Sec. Sec. 26.1xx. For example, Sec. 26.1107 in subpart K
corresponds to Sec. 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 non-pregnant 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
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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 non-pregnant 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 involving
intentional exposure, the Agency did retain exception number 4 in
subpart K. See Sec. 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 Sec. 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
Sec. 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
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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 Sec. 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 Rule. While every other
federal Common Rule agency and department has such discretion, and
while such discretion seems appropriate for first- and 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 Sec. 26.101(i).
The definitions in the Common Rule include the term research
subject to regulation; see Sec. 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 Sec. 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 Sec. 26.1125 as one of the items that must be submitted to
EPA in connection with review of proposed research. See Sec.
26.1125(f) of the regulatory text.
EPA added a new definition of person in Sec. 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
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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--Sec. Sec. 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 thirdparty 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
non-pregnant adults. To be consistent with this scope, EPA removed from
subpart
[[Page 6148]]
K all references to pregnant women, fetuses, newborns, or children.
The first sentence of Sec. 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:
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
Sec. 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 Sec.
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 Sec.
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26.117(c) of the Common Rule, the Agency has deleted the crossreference in Sec. 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 Sec. 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, Sec. 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 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 Sec. 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 Sec.
26.1116(a)(1), which is derived from Sec. 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,
Sec. 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
Sec. 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
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Federal department of agency but is subject to regulation as defined in
Sec. 26.102(e).'' These sections include Sec. Sec. 26.107 through
26.117, but not Sec. 26.103 or Sec. Sec. 26.118 through 26.124.
Sections 26.118 through 26.124 generally apply to procedures associated
only with first-party and second-party research, but which would not be
relevant to third-party research. Consistent with the thrust of Sec.
26.101(a)(2) and in order to reduce confusion, EPA has not created
parallel sections for Sec. 26.103 or, with two exceptions, any of the
sections after Sec. 26.117.
The first of these exceptions is to include in subparts K and P of
the final rule two passages parallel to Sec. 26.123 of the Common
Rule. Section 26.1123, which corresponds to Sec. 26.123(a) in subpart
A, authorizes the Administrator 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 Sec. 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 Sec. 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
Sec. 26.1601, parallel to Sec. 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 Sec. 26.125, which would have required
third parties to submit proposals for new human research for EPA
review, to Sec. 26.1125 of subpart K. In addition, EPA has revised
this section in the final rule in two ways. A new Sec. 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 Sec.
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
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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.
[[Page 6149]]
A. The Proposed Rule
The September 12 proposal contained, in Sec. 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--Sec. 26.220 in subpart B and
Sec. 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.
B. Public Comments
Almost without exception, comments on the prohibitions contained in
the proposed rule drew no distinction between third-party research and
first- and 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
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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 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 Sec. 26.111(b) and Sec. 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 third-party 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
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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 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 third-party research
generally would fall outside the scope of the prohibitions because they
would not meet the ``intent to submit'' criterion in Sec. 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 ``product-in-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 Sec. Sec.
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 Sec. 26.401(a)(1) permitted EPA to waive the prohibition when
research was conducted outside the United States; (2) proposed Sec.
26.401(a)(2) permitted EPA to waive any provision of proposed subpart
D, including the prohibition; and (3) proposed Sec. 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 Sec. 26.420 stated
``Notwithstanding any other provision of this part, under no
circumstances shall EPA or a person when covered by Sec. 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 Sec. 26.420 override all
other provisions of the entire regulation, including Sec. Sec. 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 departure from the ban in proposed Sec. 26.420.
Nonetheless, in order to remove any doubt about the scope of the
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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 Sec. Sec. 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, 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
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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
[[Page 6151]]
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.
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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 Sec. 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 Sec. 26.202 cross referenced several paragraphs
of 45 CFR 46.202 defining such terms as delivery, fetus, neonate, and
pregnancy.
? Proposed Sec. 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 Sec. 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 Sec. 26.111) before approving
proposed research with pregnant women or fetuses. (Because of the
prohibition in proposed Sec. 26.220, the provisions in proposed
Sec. Sec. 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 Sec. 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 Sec. 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.
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
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subpart D of the HHS rule, 45 CFR part 46, specifically:
? In proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 26.111), which involves ``no more than minimal risk''
only if there are adequate procedures, as specified in Sec. 26.408,
for soliciting the assent of the children and the permission of their
parents or guardians. (Because of the prohibition in proposed Sec.
26.420, the provisions in proposed Sec. Sec. 26.404, 26.405, and
26.408 would have applied only to EPA's observational research.)
? Proposed Sec. 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 Sec. 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 Sec. 26.408, for soliciting the assent of the children
and the permission of their parents or guardians.
? Proposed Sec. 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
Sec. 26.116(d)). This proposed section also granted to IRBs discretion
to determine that, in some cases, it would not be reasonable to require
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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
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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.)
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 Sec. 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
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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 Sec. 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-standard measurement techniques, EPA has adopted in Sec. 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.
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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
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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 Sec. 26.220, and removal to subpart Q of the
restriction on EPA reliance on completed research proposed at Sec.
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 Sec. 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 Sec. 26.302 as research that does
not involve intentional exposure of research subjects. In addition, EPA
has deleted from the final rule proposed Sec. 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 Sec. 26.420, and the removal to subpart Q of the
restriction on EPA reliance on completed research proposed at Sec.
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 Sec. 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 Sec. 26.402(a) and (f), EPA added definitions of
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Administrator and observational research.
? In Sec. 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 Sec. 26.405, EPA reordered the text to make its
applicability clearer. The revision was not intended to make a
substantive change.
? In Sec. 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.
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
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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., Sec. Sec. 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
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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.
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, Sec. 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
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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 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
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if it has previously been provided to the Agency, for example as part
of the submission required for protocol review under Sec. 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, Sec. 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.
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 Sec. Sec.
26.501 through 26.504 and Sec. 26.506 closely follow FDA's existing
regulations in 21 CFR 56.120 through 56.124.
B. Public Comment
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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. 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 Sec. 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
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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 Sec. 26.1502 of the final rule to reflect FIFRA terminology
and enforcement practices.
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 Sec.
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
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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
[[Page 6156]]
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 Sec. 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
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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.
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 Research Protections (OHRP) for the kinds
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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
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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 Sec. 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 expertise: Bioethics, human toxicology, 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.
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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 (Sec. 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 community-based 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 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
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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-in-use'' 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
[[Page 6158]]
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 caseby-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.
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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 Decision
(RED) documents and Interim 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
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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.
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 (Sec. 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 (Sec. 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.
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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, Sec. 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 intentionaldosing research with human subjects. For covered research initiated
after the effective date of the rule, EPA
[[Page 6159]]
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.
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? 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 involving intentional exposure of 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
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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. 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
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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.
[[Page 6160]]
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 decision-makers 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 cost-efficient 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
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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 the effective data
of this rule in terms of 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 caseby-case 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, Sec. 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
scientifically sound and ethical conduct of different types of human
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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 Sec. 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
[[Page 6161]]
ethical norms when it was conducted should not be set aside because
ethical standards have subsequently changed. EPA also believes that
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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
Sec. 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 provision codified as Sec.
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
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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
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 Sec. 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
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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.
[[Page 6162]]
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 decisionmakers 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
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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, Sec. 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 ``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
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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 Sec. 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.
Section 26.1703 prohibits EPA's reliance on data from research
involving intentional exposures of pregnant women, fetuses, or
children. Derived from proposed Sec. Sec. 26.221 and 26.421, this
section states:
Except as provided in Sec. 26.1706, in actions within the scope
of Sec. 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 Sec. 26.1706. To clarify that this
prohibition applies to EPA's non-regulatory 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 decisionmaking'' in the proposal to ``actions'' in the final rule.
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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 Sec. 26.1706, in actions within the scope
of Sec. 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 Sec. 26.1703.
The above rule text is derived from proposed Sec. 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 Sec. 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 subjects research
conducted with non-pregnant adults after the effective date
[[Page 6163]]
of the rule. It provides that the Agency will not rely on data from
such research:
Except as provided in Sec. 26.1706, in actions within the scope
of Sec. 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 Sec. 26.1703.
This rule text is based on proposed Sec. 26.602. It has been
revised to make clear that EPA may accept and rely on data from human
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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 Sec. 26.101(h). Like Sec. 26.1704, Sec. 26.1705 reaffirms,
for the sake of clarity, that the prohibition in Sec. 26.1703 against
relying on research involving pregnant women and children is unaffected
by this provision.
Finally Sec. 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 Sec. 26.1703, Sec. 26.1704,
or Sec. 26.1705, and the procedures EPA must follow in reaching that
decision, 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.
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 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
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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:
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.
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 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.
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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 third-party 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
[[Page 6164]]
human subjects research related to Agency actions under FIFRA and
FFDCA. Therefore, EPA believes that interpreting the phrase ``thirdparty 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.
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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, Sec.
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, Sec. 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:
[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
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
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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]
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
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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 second-party 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
[[Page 6165]]
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.
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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 research
that is covered by subparts K or L or by Sec. 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.
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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. 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
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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.
[[Page 6166]]
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.
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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 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
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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, 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
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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
[[Page 6167]]
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
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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.
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 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.
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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 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
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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,
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2, 300j-3, 300j-4, 300j-9, 1857 et seq.,
[[Page 6168]]
6901-6992k, 7401-7671q, 7542, 9601-9657, 11023, 11048.
? b. In Sec. 9.1 the table is amended by adding the following new
entries under the new heading ``Protection of Human Subjects'' to read
as follows:
Sec.
9.1
OMB approvals under the Paperwork Reduction Act.
* * * * *
-----------------------------------------------------------------------40 CFR citation
OMB Control No.
-----------------------------------------------------------------------* * * * *
-----------------------------------------------------------------------Protection of Human Subjects
-----------------------------------------------------------------------26.1125.................................. 2070-0169
26.1303.................................. 2070-0169
* * * * *
-----------------------------------------------------------------------* * * * *
PART 26--[AMENDED]
? 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 Sec. Sec. 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
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? c. By adding new subparts B through Q as follows:
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.
26.305 Protections applicable, after delivery, to the placenta, the
dead fetus, or fetal material.
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 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 To what does this subpart apply?
26.1102 Definitions.
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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.
26.1303 Submission of information pertaining to ethical conduct of
completed human research.
Subpart N--[Reserved]
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.
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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.
Sec.
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.
Sec.
26.202
Definitions.
The definitions in Sec. 26.102 shall be applicable to this
subpart as well. In addition, the definitions at 45 CFR
[[Page 6169]]
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.
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Sec. 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
circumstances shall EPA
intentional exposure of
therefore her fetus) or
other provision of this part, under no
conduct or support research involving
any human subject who is a pregnant woman (and
child.
Subpart C--Observational Research: Additional Protections for
Pregnant Women and Fetuses Involved as Subjects in Observational
Research Conducted or Supported by EPA
Sec.
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 Sec. 26.101(b)(1) through (b)(6) are
applicable to this subpart.
(c) The provisions of Sec. 26.101(c) through (i) are applicable to
this subpart. References to State or local laws in this subpart and in
Sec. 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.
Sec.
26.302
Definitions.
The definitions in Sec. Sec. 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 Sec. 26.202(a).
Sec. 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.
Sec.
26.304
Additional protections for pregnant women and fetuses
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involved in observational research.
The provisions of 45 CFR 46.204 are applicable to this section.
Sec. 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
Sec.
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 Sec. 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 Sec. 26.101(b)(1) and (b)(3) through (b)(6) are
applicable to this subpart. The exemption at Sec. 26.101(b)(2)
regarding educational tests is also applicable to this subpart.
However, the exemption at Sec. 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 Sec. 26.101(c) through (i) are applicable to this subpart.
Sec.
26.402
Definitions.
The definitions in Sec. 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. Mere failure to object should not, absent affirmative
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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 Sec. 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.
Sec.
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.
Sec. 26.404
minimal risk.
Observational research not involving greater than
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 Sec. 26.406.
Sec. 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
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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
[[Page 6170]]
permission of their parents or guardians, as set forth in Sec.
26.406.
Sec. 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 Sec. 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 Sec.
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 Sec. 26.404 or Sec. 26.405.
(c) In addition to the provisions for waiver contained in Sec.
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
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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 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 Sec. 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
Sec.
26.1101
To what does this subpart apply?
(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.
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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 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.
Sec.
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
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(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,
[[Page 6171]]
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
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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.
(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.
Sec. Sec.
Sec.
26.1103 through 26.1106 [Reserved]
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
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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
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.
Sec.
26.1108
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 Sec.
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.
Sec.
26.1109
IRB review of research.
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(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.
[[Page 6172]]
(b) An IRB shall require that information given to subjects as part
of informed consent is in accordance with Sec. 26.1116. The IRB may
require that information, in addition to that specifically mentioned in
Sec. 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 Sec. 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.
Sec. 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,
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(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 of the
authorities of the IRB except that the reviewers may not disapprove the
research. A research activity may be disapproved only after review in
accordance with the non-expedited procedure set forth in Sec. 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.
Sec.
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,
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and to the extent required by Sec. 26.1116.
(5) Informed consent will be appropriately documented, in
accordance with, and to the extent required by Sec. 26.1117.
(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.
Sec.
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.
Sec.
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.
Sec.
26.1114
Cooperative research.
In complying with
institutions involved
review, reliance upon
arrangements aimed at
Sec.
26.1115
this subpart, sponsors, investigators, or
in multi-institutional studies may use joint
the review of another qualified IRB, or similar
avoidance of duplication of effort.
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
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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
[[Page 6173]]
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 Sec. 26.1108(a) and Sec. 26.1108(b).
(7) Statements of significant new findings provided to subjects, as
required by Sec. 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.
Sec.
26.1116
General requirements for informed consent.
No investigator may involve a human being as a subject in research
covered by this subpart unless the investigator has obtained the
legally effective informed consent of the subject 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
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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 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
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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
(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.
Sec.
26.1117
Documentation of informed consent.
(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 Sec. 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 Sec. 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.
Sec. Sec.
26.1118 through 26.1122 [Reserved]
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Sec.
26.1123
Early termination of research.
The Administrator may require that any project covered by this
subpart be terminated or suspended when the
[[Page 6174]]
Administrator finds that an IRB, investigator, sponsor, or institution
has materially failed to comply with the terms of this subpart.
Sec.
26.1124 [Reserved]
Sec.
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 Sec. 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
Sec. 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
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Women or Children
Sec.
26.1201
To what does this subpart apply?
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 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.
Sec.
26.1202
Definitions.
The definitions in Sec. 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.
Sec. Sec. 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
Sec. 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
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Ethical Conduct of Completed Human Research
Sec.
26.1301
To what does this subpart apply?
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 Federal Food, Drug, and Cosmetic Act (21 U.S.C. 346a).
Sec.
26.1302
Definitions.
The definitions in Sec.
26.102 shall apply to this subpart as well.
Sec. 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 Sec. 26.1115(a) to be prepared and maintained by an IRB.
(b) Copies of all of the records relevant to the information
identified in Sec. 26.1125(a) through (f).
(c) Copies of sample records used to document informed consent as
specified by Sec. 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
Sec.
26.1501
To what does this subpart apply?
This subpart applies to any human research subject to subparts A
through L of this part. References to State or local laws in this
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subpart are intended to include the laws of federally recognized
American Indian and Alaska Native Tribal Governments.
Sec.
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
[[Page 6175]]
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.
Sec.
26.1503
Disqualification of an IRB or an institution.
(a) Whenever the IRB or the institution has failed to take adequate
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steps to correct the noncompliance stated in the letter sent by the
Agency under Sec. 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 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 Sec. 26.1505, or unless such
research is deemed scientifically sound and crucial to the protection
of public health, under the procedure defined in Sec. 26.1706.
Sec.
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.
Sec.
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
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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 Sec. 26.1502(c).
Sec.
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 EPA-supported research (debarment). Debarment will be
initiated in accordance with procedures specified at 40 CFR part 32.
Sec.
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 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
Sec.
26.1601
EPA review of proposed human research.
(a) EPA shall review all protocols submitted under Sec. 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 Sec.
26.123(a) or Sec. 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).
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(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.
[[Page 6176]]
Sec.
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 Sec. 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.
Sec.
26.1603
Operation of the Human Studies Review Board.
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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 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
Sec.
26.1701
To what does this subpart apply?
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.
Sec.
26.1702
Definitions.
The definitions in Sec.
this subpart as well.
26.1102 and Sec.
26.1202 shall apply to
Sec. 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 Sec. 26.1706, in actions within the scope of
Sec. 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.
Sec. 26.1704 Prohibition of reliance on unethical human research with
non-pregnant adults conducted before April 7, 2006.
Except as provided in Sec. 26.1706, in actions within the scope of
Sec. 26.1701, EPA shall not rely on data from any research initiated
before April 7, 2006, if there is clear and convincing evidence that
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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 Sec.
26.1703.
Sec. 26.1705 Prohibition of reliance on unethical human research with
non-pregnant adults conducted after April 7, 2006.
Except as provided in Sec. 26.1706, in actions within the scope of
Sec. 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 Sec.
26.1703.
Sec. 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 Sec. Sec. 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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