[Federal Register Volume 71, Number 24 (Monday, February 6, 2006)]
[Rules and Regulations]
[Pages 6138-6176]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-1045]



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Part II





Environmental Protection Agency





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40 CFR Parts 9 and 26



Protections for Subjects in Human Research; Final Rule

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

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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

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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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) 
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

    EPA is promulgating this final rule to effectuate the express 
mandate of the United States Congress as set forth in section 201 of 
the Department of the Interior, Environment, and Related Agencies 
Appropriations Act, 2006, Public Law No. 109-54 (Appropriations Act), 
which provides appropriated funds for EPA and other federal departments 
and agencies. In addition, today's final rule is authorized under 
provisions of the following statutes that EPA administers: Section 3(a) 
of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), 
which authorizes the Administrator to regulate the distribution, sale, 
or use of any unregistered pesticide in any State ``[t]o the extent 
necessary to prevent unreasonable adverse effects on the environment'' 
(defined at FIFRA section 2(bb), in pertinent part, as ``any 
unreasonable risk to man or the environment, taking into account the 
economic, social, and environmental costs and benefits of the use of 
any pesticide''); section 25(a) of FIFRA, which authorizes the 
Administrator to ``prescribe regulations to carry out the purposes of 
[FIFRA],'' and section 408(e)(1)(C) of the Federal Food, Drug, and 
Cosmetic Act (FFDCA), which authorizes the Administrator to issue a 
regulation establishing ``general procedures and requirements to 
implement [Section 408].'' In addition, EPA's expansion of its human 
subject protection regulations to include additional subparts 
supplementing EPA's codification of the Common Rule regarding first- 
and second-party research are authorized pursuant to 5 U.S.C. 301 and 
42 U.S.C. 300v-1(b).

C. Does this Action Apply to Me?

    You may be potentially affected by this action if you conduct human 
research on substances regulated by EPA. Potentially affected entities 
may include, but are not limited to, entities that conduct or sponsor 
research involving intentional exposure of human subjects that may be 
submitted to EPA under FIFRA or FFDCA. Although EPA has in the past 
received such third-party research from pesticide registrants, other 
entities could submit such information to EPA.
     Pesticide and other Agricultural Chemical Manufacturing 
(NAICS code 325320).

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    This listing is not intended to be exhaustive, but rather provides 
a guide regarding entities likely to be affected by this action. Other 
types of entities not listed in this unit could also be affected. The 
North American Industrial Classification System (NAICS) code has been 
provided to assist you and others in determining whether this action 
might apply to certain entities. To determine whether you or your 
business may be affected by this action, you should carefully examine 
the applicability provisions of 40 CFR part 26. If you have any 
questions regarding the applicability of this action to a particular 
entity, consult the person listed under FOR FURTHER INFORMATION 
CONTACT.

D. How Can I Access Electronic Copies of this Document and Other 
Related Information?

    You may access an electronic copy of this Federal Register document 
and the associated electronic docket at http://www.regulations.gov, or 
you may access this Federal Register document electronically through 
the EPA Internet under the ``Federal Register'' listings at http://www.epa.gov/fedrgstr/. A frequently updated electronic version of the 
Code of Federal Regulations (CFR) is available at http://www.gpoaccess.gov/ecfr/ .

II. Background

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

    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.
    Animal data alone can sometimes provide an incomplete or misleading 
picture of a substance's safety or risks. Sometimes human research 
shows people to be more susceptible than animals to the effects of a 
chemical, and supports regulatory measures more protective than could 
be justified by animal data alone. This has been the case, for example, 
for arsenic, certain air pollutants, and the pesticide ingredients 
methyl isothiocyanate (MITC) and hexavalent chromium. Even when human 
research does not show people to be more sensitive than animals, 
scientifically sound human data developed under strict ethical 
standards can strengthen the basis for EPA regulatory actions.

C. Societal Concern over the Ethics of Human Research

    Scientific experimentation with human beings has always been 
controversial. The history of human research contains well-known 
examples of unethical behavior in the name of science, which have led 
to reforms in the way the government and others carry out and oversee 
human research. Through these reforms, the standards for ethical human 
research have evolved to become progressively more stringent and 
protective of the subjects of the research. In the United States the 
``Common Rule,'' a regulation followed by EPA and 17 federal 
departments and agencies, contains a widely accepted set of standards 
for conducting ethical research with human subjects, together with a 
set of procedures designed to ensure that the standards are met. See 
Unit V.
    For several years EPA has been at the center of an intense debate 
about the acceptability of intentional dosing human toxicity studies 
for pesticides, and about what to do with human studies that are 
ethically deficient. In this debate some have argued that all research 
involving intentional exposure of human subjects to pesticides is 
fundamentally unethical and should never be conducted or accepted. 
Others, while acknowledging the possibility of

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ethical human research with pesticides, have argued that EPA should 
simply refuse to consider data from ethically problematic research in 
its regulatory decisions. Those who hold this view interpret Agency 
reliance on an ethically flawed study as an endorsement of the 
investigators' behavior, and as encouragement to others to engage in 
similarly unethical research. Some also argue that EPA's reliance on 
ethically deficient human data could directly benefit the wrong-doer. 
For example, if EPA based a regulatory decision on a human study that 
shows humans to be less sensitive than animals, the result might be a 
less stringent regulatory measure, advantageous to the company that 
conducted the study. If the key study was unethical, the company could 
benefit from its own misconduct.
    On the other hand, human research has contributed enormously to 
scientific understanding of the risks posed by many substances in the 
environment, and to some of EPA's past regulatory actions. With this in 
mind, others argue that the Agency should consider all relevant and 
scientifically sound information--not excluding ethically deficient 
human data--because to do so will lead to better decisions, based on 
assessments that better reflect actual risks. Holders of this view 
argue that the ethical deficiencies of the research are the 
responsibility of the researchers, not of EPA. They further argue that 
EPA can do no additional harm to the subjects of the research by 
relying on scientifically valid and relevant data from an ethically 
deficient study, whereas EPA's refusal to rely on such data could do 
nothing to benefit the subjects of the research. Moreover, they assert 
that while the Agency cannot undo what has already happened, EPA can 
clearly express its disapproval of past unethical conduct. Holders of 
this view also stress the importance of strengthening protections for 
volunteers who participate in future studies, while taking advantage of 
all that past research can offer to benefit society.

D. EPA's Solicitation of Expert Advice

    In response to public concerns over human research with pesticides, 
EPA convened an advisory committee under the joint auspices of the EPA 
Science Advisory Board (SAB) and the FIFRA Scientific Advisory Panel 
(SAP) to address issues of the scientific and ethical acceptability of 
such research. This committee, known as the Data from Testing of Human 
Subjects Subcommittee (DTHSS), met in December 1998 and November 1999, 
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 
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 
Agency must decide what standard to apply to assess the ethical 
acceptability of research performed before the new rule takes effect. 
The choices are: To apply today's standards of ethical conduct to 
research performed in the past, or to judge past research against the 
ethical norms prevailing when it was conducted.
    Codes of ethical research conduct regulate the behavior of 
investigators before and during the research. It is reasonable to 
expect investigators to follow ethical codes that prevail when they do 
their work; but EPA believes it is unreasonable to expect them to 
anticipate and follow standards that may be developed after their work 
is done. EPA believes that scientifically meritorious research that 
adhered to accepted high ethical standards when it was conducted should 
not be set aside because ethical standards have subsequently changed. 
EPA also believes that ethical standards are likely to continue to 
change in the future and that if and when they do, such a change should 
not invalidate or make unacceptable otherwise meritorious research 
conducted now, in conformity with high ethical standards of today. 
Other parts of the U.S. government, and other countries, have arrived 
at a similar position.
    In the final rule, EPA has implemented the applicable 
recommendation of the NAS, and will accept scientificatiated before the 
rule becomes effective unless there is clear and convincing evidence 
that it was fundamentally unethical or significantly deficient with 
respect to the ethical standards prevailing when the research was 
conducted.
    The second salient issue concerns whether it is ever justified to 
rely on a

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

III. EPA's Proposed Human Studies Rulemaking and General Public 
Comments

    Summary: This unit reviews the general public comments on EPA's 
proposed rulemaking. The detailed comments are addressed in subsequent 
units of this preamble.
    An extensive review of the historical development of ethical 
standards for the conduct of human research and the events leading up 
to the promulgation of this final rule appeared in the preamble to the 
proposed rule, available in the public docket for this action.
    Today's final rule is the first to emerge from the process which 
began with publication of an Advance Notice of Proposed Rulemaking in 
the Federal Register on May 7, 2003 (68 FR 24410) (FRL-7302-8). On 
February 8, 2005 (70 FR 6661) (FRL-7695-4), EPA published and invited 
public comment on a Federal Register notice announcing its plan to 
establish a comprehensive framework for deciding whether to consider or 
rely on certain types of research with human subjects.
    On September 12, 2005 (70 FR 53838) (FRL-7728-2), EPA published in 
the Federal Register a notice of proposed rulemaking to strengthen the 
protections for people who participate as subjects in human research. 
The Agency proposed to ban intentional dosing human testing for 
pesticides when the subjects are pregnant women or children, to 
formalize and further strengthen existing protections for subjects in 
human research conducted or supported by EPA, and to extend new 
protections to adult subjects in human research for pesticides, 
involving intentional exposure of human subjects and conducted by 
others who intend to submit the research to EPA. The proposal also 
contained provisions to establish an independent Human Studies Review 
Board responsible for reviewing proposals to conduct new, intentional-
exposure human research under the pesticide laws and EPA decisions to 
rely on the results of certain types of completed human research in its 
actions under the pesticides laws.
    EPA received approximately 50,000 comments during the 90-day public 
comment period. The vast majority of the comments were submitted by 
private individuals as part of e-mail and letter-writing campaigns. The 
remaining unique comments came from individuals and organizations 
representing a range of stakeholders including pesticide companies, 
farm groups and other pesticide users, and environmental and public 
health advocacy groups. EPA has reviewed, summarized, and responded to 
these comments in the Response to Comments document available in the 
docket for this rule. In addition, this unit summarizes the major 
themes raised by the comments on the proposal, and explains how EPA has 
addressed them in the final rule.
    Comment: All human research with pesticides is fundamentally 
unethical.
    Response: EPA agrees with the advice it has received, as discussed 
in Unit II., from its advisory committees. The SAB/SAP Data from 
Testing of Human Subjects Subcommittee agreed that although ethical 
human research with pesticides was possible, the threshold of 
justification should be set very high. The NAS Committee likewise 
counseled care, recommending many specific conditions which should be 
satisfied, but nonetheless acknowledged the possibility of ethical 
research when those conditions were met. On that basis EPA has gone 
forward with this final rule.
    Comment: Comments objected to the Agency's rulemaking on the ground 
that it would promote unethical research on human subjects by pesticide 
companies.
    Response: EPA expects its tougher new rules will eliminate all 
unethical research and will decrease the overall number of future 
intentional dosing studies conducted for pesticides. The additional 
science and ethics reviews by EPA and the Human Studies Review Board 
should eliminate any proposed unethical research.
    Over the period 1996 to 2001, EPA received approximately 33 
intentional dosing studies of all types annually. These included 
studies measuring worker exposure; the efficacy of insect repellents; 
studies of absorption, distribution and excretion that help EPA assess 
exposure; and studies of systemic toxicity. Of these 33, only 4 a year, 
on average, involved intentional exposure of human subjects to measure 
minor, reversible systemic toxic effects. (Systemic effects are those 
that occur within the body, such as trembling, nausea, or headaches 
resulting from chemical changes in the nervous system.) See the 
Economic Analysis, Appendix B.
    Since 1996 we have received about 26 intentional dosing, systemic 
toxicity studies on humans. After this rule is finalized, we expect 
that number to decrease from an average of 3 a year to as few as 0 or 1 
per year. We expect that number of non-toxicity intentional dosing 
studies to remain about the same.
    Comment: The proposal was unclear.
    Response: Many comments on the proposed rule reflected confusion 
about which provisions applied to EPA and which to regulated third 
parties, and about how the standards applying to the conduct of new 
research by EPA or third parties differed from the standards applying 
to EPA decisions to consider

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completed research. These different elements were mingled in some 
subparts of the proposed rule, contributing to this confusion. A 
concerted effort has been made in the final rule to eliminate these 
potential causes of confusion, by sharpening the focus of each subpart 
and grouping subparts in three broad groups:
     Rules applying to EPA's conduct and support of new 
research with human subjects.
     Rules applying to certain types of new third-party 
research for pesticides with human subjects.
     Rules applying to EPA in its regulatory capacity.
    Comment: Ethical standards can be evaded simply by denying intent 
to submit the results of the research to EPA.
    Response: The final rule, like the proposal, extends the Common 
Rule requirements only to third-party research intended for submission 
to EPA under the pesticide laws, FIFRA and FFDCA. EPA believes this is 
appropriate because there has not been adequate consideration of the 
policy consequences of extending the provisions of the final rule to 
investigators who have no intent to provide their research results to 
EPA and would otherwise have no reason to be aware of these 
requirements.
    EPA also disagrees that the approach used in the final rule makes 
it easy to evade ethical standards for research by denying the intent 
to submit. Several elements in the final rule interact to ensure the 
application of appropriate standards. First is the explicit presumption 
in the rule that all research submitted by a pesticide registrant was 
intended for submission to EPA. Specific, credible documentation would 
have to be provided to rebut this presumption; a denial of intent, 
standing alone, could not serve as a rebuttal.
    Second, if a submitter successfully rebutted the presumption of 
intent, it would make little practical difference, and would certainly 
not compel the Agency to accept unethically conducted research. Under 
the final rule, whether or not it was intended for submission to EPA 
when research was initiated, and whether or not it was otherwise 
subject to the requirements of subpart K: (1) After the effective date 
of the rule, all reports of human research submitted to EPA under the 
pesticide laws are required by subpart M to be accompanied by 
documentation of ethical conduct of the research, (2) all completed 
post-rule 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 
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 
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.
                                  26.201 thru         Protection of                            26.101 thru
                                  26.124              Subjects in Human                        26.124
                                                      Research Conducted
                                                      or Supported by
                                                      EPA
--------------------------------------------------------------------------
B                                Sec.  Sec.          Prohibition of       B and D             Sec.  Sec.
                                  26.201 thru         Human Subjects                           26.220 and 26.420
                                  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                 n/a
                                                      subpart apply?
--------------------------------------------------------------------------
B                                Sec.   26.202(a)    Definition of        A                   Sec.   26.102(k)
                                                      research involving
                                                      intentional
                                                      exposure of a
                                                      human subject
--------------------------------------------------------------------------
B                                Sec.   26.202(b)    Definition of child  D                   Sec.   26.402(a)
--------------------------------------------------------------------------
B                                Sec.   26.203       Prohibition of EPA   B and D             Sec.  Sec.
                                                      human subjects                           26.220 and 26.420
                                                      research involving
                                                      intentional
                                                      exposure of
                                                      pregnant women,
                                                      fetuses, or
                                                      children
--------------------------------------------------------------------------
C                                Sec.  Sec.          Additional           B                   Sec.  Sec.
                                  26.301 thru         Protections for                          26.201 thru
                                  26.305              Pregnant Women or                        26.206
                                                      Fetuses Involved
                                                      as Subjects in
                                                      Observational
                                                      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 Non-
                                                      Pregnant 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)
                                                      retains final
                                                      judgment as to
                                                      whether a
                                                      particular
                                                      activity is
                                                      covered by this
                                                      subpart
--------------------------------------------------------------------------
K                                Sec.   26.1101(d),  Relation to other    A                   Sec.   26.101(e),
                                  (e), and (f)        Federal, State,                          (f), and (g)
                                                      Tribal, Local, or
                                                      foreign laws or
                                                      regulations
--------------------------------------------------------------------------
K                                Sec.   26.1101(g)   For purposes of      A                   Sec.   26.101(k)
                                                      determining a
                                                      person's intent
                                                      under paragraph
                                                      (a) of this
                                                      section . . .
--------------------------------------------------------------------------

[[Page 6144]]

 
K                                Sec.  Sec.          Definitions          A                   Sec.  Sec.
                                  26.1102(a) thru                                              26.102(a) thru
                                  26.1102(h)                                                   26.102(i)
--------------------------------------------------------------------------
K                                Sec.   26.1102(i)   Definition of        A                   Sec.   26.102(k)
                                                      research involving
                                                      intentional
                                                      exposure . . .
--------------------------------------------------------------------------
K                                Sec.   26.1102(j)   Definition of        n/a                 n/a
                                                      person
--------------------------------------------------------------------------
K                                Sec.  Sec.          IRB and informed     A                   Sec.  Sec.
                                  26.1107 thru        consent                                  26.107 thru
                                  26.1117             requirements                             26.117
--------------------------------------------------------------------------
K                                Sec.   26.1123      Early termination    A                   Sec.   26.123(a)
                                                      of research
--------------------------------------------------------------------------
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
--------------------------------------------------------------------------
P                                Sec.   26.1603      Operation of the     A                   Sec.
                                                      Human Studies                            26.124(b)(5)
                                                      Review Board
--------------------------------------------------------------------------
Q                                Sec.  Sec.          Ethical Standards    B, D, and F         Sec.  Sec.
                                  26.1701 thru        for Assessing                            26.221, 26.421,
                                  26.1703             Whether to Rely on                       26.601, 26.602,
                                                      the Results of                           and 26.603
                                                      Human Subjects
                                                      Research in EPA
                                                      Actions
--------------------------------------------------------------------------
Q                                Sec.  Sec.          Applicability and    n/a                 n/a
                                  26.1701 and         Definitions
                                  26.1702
--------------------------------------------------------------------------
Q                                Sec.   26.1703      Prohibition of       B and D             Sec.  Sec.
                                                      reliance on                              26.221 and 26.421
                                                      research involving
                                                      intentional
                                                      exposure of
                                                      pregnant women,
                                                      fetuses, or
                                                      children
--------------------------------------------------------------------------
Q                                Sec.   26.1704      Prohibition of       F                   Sec.   26.601
                                                      reliance on
                                                      unethical human
                                                      research conducted
                                                      before the
                                                      effective date of
                                                      the final rule
--------------------------------------------------------------------------
Q                                Sec.   26.1705      Prohibition of       F                   Sec.   26.602
                                                      reliance on
                                                      unethical human
                                                      research conducted
                                                      after the
                                                      effective date of
                                                      the final rule
--------------------------------------------------------------------------
Q                                Sec.   26.1706      Criteria and         F                   Sec.   26.603
                                                      procedures for
                                                      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 
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.
    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 
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 third-
party 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 
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:
     [A]ll research involving intentional exposure of a human 
subject if, at any time prior to initiating such research, any 
person who conducted or supported such research intended:
    (1) To submit results of the research to EPA for consideration 
in connection with any regulatory action that may be performed by 
EPA under the Federal Insecticide, Fungicide, and Rodenticide Act (7 
U.S.C. 136 et seq.) or section 408 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 346a); or
    (2) To hold the results of the research for later inspection by 
EPA under the Federal Insecticide, Fungicide, and Rodenticide Act (7 
U.S.C. 136 et seq.) or section 408 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 346a).

    In effect, this provision would have included all intentional-
exposure human research conducted with the intent to submit the results 
to the Agency under the pesticide laws. The proposal also established a 
rebuttable presumption that any information submitted by a person 
regulated under the pesticide laws was generated with the intent to 
submit it to EPA.
    In 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

    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 
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 
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 
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 third-
party research involving intentional exposure of human subjects who are 
pregnant women (and therefore their fetuses) or children. Thus subpart 
K covers only third-party research involving intentional exposure of 
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.  
26.117(c) of the Common Rule, the Agency has deleted the cross-
reference 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 non-
pregnant 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 
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-by-
case 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 
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 
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 
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

[[Page 6150]]

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 
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 first- 
and 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 
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.
    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 
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 
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

[[Page 6152]]

prohibitions on research involving intentional exposure of pregnant 
women, fetuses, or children. These comments are addressed in Unit VIII. 
This unit covers the public comments which addressed the adoption of 
additional protections for pregnant women and children as subjects in 
observational research conducted or supported by EPA.
    Comment: Some commenters supported EPA's proposal to adopt only 
some of the provisions of the HHS regulations in 45 CFR part 46, 
subparts B and D that create additional protections for pregnant women, 
fetuses, and children in observational research. Other comments 
recommended the Agency adopt these HHS regulations in their entirety. 
By doing so, EPA and HHS would follow consistent approaches. These 
comments also noted HHS has operated under these regulations for over 
20 years without significant debate over their ethical adequacy.
    Response: The Agency agrees there is considerable value in 
employing consistent approaches in similar areas of research. 
Consistency makes it easier for affected researchers to comply and 
helps to build a broader consensus on what constitutes ethical 
behavior. Accordingly, EPA is adopting large parts of the HHS 
regulations from 45 CFR part 46, subparts B and D essentially verbatim. 
The Agency, however, is not promulgating all of these HHS rules 
because, in EPA's judgment, the omitted provisions would never apply to 
observational research. Specifically, EPA has not adopted the following 
sections from the HHS rules: 45 CFR 46.205, 46.207, 46.406, 46.407, and 
46.409. These sections would apply only when proposed research would 
present more than a minimal risk to the subjects and would have no 
prospect for direct benefit to the subjects. EPA simply cannot conceive 
of observational research that could not meet such criteria, and in the 
unlikely event that an investigator proposed such research, EPA would 
not expect to approve it.
    Comment: Some comments objected to the inclusion in the proposed 
rule of provisions that allowed observational research if an IRB judged 
the potential risks to subjects as ``minimal.'' These comments claimed 
that the concept of ``minimal risk'' was not adequately defined and 
potentially subject to abuse. These comments recommended that no 
observational research be allowed unless there was ``no risk'' to 
subjects. (Many of these comments further argued that no human research 
was totally risk free and therefore no human research should be 
allowed.)
    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 
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.
    While EPA sees benefit to using a definition consistent with HHS, 
the Agency is concerned about the added complexity for investigators 
who are conducting research in multiple jurisdictions. In addition, EPA 
questions whether youngsters no older than 15 years, as an adult is 
defined in some states, are sufficiently mature to make decisions about 
whether to volunteer to participate in human research. In light of 
these concerns and the broad support for EPA's proposal, EPA has 
decided to retain the proposed definition of child as a person younger 
than 18 years old.
    Comment: Some comments found unclear the provisions in proposed 
subpart D allowing the waiver, under narrow conditions, of the 
requirements for permission of parents and assent of children to 
participate in observational research conducted or supported by EPA. 
Other comments objected to these proposed provisions asserting that 
children should never become subjects

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

C. The Final Rule

    Subpart C of the Agency's final rule retains most of the rule text 
appearing in proposed subpart B. The most significant changes from the 
proposal are the isolation in subparts B and L of the prohibition of 
new research proposed at 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 
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 
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

[[Page 6154]]

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 
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 third-
party 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 
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 
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

    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 
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 
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., third-
party research involving intentional exposure of human subjects, when 
the results of such research are intended to be submitted to EPA under 
the pesticide laws.
    The same section also provided that EPA would review the results of 
completed research covered by the rule. This section of the proposal 
also stated that, after completing its initial staff assessment of a 
research proposal or a completed study if EPA intended to rely on the 
results in its decision-making under the pesticide laws, the Agency 
would send its review and supporting materials concerning the study to 
the HSRB for further review and comment.
    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 
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

[[Page 6157]]

the areas of greatest concern for most commenters, EPA believes that 
its decision to establish the HSRB under FACA adequately addresses 
these comments.
    Comment: Some comments complained that the proposed rule did not 
vest the HSRB with authority to disapprove proposed new research or EPA 
decisions to rely on the results of completed human studies. Other 
comments supported giving the HSRB only an advisory role.
    Response: EPA believes the HSRB should have an advisory role. The 
decision to disapprove proposed new research or to decide whether or 
not to rely on the results of completed studies is inherently 
governmental. The Agency cannot legally confer authority to make such 
decisions on an advisory committee. The Agency notes, however, that it 
expects to give considerable weight to the advice of the HSRB.
    2. HSRB membership and qualifications.
    Comment: Many comments emphasized that the HSRB must be 
independent, that its members must have no conflicts of interest, 
including any financial relationships with the pesticide industry.
    Response: EPA agrees. Chartering the HSRB as a federal advisory 
committee to provide expert advice means that all candidates for 
membership on the HSRB must meet the federal requirements governing 
conflicts of interest. Although other requirements relating to the 
operation of the HSRB as an advisory committee are not specified in the 
final rule, EPA did retain in the final rule a requirement that members 
have no conflicts of interest. Specifically, the final rule provides 
that HSRB members must ``meet the ethics and other requirements for 
special government employees.'' See 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.
    Response: EPA does not believe that it is necessary to include non-
expert community members on the HSRB. However, under FACA, the public, 
including non-expert community representatives have opportunities to 
provide both written and oral public comment to the HSRB. In addition, 
the HSRB has the flexibility under FACA to ask representatives of 
community groups to make presentations to the committee on specific 
topics. EPA also notes that, before a proposal reaches the HSRB, an IRB 
will have reviewed and approved it. Such IRBs are required by the new 
rules (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 
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 case-
by-case basis. Finally, EPA believes that even if a study follows an 
established protocol, unanticipated scientific and ethical issues may 
arise that will warrant expert advice.

C. The Final Rule

    As a result of the reorganization of the final rule, all provisions 
relating to EPA and HSRB review of proposals for new, third-party 
research or reports of completed studies, or to the establishment of 
the HSRB, now appear in subpart P.
    The final rule reflects one significant change from the proposal. 
Under the final rule, the HSRB will review all research involving 
intentional exposure conducted after the effective date of the final 
rule, as well as all research involving intentional exposure performed 
before the rule takes effect, if the purpose of the research was to 
identify or measure a toxic effect. But the final rule grants to the 
Agency discretion to decide whether studies performed before the 
effective date of the final rule that do not measure toxicity should 
undergo HSRB review.
    After publishing the proposal, EPA examined how the proposal would 
affect its plans to complete tolerance reassessment by August 2006, as 
required by the 1996 FQPA amendments to FFDCA. The Agency reviewed the 
existing toxicity and exposure databases for upcoming tolerance 
reassessment decisions and determined that as many as several hundred 
studies relevant to the risk assessments for these actions appeared to 
meet the definition of ``research involving intentional exposure of 
human subjects.'' Only a relative few of these intentional exposure 
studies measure the toxicity of a pesticide; the great majority of them 
measure the levels of potential human exposure resulting from pesticide 
use, the efficacy of insect repellents, or the absorption, 
distribution, metabolism, and excretion of pesticides.
    Since the enactment of the Food Quality Protection Act in 1996 EPA 
has relied on many of these non-toxicity, intentional-exposure human 
studies in its registration and reregistration decisions. Moreover, the 
Agency has afforded multiple opportunities for public comment on 
several hundred draft and final Reregistration Eligibility 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 
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. 
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 intentional-
dosing 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.
     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 
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 
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 
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 case-
by-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 
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 
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 
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 
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 decision-
makers to rely on unethical data. (See Unit II.) The exception would be 
used when scientifically sound but ethically flawed data show that the 
Agency needs to take a more protective action than could be justified 
without considering the human research. Invoking the exception would 
allow EPA to protect the health of many people--perhaps millions; a 
greater public good than any benefits that would flow from refusing to 
rely on the data. In EPA's moral calculus, the greater good should and 
will guide the choice whether to use unacceptable data.
    The Agency disagrees with the argument that the final rule should 
contain no exceptions to the basic principle of refusing to rely on 
unethical research, because an exception would encourage the conduct of 
unethical research. A public refusal by EPA to rely on unethical data 
brings shame to the investigator who acted unethically, and in most 
cases also directly affects the financial interests of the 
investigator, sponsor, or both. Such a refusal serves as an important 
deterrent to other investigators, discouraging unethical research in 
the future.
    To further ensure that EPA's exceptional use of ethically flawed 
data does not encourage unethical research conduct, 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 
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 decision-
making'' in the proposal to ``actions'' in the final rule.
    Section 26.1704 defines the ethical standard EPA will use to decide 
whether to rely on the results of research conducted with non-pregnant 
adults before the effective date of the rule. It provides:
    Except as provided in 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 
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

    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.
    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 ``third-
party intentional dosing human toxicity studies for pesticides'' to 
require either submission or intent to submit under FIFRA or FFDCA 
reflects the intent of the Congress as expressed in section 201 of the 
Appropriations Act.
    The third requirement of the Appropriations Act is that the final 
rule ``not permit the use of pregnant women, infants or children as 
subjects.'' Today's final rule effectuates this mandate by: (1) 
Categorically prohibiting EPA from conducting or supporting research 
involving intentional exposure to any substance of human subjects who 
are pregnant women or children (subpart B of the final rule, 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 
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 
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.

    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.

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 
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.

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 
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 
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-for-
profit 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

    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.

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 
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.

0
Therefore, 40 CFR chapter I is amended as follows:
0
1. Part 9 is amended as follows:

PART 9--[AMENDED]

0
a. The authority citation for part 9 continues to read as follows:

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

[[Page 6168]]

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

0
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]

0
2. Part 26 is amended as follows:
0
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).

0
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

0
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.
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.
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.


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 other provision of this part, under no 
circumstances shall EPA conduct or support research involving 
intentional exposure of any human subject who is a pregnant woman (and 
therefore her fetus) or child.

Subpart C--Observational Research: Additional Protections for 
Pregnant Women and Fetuses Involved as Subjects in Observational 
Research Conducted or Supported by EPA


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 
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 
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   Observational research not involving greater than 
minimal risk.

    EPA will conduct or fund observational research in which the IRB 
finds that no greater than minimal risk to children is presented, only 
if the IRB finds that adequate provisions are made for soliciting the 
assent of the children and the permission of their parents or 
guardians, as set forth in 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 
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 
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. 
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 
(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 
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.  26.1103 through 26.1106 [Reserved]


Sec.  26.1107  IRB membership.

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

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


Sec.  26.1115  IRB records.

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

[[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 
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 
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]


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 
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 
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 
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 
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 
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).
    (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.

    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.  26.1102 and Sec.  26.1202 shall apply to 
this subpart as well.


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 
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