[Federal Register: September 12, 2005 (Volume 70, Number 175)]
[Proposed Rules]
[Page 53837-53866]
[DOCID:fr12se05-11]

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Part II

Environmental Protection Agency

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40 CFR Part 26

Protections for Subjects in Human Research; Proposed Rule

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 26

[OPP-2003-0132; FRL-7728-2]
RIN 2070-AD57

Protections for Subjects in Human Research

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: EPA proposes and invites public comment on a rulemaking 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
intentional dosing human studies for pesticides conducted by others who
intend to submit the research to EPA. This proposal, the first of
several possible Agency actions, focuses on third-party intentional
dosing human studies for pesticides, but invites public comment on
alternative approaches with broader scope.

DATES: Comments must be received on or before December 12, 2005. Under
the Paperwork Reduction Act, comments on the information collection
provisions must be received by OMB on or before October 12, 2005.

ADDRESSES: Submit your comments, identified by docket identification
(ID) number OPP-2003-0132, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov/.

Follow the on-line instructions for submitting comments.
     Agency Website: http://www.epa.gov/edocket/. EDOCKET,

EPA's electronic public docket and comment system, is EPA's preferred
method for receiving comments. Follow the on-line instructions for
submitting comments.
     E-mail: Comments may be sent by e-mail to
<EMAIL_ADDRESS>Attention: Docket ID Number OPP-2003-0132.

     Mail: Public Information and Records Integrity Branch
(PIRIB) (7502C), Office of Pesticide Programs (OPP), Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001, Attention: Docket ID Number OPP-2003-0132. In addition, please
mail a copy of your comments on the information collection provisions
to the Office of Information and Regulatory Affairs, Office of
Management and Budget (OMB), Attn: Desk Officer for EPA, 725 17th St.,
NW., Washington, DC 20503.
     Hand Delivery: Public Information and Records Integrity
Branch (PIRIB), Office of Pesticide Programs (OPP), Environmental
Protection Agency, Rm. 119, Crystal Mall 2, 1801 S. Bell St.,
Arlington, VA, Attention: Docket ID Number OPP-2003-0132. Such
deliveries are only accepted during the Docket's normal hours of
operation, and special arrangements should be made for deliveries of
boxed information.
     Instructions: Direct your comments to docket ID number
OPP-2003-0132. EPA's policy is that all comments received will be
included in the public docket without change and may be made available
online at http://www.epa.gov/edocket/, including any personal

information provided, unless the comment includes information claimed
to be Confidential Business Information (CBI) or other information
whose disclosure is restricted by statute. Do not submit information
that you consider to be CBI or otherwise protected through EDOCKET,
regulations.gov, or e-mail. The EPA EDOCKET and the regulations.gov
websites are ``anonymous access'' systems, which means EPA will not
know your identity or contact information unless you provide it in the
body of your comment. If you send an e-mail comment directly to EPA
without going through EDOCKET or regulations.gov, your e-mail address
will be automatically captured and included as part of the comment that
is placed in the public docket and made available on the Internet. If
you submit an electronic comment, EPA recommends that you include your
name and other contact information in the body of your comment and with
any disk or CD ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA
may not be able to consider your comment. Electronic files should avoid
the use of special characters, any form of encryption, and be free of
any defects or viruses. For additional information about EPA's public
docket visit EDOCKET on-line.
     Docket. All documents in the docket are listed in the
EDOCKET index at http://www.epa.gov/edocket/. Although listed in the

index, some information is not publicly available, i.e., CBI or other
information whose disclosure is restricted by statute. Certain other
material, such as copyrighted material, is not placed on the Internet
and will be publicly available only in hard copy form. Publicly
available docket materials are available either electronically in
EDOCKET 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<PHONE_NUMBER>.

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:<PHONE_NUMBER>; e-mail address:
<EMAIL_ADDRESS>

SUPPLEMENTARY INFORMATION: This proposed rule, the first of several
possible Agency actions, would significantly strengthen the ethical
framework for conducting and reviewing human studies, especially
intentional dosing human studies for pesticides.
    With respect to human research conducted by EPA (``first-party
research''), or by others with EPA's support (``second-party
research''), this proposed rule would: (1) Categorically prohibit any
intentional dosing studies involving pregnant women or children as
subjects; and (2) adopt the Department of Health and Human Services
(HHS) regulations that provide additional protections to pregnant women
and children as subjects of other than intentional dosing studies.
    With respect to human research conducted by third parties--i.e., by
others without any support from EPA or other federal government
agencies--the proposed rule would: (1) Categorically prohibit any
third-party intentional dosing studies for pesticides involving
pregnant women or children as subjects; (2) extend the provisions of
the Federal Policy for the Protection of Human Subjects of Research
(the ``Common Rule'') to all other third-party intentional dosing human
studies intended for submission to EPA under the pesticide laws; (3)
require, before testing is initiated, submission to EPA of protocols
and related information for proposed research covered by this extension
of the Common Rule; and (4) require information about the ethical
conduct of covered human studies when the results of the research are
submitted to EPA.
    In addition, the proposed rule would: (1) Establish an independent
Human Studies Review Board to review proposals for covered intentional
dosing human research and reports of completed research; (2) specify

measures EPA would consider to address non-compliance with the
provisions of a final rule along the lines of this proposal; (3) define
the ethical standards EPA would apply in deciding whether to rely on
relevant, scientifically sound data derived from intentional dosing
human studies for pesticides; and (4) forbid EPA to rely in its
decision-making under the pesticide laws on human research involving
intentional exposure of pregnant women or children.
    This document is organized into 14 units:
     Unit I. contains ``General Information'' about the
applicability of this proposed rule, how to obtain additional
information, how to submit comments in response to the request for
comments, and certain other related matters.
     Unit II. summarizes the Agency's goals for this proposed
rulemaking and the terms of the proposal itself, and places the
proposal in the context of the larger debate over the conduct and
regulatory use of research with human subjects.
     Unit III. provides background information about the
history of human subjects research protection and about events leading
up to this proposal.
     Unit IV. discusses EPA's proposal to extend the
requirements of its codification of the Common Rule, 40 CFR part 26, to
third-party intentional dosing human studies for pesticides. (EPA and
other federal departments and agencies who have adopted the Common Rule
conduct research with human subjects to provide critical information on
environmental risks, exposures, and effects in humans. This is referred
to in this document as ``first-party'' research. EPA and other Common
Rule departments and agencies also support with contracts, grants, or
in other ways research with human subjects conducted by others. This is
referred to as ``second-party'' research. When research with human
subjects is conducted by others without support from EPA or other
Common Rule departments or agencies, it is referred to as ``third-
party'' research.)
     Unit V. discusses EPA's proposal to require submission of
protocols and other information about proposed third-party intentional
dosing human studies for pesticides before the studies begin, so that
EPA and an advisory Human Studies Review Board may review and comment
on the ethical and scientific aspects of the proposals.
     Unit VI. discusses rulemaking to ban research with
pesticides involving intentional dosing of children, and to adopt
additional protections, beyond those in the Common Rule, for children
as subjects of other types of research. This ban would apply both to
EPA and to regulated third parties.
     Unit VII. addresses rulemaking to ban research with
pesticides involving intentional dosing of pregnant women, fetuses, or
newborns, and to adopt additional protections, beyond those in the
Common Rule, for pregnant women, fetuses, and newborns as subjects of
other types of research. This ban, too, would apply both to EPA and to
regulated third parties.
     Unit VIII. explains EPA's decision to defer adoption of
additional protections for prisoners as research subjects.
     Unit IX. discusses possible measures that EPA might use to
address noncompliance with the requirements of a final rule along the
lines of this proposal.
     Unit X. discusses the ethical standards that EPA proposes
to use in deciding whether or not to rely on completed human studies in
Agency decision-making.
     Unit XI. demonstrates the compliance of this proposal with
the requirements in the Department of the Interior, Environment, and
Related Agencies Appropriations Act, 2006, regarding third-party
intentional dosing human toxicity studies for pesticides.
     Unit XII. discusses EPA's responses to comments from the
Department of Health and Human Services on a draft of this proposal.
     Unit XIII. discusses the Agency's evaluation of the
impacts of this proposal as required under various statutes and
Executive Orders.
     Finally, Unit XIV. discusses the Agency's thinking with
respect to the effective date of a final rule.

I. General Information

A. Does this Action Apply to Me?

    This action is directed to the public in general. This action may,
however, be of particular interest to those who conduct human research
on substances regulated by EPA. Since other entities may also be
interested, the Agency has not attempted to describe all the specific
entities that may be affected by this action. If you have any questions
regarding the applicability of this action to a particular entity,
consult the person listed under FOR FURTHER INFORMATION CONTACT.

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

    In addition to using EDOCKET (http://www.epa.gov/edocket/), 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/
.

C. What Should I Consider as I Prepare My Comments for EPA?

    1. Submitting CBI. Information so marked will not be disclosed
except in accordance with procedures set forth in 40 CFR part 2.
    2. Tips for preparing your comments. When submitting comments,
remember to:
    i. Identify the rulemaking by docket number and other identifying
information (subject heading, Federal Register date, and page number).
    ii. Follow directions. The agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
    iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
    iv. Describe any assumptions and provide any technical information
and/or data that you used.
    v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
    vi. Provide specific examples to illustrate your concerns, and
suggest alternatives.
    vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
    viii. Make sure to submit your comments by the comment period
deadline identified.

II. Summary of EPA Goals and the Context for the Proposed Rulemaking

    EPA is charged with protecting public health and the environment by
regulating air and water pollutants, pesticides, hazardous wastes,
industrial chemicals, and other environmental substances. To meet this
responsibility EPA collects and reviews the best available scientific
information to understand how these substances may affect human health
and the world we live in. The Agency typically 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 on toxicity
with estimates of exposure, EPA can estimate the risk posed by a
substance to an exposed population, and then decide

whether that risk justifies regulation of releases of the substance
into the environment.

A. How EPA Assesses Risks to People

    The Agency's understanding of potential risks to people is usually
based on tests performed with laboratory animals. For example, EPA
typically requires pesticide companies to perform over 20 different
kinds of animal studies to identify or measure toxic effects before a
pesticide can be registered for use. These studies 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, they provide a good general understanding of a
pesticide's potential effects. Comparable animal data are usually
available when EPA makes regulatory decisions about other kinds of
environmental substances as well.
    Animal studies, however, are not the only source of relevant
information for characterizing potential risks. Sometimes EPA can
better understand the potential risks of a substance by looking at how
people respond when they have been directly exposed to it. For example,
EPA uses information from accident and incident reports, in which
people may have been exposed to a substance after a spill or some other
unintentional release. EPA also uses data from epidemiological studies
comparing health outcomes of two otherwise similar groups of people who
differ in their level of exposure to a particular substance (e.g.,
those who work with a chemical vs. those who do not).
    In addition to incident and epidemiology data, human exposure
studies have also improved EPA's risk assessments. EPA often bases its
estimates of potential human exposure to environmental substances on
monitoring studies measuring concentrations of a substance in air,
water, food, or on surfaces. This kind of information about
environmental concentrations can then be used to predict the amount of
a substance people will breathe, eat, drink, or absorb through their
skin. 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, the actual exposure of a farmer applying a pesticide will
depend on such factors as the type of spray equipment used, the amount
and kind of pesticide used, the type of protective clothing worn (e.g.,
gloves, respirator, long pants), and how many hours are worked each
day. To determine more accurately the exposures farmers and other
applicators actually receive, EPA requires pesticide companies to
measure the amount of pesticide deposited on an applicator's body and
clothing during a spray session. The results of studies like this
provide critical data about exposures that can be used to define
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 were necessary for a pesticide to be
used safely, or how soon harvesters or others could safely enter
pesticide-treated areas.
    Another type of human study that can contribute to EPA's risk
assessments involves intentional exposure of subjects to low doses of a
substance to measure how the substance is absorbed, distributed,
metabolized, and excreted in humans. Humans respond to some substances
in different ways from animals, and studies of this kind can provide
essential support for safety monitoring programs, such as those which
analyze and measure the known metabolites of a substance in the blood
or urine of workers or others to determine if they've been exposed to
the substance.
    Although EPA has not and will not use its authorities to require or
encourage it, third parties have occasionally conducted and submitted
to EPA reports of research involving intentional dosing of human
subjects to identify or measure toxic effects. These studies typically
involve intentional exposure to an environmental substance in a
controlled laboratory or clinical setting.
    Decades of experience in reviewing both animal and human studies of
all kinds has demonstrated that animal data alone can sometimes provide
an incomplete or even a misleading picture of the safety or risks of a
substance. Sometimes human data show that people are more sensitive
than animals, and support regulatory measures more protective than
would be indicated by animal data. This has been the case, for example,
for arsenic, certain air pollutants, and certain pesticide active
ingredients such as methyl isothiocyanate (MITC) and hexavalent
chromium. More often, though, information from human studies confirms
insights based on animal testing. Even in these cases, however, the
availability of scientifically sound human data can strengthen the
basis for EPA's regulatory actions.

B. Societal Concern over Ethically Deficient Human Research

    Scientific experimentation involving human beings has raised
controversy for a long time. 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. Not all
previously conducted human studies, however, met the ethical standards
of their own time, and some older research falls well short of today's
ethical standards. Even contemporary research is sometimes ethically
deficient.
    For over 7 years EPA has been at the center of an intense debate
about the acceptability of certain intentional dosing human studies for
pesticides, and about what to do with human studies which are ethically
deficient. In this debate some have argued that EPA should disassociate
itself entirely from ethically problematic research behavior by
refusing to consider the resulting data 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 problematic research.
They 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 that would be advantageous to the company that conducted the
study. If the key study was ethically deficient, then the company could
benefit from its misconduct.
    On the other hand, data from human research has contributed
enormously to scientific understanding of the risks posed by every kind
of environmental substance. Recognizing the importance of such
knowledge to EPA's past regulatory actions, some argue that the Agency
should take all relevant and scientifically sound information--not
excluding ethically deficient human data--into account in its
regulatory decision-making. They argue that any ethical deficiencies
are the fault of the researchers, not of EPA. They further argue that
by relying on scientifically valid and relevant data from an ethically

deficient study EPA does no additional harm to the subjects of the
research, and 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. They note that to
replicate scientifically sound but ethically flawed human studies may
not be ethical, no matter how carefully such replicate research might
be conducted, since any increment of risk to potential subjects would
not be justified by anticipated new generalizable knowledge. Holders of
this view also stress the importance of strengthening protections for
volunteers who participate in future studies, while taking advantage of
all that can be learned from past research to benefit society.
    EPA finds compelling many of the points made by both sides, and
agrees with those who say that the possibility of conducting and using
human studies in regulatory decision-making must be approached with the
utmost caution. Each side bases its arguments on important societal
values. Our mission is to make the best possible regulatory decisions
to protect public health and the environment in this country, and to
support similar efforts around the world. We do not want to ignore
potentially important information that might benefit our decision-
making. At the same time, we agree that our conduct should encourage
high ethical standards in research with human subjects and strongly
discourage unethical research.
    Many participants in the public debate over whether EPA should rely
on scientifically sound and relevant but ethically flawed data have
tended to frame possible policy choices in ways that discount or ignore
the values and goals of those with whom they disagree. But the Agency
must find a way to reconcile multiple goals.
     EPA believes it must fulfill its mandate to do the best
possible job of protecting public health. We think our decisions are
generally better if they reflect consideration of all available,
scientifically valid, and relevant knowledge.
     EPA believes its goal is to ensure, to the extent
possible, that all people who participate as subjects of human research
are treated ethically, are fully informed of the potential risks, and
experience no harm from their participation. We hope--through our
rules, policies, procedures, and regulatory actions--to discourage or
prevent the conduct of human studies that do not meet rigorous ethical
and scientific standards. (A scientifically inadequate human study is
inherently unethical, because it fails to provide new information
reliable enough to justify subjecting volunteers to any risks by
participating in the study.)
     EPA believes the federal government should use all of its
authorities to make clear that certain kinds of human research can
never be acceptable. In particular, we regard as unethical and would
never conduct, support, require, or approve any study involving
intentional exposure of pregnant women, infants, or children to a
pesticide.

C. EPA Consultation with the National Academy of Sciences

    The conduct and consideration of data from human research
inevitably raises difficult, contentious issues, and EPA has sought
counsel from others in trying to resolve these issues. We have asked
for expert advice from our Agency scientific peer review groups, and we
have sought public comments through multiple Federal Register Notices
(see Unit III.). The most extensive advice has come from the National
Academy of Sciences (NAS) who, at the Agency's request, prepared a
report entitled ``Intentional Human Dosing Studies for EPA Regulatory
Purposes,'' issued in February 2004 (NAS Report).
    The NAS developed its report after long and thoughtful
consideration of the full range of issues. Their recommendations
addressed whether or not EPA should rely on the results of ethically
deficient human studies, and what standards should guide the conduct of
future human research. 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 federal regulations
known officially as the ``Federal Policy for the Protection of Human
Subjects of Research'' but generally referred to as 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. 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.
    The Common Rule has been promulgated in regulations by 15 federal
departments and agencies, including EPA. In addition, the Central
Intelligence Agency must comply with all subparts of 45 CFR part 46
under Executive Order 12333. The Common Rule establishes a
comprehensive framework for the review and conduct of proposed human
research to ensure that it will be performed ethically. The central
requirements of the Common Rule are: (1) That people who participate as
subjects in covered research are selected equitably and give their
fully informed, fully voluntary written consent; and (2) that proposed
research be reviewed by an independent oversight group referred to as
an Institutional Review Board (IRB), and approved only if risks to
subjects have been minimized and are reasonable in relation to
anticipated benefits, if any, to the subjects, and the importance of
the knowledge that may reasonably be expected to result.

D. Summary Scope of this Proposal

    The Agency recognizes that issues arise about human testing of all
classes of environmental substances, not only pesticides, and under all
its legal authorities, and not only the pesticide laws. This proposal,
however, focuses on the most pressing of issues: defining appropriate
ethical standards for investigator conduct and for Agency use of third-
party intentional dosing human studies for pesticides.
    The Agency acknowledges that a final rule along the lines being
proposed would not address, much less resolve, all the issues in the
current debate about human research. But the Agency views this proposal
as an essential and urgently needed first step in what could be a
series of Agency actions to address a wider range of human research
under other statutory authorities. Although we believe a stepwise
approach will put stronger protections in place sooner, EPA is open to
considering an expanded scope for this proposed rule to address either
a broader range of human research designs or decision-making under
other statutory authorities. Accordingly, in later units of this
preamble the Agency has identified alternatives to each aspect of this
proposal. Note that there are many ways in which the different elements
of the proposed rule and the identified alternatives could be combined;
we encourage commenters to consider and address how the whole of the
rule should fit together, in addition to the merits of specific
alternatives. Public comment will play an important part in our choices
for the scope and terms of the final rule.

III. Introduction

A. Ethical Standards for Conducting Human Research

    Over the years, scientific research with human subjects has
provided

valuable information to help characterize and control risks to public
health, but its use has also raised particular ethical concerns for the
welfare of the human participants in such research as well as
scientific issues related to the role of such research in assessing
risks. Society has responded to these concerns by defining general
standards for conducting human research.
    In the United States, the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research issued in 1978 The
Belmont Report: Ethical Principles and Guidelines for the Protection of
Human Subjects of Research. This document can be found in the docket
for this proposed rule and on the web at http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm.
 For many U. S. federal departments

and agencies, the principles of the Belmont Report are implemented
through the Federal Policy for the Protection of Human Subjects (the
Common Rule). The Common Rule, promulgated by 15 federal departments
and agencies, including the EPA, on June 18, 1991 (56 FR 28003),
applies to all research involving human subjects conducted, supported
or otherwise subject to regulation by any federal department or agency
that has adopted the Common Rule and has taken appropriate
administrative action to make it applicable to such research. The
Common Rule as promulgated by EPA (40 CFR part 26) has applied to human
subjects research conducted or supported by EPA since it was put into
place in 1991.
    The World Medical Association, a voluntary federation of national
medical associations, has developed and maintains ethical standards
documented in the Declaration of Helsinki, first issued in 1964 and
revised several times since then. The latest version of the Declaration
is available at: http://www.wma.net/e/policy/b3.htm. These standards

apply internationally to research on the diagnosis and treatment of
human disease, or that adds to understanding of the causes and
development of disease.
    In addition, many public and private research and academic
institutions and private companies, both in the United States and in
other countries, including non-federal U.S. and non-U.S. government
organizations, have their own specific policies related to the
protection of human participants in research.
    Much of the scientific information supporting EPA's risk
assessments is generated by researchers who are not part of or
supported by a federal agency. This includes a significant portion of
the research with human subjects submitted to the Agency or retrieved
by the Agency from published sources. Such research, referred to here
as ``third-party'' research, may be governed by specific institutional
policies intended to protect research participants, may fall within the
scope of the Declaration of Helsinki, or might actually be covered by
the Common Rule if the particular testing institution holds an
assurance approved by the Department of Health and Human Services'
(HHS) Office for Human Research Protections (OHRP). (Under a ``federal-
wide assurance'' issued by OHRP, a research institution may voluntarily
promise to apply the Common Rule to all its research with human
subjects, without regard to the source(s) of funding or other support).
Some research reports provide insufficient information to support a
judgment whether institutional policies are consistent with or as
protective of human subjects as the Common Rule, or even to tell
whether such policies or standards were followed. Thus, even
scientifically well-conducted third-party human studies may raise
difficult questions for the Agency when it seeks to determine their
acceptability for consideration.

B. Human Research Issues in EPA's Pesticide Program

    Although data from human studies have contributed to assessments
and decisions in most EPA programs, issues about consideration of and
reliance on third-party human research studies have arisen most
frequently, but not exclusively, with respect to pesticides. Under the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C.
136-136y), EPA requires pesticide companies to conduct studies needed
to evaluate the safety of their products. While some studies involving
human subjects are required, EPA has never required intentional dosing
human toxicity studies with pesticides. EPA has, however, required
studies to measure potential exposure to pesticides of users or of
workers and others who re-enter areas legally treated with pesticides.
Other required tests have evaluated the effectiveness of pesticide
products intended to repel insects and other pests from human skin. In
addition, EPA has required studies to define pesticide metabolism and
metabolic products in humans, as a guide to interpretation of
biomonitoring studies of agricultural workers and others to protect
them from exposure to potentially dangerous levels of pesticide
residues.
    The public controversy over human testing and pesticides has
centered on studies involving intentional dosing of human subjects with
a pesticide to identify or measure its toxic effects. Although the
Agency has never required or encouraged anyone to perform such tests,
pesticide companies have sometimes chosen to conduct them and submit
them to the Agency. For some two decades before passage of the Food
Quality Protection Act (FQPA) in 1996, such studies were rare, but when
they were submitted EPA considered them, and factored relevant
information into its human health risk assessments. After passage of
FQPA, submission of this kind of study to the Office of Pesticide
Programs increased; the Agency has received some twenty studies of this
kind since 1996.
    Submission of these studies following FQPA elicited a strong
expression of public concern. In response, 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
advisory 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 docket for this proposed rulemaking, and on the web at: http://www.epa.gov/science1/pdf/ec0017.pdf
.

    The DTHSS advisory committee heard many comments at their two
public meetings, and further comments have been submitted in response
to their published report. The 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.
Yet no clear consensus emerged from the advisory committee on many
other points, among them both the scientific merit and 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.
    Some public commenters have asserted that the DTHSS committee did,
in fact, achieve consensus. Although the full committee agreed on some
subjects, the members filed both majority and minority reports
differing on one of the most important issues under discussion--whether
it is ever ethical to conduct or for EPA to consider a study sponsored
by a pesticide company in which human subjects were intentionally dosed
with a pesticide to evaluate its toxicity. The disagreement within the
committee was vehement. After nearly 18 months of discussion, two
members filed a minority report and resigned from the committee to
protest the position taken by the committee majority.
    In December 2001, EPA asked the advice of the NAS on the many
difficult scientific and ethical issues raised in this debate, and also
announced the Agency's interim approach to third-party intentional
dosing human toxicity studies. The Agency's announcement is in the
docket for this proposed rulemaking. The announcement promised that
when it received the NAS report, ``EPA will engage in an open and
participatory process involving federal partners, interested parties
and the public during its policy development and/or rule making
regarding future acceptance, consideration or regulatory reliance on
such human studies.'' In addition, the press release also stated that
while the Academy was considering these issues, EPA ``will not consider
or rely on any such human studies in its regulatory decision-making.''
    In early 2002, various parties from the pesticide industry
petitioned the U. S. Court of Appeals for the D. C. Circuit for review
of EPA's December 2001 press release. These parties argued that the
interim approach announced in the Agency's December 2001 Press Release
constituted a ``rule'' promulgated in violation of the procedural
requirements of the Administrative Procedure Act and the Federal Food,
Drug, and Cosmetic Act. On June 3, 2003, the Court found for the
petitioners and vacated EPA's interim approach, stating:
    For the reasons enumerated previously, we vacate the directive
articulated in EPA's December 14, 2001 Press Release for a failure
to engage in the requisite notice and comment rulemaking. The
consequence is that the agency's previous practice of considering
third-party human studies on a case-by-case basis, applying
statutory requirements, the Common Rule, and high ethical standards
as a guide, is reinstated and remains in effect unless and until it
is replaced by a lawfully promulgated regulation. See CropLife
America v. Environmental Protection Agency, 329 F.3d 876, 884 - 85
(D.C. Cir. 2003) (referred to as the CropLife America case).

    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. The membership, meeting schedule, and
other information about the work of this committee can be found on the
NAS website at: http://www4.nas.edu/webcr.nsf/ 5c50571a75df494485256a

95007a 091e/ 9303f725c15902f685256c44005d8931 ?OpenDocument. The
committee issued 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/
.

    On May 7, 2003, EPA issued an advance notice of proposed rulemaking
(ANPR) on Human Testing announcing its intention to undertake notice-
and-comment rulemaking on the subject of its consideration of or
reliance on research involving human participants (68 FR 24410) (FRL-
7302-8). The ANPR invited public comment on a broad range of issues,
and EPA received over 600 submissions in response. Approximately 15
were from pesticide companies, pesticide users, and associated trade
associations and groups. These comments mostly favored the Agency's use
of data from scientifically sound, ethically appropriate studies
conducted with human participants. Several of these groups urged EPA to
apply the Common Rule to human research conducted by third parties for
submission to EPA. About 60 submissions came from religious groups,
farm-workers' and children's advocacy groups, and environmental and
public health advocacy organizations. Most of these groups generally
opposed on ethical grounds EPA's consideration of results from human
testing, especially those involving intentional dosing of test
participants with pesticides. Some of these commenters suggested,
however, that, under certain strict conditions, EPA might appropriately
consider data from human studies that complied with the Common Rule.
Over 500 private citizens submitted identical comments opposing the use
of data from human studies with pesticides in EPA's regulatory
decision-making. A sizeable number of other private citizens expressed
dismay in their comments at what they misunderstood to be an EPA
proposal to test pesticides on human subjects.

C. EPA's Announcement of its Plan and Process

    After consideration of the Court of Appeals' decision in the
CropLife America case, the public comments on the ANPR, and the NAS
report, EPA set out to address the issues involving the conduct and
reliance on human research. On February 8, 2005, EPA published and
invited public comment on a Federal Register Notice announcing EPA's
plan to establish a comprehensive framework for deciding whether to
consider or rely on certain types of research with human participants
(70 FR 6661) (FRL-7695-4). Among other actions called for in this plan
were issuing proposed and final rules and supplemental guidance, and
expanding the functions and staff of EPA's Human Subjects Research
Review Office (HSRRO) and relocating those functions to the Office of
the Administrator.
    The February 8, 2005, Federal Register Notice also described the
Agency's case-by-case process for evaluating human studies, which the
D.C. Circuit required to remain in effect until superseded by
rulemaking. (EPA's application of this process with respect to third
party intentional dosing human toxicity studies for pesticides was
suspended by the EPA 2006 Appropriations Act discussed in Unit XI.) As
the Notice explained:
    As mandated by the D.C. Circuit in the CropLife America case,
EPA has resumed consideration of third-party human studies on a
case-by-case basis, applying statutory requirements, the Common
Rule, and high ethical standards as a guide. In its consideration
and review of human studies submitted to the Agency, EPA will
continue to generally accept scientifically valid studies unless
there is clear evidence that the conduct of those studies was
fundamentally unethical (e.g., the studies were intended to
seriously harm participants or failed to obtain informed consent),
or was significantly deficient relative to the ethical standards
prevailing at the time the study was conducted.

    In response to the February 8, 2005, Federal Register Notice, EPA
received approximately 150 comments opposing pesticide research with
human subjects. In addition, other comments urged adoption of new
standards and specific safeguards for vulnerable populations; argued
that intentional dosing of humans to determine toxic effects is
inherently unethical; encouraged EPA to reinstate its previous
moratorium on such tests; suggested that intentional human dosing
studies are superior to animal studies in indicating the actual

toxic effects of a compound in humans, and that human testing is
acceptable if subjects are adequately informed and provided with
medical monitoring; expressed concern that the small number of subjects
in many human studies may not yield statistically significant results
relevant to various subpopulations; urged that third-party researchers
be required to submit protocols for review; stated that human subjects
testing should not be conducted just to provide a no-observed-effect-
level (NOEL) for a single endpoint and that the studies should be
conducted so as to maximize the amount of data collected; asserted that
the Common Rule should be the minimum standard for studies submitted to
EPA and that researchers should also comply with the Nuremberg Code,
Belmont Report, and Declaration of Helsinki; and argued that dosing
humans with pesticides to determine a NOEL or no-observed-adverse-
effect-level (NOAEL) is always unethical.
    EPA has reviewed each of the comments submitted in response to the
May 7, 2003, ANPR and the February 8, 2005, Proposed Plan and
Description of Review Process. These comments have provided useful
input as the Agency has developed this proposal. EPA also expects to
receive many useful and informative comments in response to this
proposal. When a final rule is published, EPA will respond to the
comments received in response to all three of these documents.

D. Legal Authority

    The proposed rule described in this document is authorized under
provisions of the following statutes that EPA administers. Section
25(a) of the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA) authorizes the Administrator to ``prescribe regulations to
carry out the purposes of [FIFRA].'' Section 408(e)(1)(C) of the
Federal Food, Drug, and Cosmetic Act (FFDCA) authorizes the
Administrator to issue a regulation establishing ``general procedures
and requirements to implement [Section 408].'' In addition, the
proposed amendments to 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).
    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 the Environmental Protection Agency and other
federal departments and agencies. Unit XI. of this preamble discusses
how this proposal meets the requirements of section 201 of the
Appropriations Act, which 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 EPA 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.

IV. Extending the Common Rule to Future Third-Party Human Research

    This unit concerns rulemaking to extend the requirements of EPA's
Common Rule, 40 CFR part 26, to certain types of human research
conducted or supported after the effective date of the rule by
regulated third parties.
Summary of the EPA Proposal
    EPA proposes to extend the requirements of EPA's Common Rule (40
CFR 26.101 through 26.124) to third-party research, conducted after the
effective date of the rule, which involves intentional exposure of
human subjects, if the researcher intended to submit the resulting
information to EPA, or to hold the information for later inspection by
EPA, under FIFRA or the FFDCA.

A. Background

    The Common Rule applies to ``all research involving human subjects
conducted, supported or otherwise subject to regulation by any federal
department or agency which takes appropriate administrative action to
make [the Common Rule] applicable to such research.'' See 40 CFR
26.101(a). The Common Rule defines ``research'' as:
    a systematic investigation, including research development,
testing and evaluation, designed to develop or contribute to
generalizable knowledge. Activities which meet this definition
constitute research for purposes of this policy, whether or not they
are conducted or supported under a program which is considered
research for other purposes. For example, some demonstration and
service programs may include research activities.
See 40 CFR 26.102(d).

    EPA has promulgated the Common Rule, making it applicable to human
research that the Agency conducts or supports. The requirements of
EPA's codification of the Common Rule currently do not, however, apply
to third-party human research intended for submission to or considered
by EPA, except when the research is conducted under an applicable
assurance of Common Rule compliance approved by OHRP and that has been
voluntarily extended to cover third-party research.
    Currently no federal agency has taken administrative action to
extend the requirements of the Common Rule to third-party human
research. In 1980 and 1981, however, the Food and Drug Administration
(FDA) promulgated separate regulations that required parties conducting
covered human research to comply with provisions regarding
Institutional Review Board (IRB) review and informed consent. See
Protection of Human Subjects; Informed Consent, 46 FR 8942 (January 27,
1981) and Protection of Human Subjects; Standards for Institutional
Review Boards for Clinical Investigations, 46 FR 8958 (January 27,
1981). These regulations have since been amended several times to make
them substantively equivalent to the Common Rule.
    The FDA rules apply to certain testing by third parties,
specifically to:
    all clinical investigations regulated by the Food and Drug
Administration under sections 505(i) and 520(g) of the Federal Food,
Drug, and Cosmetic Act, as well as clinical investigations that
support applications for research or marketing permits for products
regulated by the Food and Drug Administration, including foods,
including dietary supplements, that bear a nutrient content claim or
a health claim, infant formulas, food and color additives, drugs for
human use, medical devices for human use, biological products for
human use, and electronic products.
See 21 CFR 50.1.

    The FDA regulation defines ``clinical investigation'' to mean:
    . . . any experiment that involves a test article and one or
more human subjects and that either is subject to requirements for
prior submission to the Food and Drug Administration under section
505(i) or 520(g) of the act, or is not subject to requirements for
prior submission to the Food and Drug Administration under these
sections of the act, but the results of which are intended to be
submitted later to, or held for inspection by, the Food and Drug
Administration as part of an application for a research or marketing
permit. The term does not include experiments that are subject to
the provisions of Part 58 of this chapter, regarding nonclinical
laboratory studies.
See 21 CFR 50.3(c).

FDA regulations further define ``nonclinical laboratory study'' as a
laboratory-based experiment not involving humans. See 21 CFR 58.3(d).
    The NAS committee did not directly address extending the
requirements of the Common Rule to third-party human research; however,
the committee did discuss the Common Rule at length, using it as the
starting point for its analyses of ethical issues arising from
consideration of the results of intentional human dosing studies for
EPA regulatory purposes. See, e.g., NAS Report, chapter 2 and chapters
4-6. The NAS also recommended a number of steps to EPA to strengthen
protections for human subjects involved in intentional dosing studies.
See NAS Report, chapters 4 and 5. While it seems evident the NAS
committee would support extending the requirements of the Common Rule
beyond first and second parties, the committee did not declare a
position on the scope of third-party human research which should be
covered by such an extension.
    The NAS committee's most direct statements appear in connection
with their Recommendation 6-1:
    EPA should require that all human research conducted for
regulatory purposes be approved in advance by an appropriately
constituted IRB or an acceptable foreign equivalent.

(Italics in the original.) In explaining this recommendation, the NAS
suggested ``EPA may wish to use FDA's implementation of its equivalent
of the Common Rule (21 CFR Part 50) as a guide for its adoption of such
a requirement.'' NAS Report, p. 133.
    EPA interprets the NAS phrase ``research conducted for regulatory
purposes'' in this context to mean research intended to be submitted to
EPA for consideration in connection with any regulatory actions that
may be performed by EPA. (The NAS did not limit this or other
recommendations to human research received under specific EPA statutory
authorities.) The Agency interprets the NAS recommendation for prior
IRB approval of all such research to be equivalent to a recommendation
that the Common Rule should be extended to it. The NAS recommendations
do not specifically address application of the Common Rule requirements
for informed consent, but they do characterize non-consensual research
as fundamentally unethical. With these interpretations, adoption and
implementation of the NAS recommendations would put EPA in a position
very similar to that of FDA.

B. Proposal

    EPA proposes to extend the requirements of EPA's Common Rule (40
CFR 26.101 through 26.124) to third-party research conducted after the
effective date of the rule, which involves intentional exposure of
human subjects, if the researcher intended to submit the resulting
information to EPA, or to hold the information for later inspection by
EPA, under FIFRA or the FFDCA.
    Extension of the Common Rule is supported by a significant number
of public comments which favored applying equivalent ethical standards
to both EPA and third-party research. EPA agrees, and for this reason
is proposing no changes to the substantive content of the Common Rule.
    EPA has also given a great deal of thought to the scope of the
proposed extension of the Common Rule. In the May 7, 2003, ANPR the
Agency identified many factors that could possibly be used to define
the range of future third-party research to which the requirements of
the Common Rule might be extended. Among these factors are the nature
or purpose of the substance tested, the design of the research, and the
affiliation or purpose of the investigators.
    EPA proposes to extend its codification of the Common Rule to
third-party research intended for submission to EPA under the pesticide
laws, and involving intentional dosing for any purpose. The figure
below illustrates how these factors are related. The entire circle
represents the universe of third-party human studies conducted for
pesticides after the effective date of the rule. Segment A represents
toxicity studies i.e., studies involving intentional dosing to identify
or measure a toxic effect which are intended to be submitted to EPA
under the pesticide laws, FIFRA or FFDCA. Segment B represents all
other human studies intended for submission to EPA under the pesticide
laws which involve intentional dosing, but for purposes other than
identifying or measuring toxic effects. Examples in this category would
include studies of Absorption, Distribution, Metabolism, and Excretion
(ADME), insect repellent efficacy studies, and some non-occupational
exposure studies. Segment C represents other studies intended for
submission to EPA under the pesticide laws which do not involve
intentional dosing. Examples in this category would include most
occupational exposure studies, and studies involving use of registered
pesticides for approved uses according to label directions.
    Segments A, B, and C taken together represent all human studies
intended for submission to EPA under the pesticide laws. Segment D
represents all other pesticide studies, defined only by their not being
intended for submission to EPA. Examples in this category would include
studies conducted for publication, or to meet regulatory requirements
in countries other than the U.S., or by state governments for their own
use.
    Segments A and B taken together represent all intentional dosing
human studies intended for submission to EPA under the pesticide laws.
This is the scope of extension of EPA's Common Rule proposed in Sec.
26.102(j) of the regulatory text.
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    This scope for extending EPA's Common Rule was selected as a
priority in order to address public concern. Intentional dosing human
studies with pesticides have generated the greatest level of public
concern, and although the Agency's previous Federal Register Notices in
May 2003 and February 2005, have broadly addressed human studies under
all EPA statutes, stakeholder comments have overwhelmingly focused on
human research with pesticides. The Agency intends, however, to
continue to explore the feasibility of extending EPA's Common Rule to
third-party studies used to inform decisions under statutory
authorities other than FIFRA or the FFDCA, and is open to the
possibility of applying EPA's Common Rule to a different range of
pesticide research.
    Three key elements define the range of research which would fall
within the scope of this proposed rule. First is when the research is
conducted. The proposed rule would apply EPA's Common Rule to covered
research initiated after the effective date of the final rule. Such a
provision would allow researchers to come into compliance with the new
requirements in an orderly manner.
    The second element is research involving intentional dosing or
exposure of a human subject. Proposed Sec.  26.102(k) of the regulatory
text defines ``research involving intentional exposure of a human
subject'' as ``a study of an environmental 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.'' Human studies that do not involve
intentional exposure are limited by the terms of this proposed
definition to those where the exposure of the subjects would have
occurred even if the subjects had not been participating in research.
For example, under this definition a study would not be considered to
involve intentional exposure if it 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.
While they are participating in the research these workers' urine and
blood may be collected for analysis to evaluate biological responses,
or they may wear patches attached to their clothing that are collected
at the end of the shift for analysis to measure exposure.
    Studies which do not involve intentional exposure such as passive
observation or ambient monitoring studies do not alter the level of
exposure of a subject to an environmental substance, and in fact any
exposure is not a consequence of the subject's participation in the
research, but results from the subject's pursuit of normal work or life
activities. Thus extending EPA's Common Rule only to third-party
research involving intentional exposure focuses on the cases where
heightened oversight is potentially most important.
    Although pesticide studies which do not involve intentional
exposure would not be covered by this proposed extension of EPA's
Common Rule, FIFRA section 12(a)(2)(P) would apply

because a pesticide is involved. This provision of FIFRA makes it
unlawful for 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 or mental health consequences
which are reasonably foreseeable therefrom, and (ii) freely volunteer
to participate in the test.'' This essential protection of the
integrity and safety of the subjects does not depend on application of
the Common Rule to the research.
    The third element in the proposed extension of EPA's Common Rule is
the intent of the investigator to submit the research to EPA under the
pesticide laws. The proposed rule would apply only to research that was
intended, when it was initiated, to be submitted to EPA, or to be held
for EPA's later inspection, under FIFRA or FFDCA. The intent to submit
under the pesticide laws both defines the scope of the extension to
pesticides and their ingredients, and meets the requirement of the
Common Rule that covered research be ``otherwise subject to
regulation.'' Research not intended for submission to EPA may not meet
this standard.
    The proposal at Sec.  26.101(k) of the regulatory text also
specifies the following approach to determining the intention of
research sponsors or investigators to submit the results of the
research to EPA:
    For purposes of determining a person's intent under paragraph
(j) 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 its statutory
authorities and, at the time the research was initiated, the results
of the research would be relevant to EPA's exercise of that
statutory authority with respect to that class of people, products
or activities.

This would provide a straightforward basis for both researchers and the
Agency to determine before research is initiated whether the
requirements of EPA's Common Rule apply to it.
    EPA considered extending its codification of the Common Rule to all
human research which the Agency obtains and uses in its decision-
making, without regard to the intent of the investigators or sponsors
to submit it to the Agency. This approach would extend Common Rule
protections to the subjects of a wider range of research, but it would
entail serious problems in implementation. Much research of relevance
to EPA decision-making is conducted by people who are not regulated by
the Agency and can be presumed to have no intention to submit it to the
agency. This may include research done in academic institutions, much
research done outside the U.S., and a substantial portion of published
research. As a practical matter, EPA is unable to identify in advance
what research (conducted without the intention to submit it to EPA)
might someday be relevant to an EPA decision. Thus, a researcher could
not readily tell before conducting the research whether it would fall
within the scope of an extension of EPA's Common Rule. The researcher
would only know with certainty whether EPA had decided to use the
results of his or her research after it was completed, when it would be
impossible to comply with the Common Rule. The commitment to comply
with the Common Rule must be made before conducting the research, since
it imposes procedural and other requirements on the conduct of the
research. Thus, the requirement to comply with the Common Rule must
also be known before the research begins. While EPA has not put this
forward as its preferred approach, the Agency encourages comment and
suggestions that may modify its proposed position.
C. Topics for Public Comment
    The Agency has considered a number of alternatives to the proposed
rule and invites public comment on whether EPA should adopt any
combination of these alternatives for the final rule, including any
potential constraints:
    1. Extending the application of EPA's Common Rule to all research
with human subjects intended for submission to EPA under some or all of
its statutory authorities, rather than limiting it to studies intended
for submission under FIFRA or FFDCA.
    2. Limiting the application of EPA's Common Rule to research with
human subjects involving intentional exposure for the purpose of
identifying or measuring a toxic effect, rather than applying it to all
studies involving intentional exposure.
    3. Extending the application of EPA's Common Rule to all research
with human subjects, rather than limiting it to research involving
intentional exposure.
    4. Extending the application of EPA's Common Rule to all research
with human subjects that EPA uses in its decision-making, rather than
limiting it to research intended for submission to EPA.
    5. Adopting an alternative definition of intentional exposure that
would limit it to research conducted in laboratories or clinics, and
exposing subjects to an environmental substance at a level above the
median ambient levels in the environment.
    6. Adopting an approach to determining a person's intent to submit
research to EPA differing from that proposed in Sec.  26.101(k) of the
regulatory text.
    7. Codifying all requirements applicable to regulated third parties
in a separate part of 40 CFR, so that the provisions of 40 CFR part 26
would apply only to research conducted or supported by EPA.
All of the alternatives identified above assume that EPA would accept
for review, in at least some circumstances, some research involving
intentional exposure of a human subject to a pesticide. It should be
noted, however, that some public comments received on the ANPR
advocated a rule that would prohibit EPA from considering any research
involving intentional dosing of a human subject with a pesticide. EPA's
request for comment on an alternative reflecting that view appears in
Unit X.

V. Submission of Protocols, and Establishment of the Human Studies
Review Board

    This unit discusses rulemaking to require third parties who intend
to conduct covered human research to submit a protocol and other
information about the proposed research to EPA for a scientific and
ethical review, and to establish a Human Studies Review Board.
Summary of EPA Proposal
    EPA proposes to require prior submission of protocols and related
information for proposed third-party human research covered by the
rule. This rule as proposed would apply to the same range of research
to which EPA's Common Rule would be extended--i.e., all intentional
dosing human studies intended for submission to EPA under the pesticide
laws. EPA also proposes to establish a Human Studies Review Board to
provide an additional scientific and ethical peer review for such
research. Finally, the Agency proposes to require that submitted
reports of covered third-party studies include detailed documentation
of the ethical conduct of the studies.

A. Background

    The Common Rule requires that the protocol and other information
concerning any proposed human

research be reviewed and approved by an IRB before the research is
initiated. The Common Rule further provides that although a decision by
an IRB to reject a proposal cannot be overruled, requirements in
addition to IRB approval may be imposed before research may proceed. 40
CFR 26.103, 26.112, and 26.124.
    Since its adoption of the Common Rule, EPA has followed an internal
procedure requiring prior approval by the Agency's Human Subjects
Research Review Official (HSRRO) of all proposed first- and second-
party research with human subjects conducted or supported by EPA, in
addition to and subsequent to approval of the research proposal by the
cognizant local IRB.
    In addition to compliance with its rules equivalent to the Common
Rule (21 CFR parts 50 and 56), FDA rules governing research with
Investigational New Drugs (INDs) require FDA's prior review of
protocols for certain clinical studies for INDs. See 21 CFR part 312.
    The NAS committee addressed the question of prior EPA review of
protocols for proposed human studies directly in their recommendation
6-2:
    To ensure that intentional dosing studies conducted for EPA
regulatory purposes meet the highest scientific and ethical
standards, EPA should establish a Human Studies Review Board to
address in an integrated way the scientific and ethical issues
raised by such studies. To the extent possible, this board should
review in a timely manner the protocols and the justification for
all intentional dosing studies intended for submission to EPA, as
well as study results when completed. These reviews should be
conducted regardless of the sponsor or site of performance, and EPA
should communicate the results of the reviews to relevant parties.

    In the discussion supporting this recommendation, the NAS Committee
advocated that EPA's review of protocols should precede review by local
IRBs, so that each IRB, which is likely to see proposals for research
with environmental substances only infrequently, would have the benefit
in their deliberations of the review by the EPA board, which would see
all such proposals, and would develop specialized expertise in their
assessment. NAS Report, p. 135.
    The NAS Committee envisioned a process of prior review of protocols
analogous to that used by FDA in their review of protocols for INDs.
They further recommended that the conclusions of the EPA protocol
review should be advisory, rather than mandatory, that the Human
Studies Review Board should be relatively small, consisting of
individuals with expertise in both scientific disciplines and
bioethics, and should report directly to the Office of the
Administrator of EPA. NAS Report, pp. 135-36.
    The NAS Committee also considered whether submission of protocols
for proposed research to EPA should be mandatory or voluntary:
    The main argument for mandatory review was the importance of
this review process. . . . [R]equiring review of proposed
experiments in advance would lead to fewer inappropriate studies. In
addition, making pre-experiment review mandatory should build public
confidence that problematic experiments are being minimized and
would guarantee that EPA knew of all relevant industry-sponsored
experiments. [NAS Report, p. 138.]

    In summary the Committee stated on p. 138:
    Ultimately the committee concluded that pre-experiment review of
studies intended for submission to EPA should be mandatory, if
legally and logistically feasible.

B. Proposal

    EPA proposes to require prior submission of protocols and related
information for proposed third-party human research covered by the
rule. The rule would apply to the same range of research to which EPA's
Common Rule would be extended--i.e., all intentional dosing human
studies intended for submission to EPA under the pesticide laws. EPA
also proposes to establish a Human Studies Review Board to provide an
additional scientific and ethical peer review for such research.
Finally, the Agency proposes to require that submitted reports of
covered third-party studies include detailed documentation of the
ethical conduct of the studies.
    The Agency agrees with the NAS that review of proposals by EPA and
the Human Studies Review Board (HSRB) could identify scientific and
ethical concerns that an IRB might not recognize. The Agency also
thinks that the number of studies likely to be submitted and the
resulting review burden will be consistent with timely responses to
protocol submissions.
    There are potential advantages to placing the EPA review of
proposals either before or after the review by local IRBs. On the one
hand, the NAS committee argues that if the EPA and HSRB reviews come
first, it would improve the consistency and quality of the reviews and
benefit the local IRBs who would be likely to see far fewer study
proposals of this sort than the EPA reviewers. On the other hand,
reviewing the proposals after IRB approval would be consistent with
FDA's practice in reviewing clinical trials for investigational new
drugs, and with EPA's practice in overseeing its own first- and second-
party research, and would give the EPA reviewers the benefit of the
results of the IRB review. This sequence would also reinforce the
centrality of the IRB judgment in the overall scheme of implementing
the Common Rule.
    Based on its experience with central review of its first- and
second-party research with human subjects, EPA is concerned that if the
HSRB review precedes the IRB review, many relatively routine issues of
research design and documentation now handled between the IRB and
investigators would add to the workload of the HSRB. Conversely, if the
IRB reviews at the relevant institutions are placed first in sequence,
they will continue to solve many of the general ethics and science
considerations commonly encountered in study design, facilitating a
more focused and efficient secondary review by the HSRB of issues
peculiar to covered studies. The HSRB could share accumulated insights
about the issues surrounding intentional dosing studies with
environmental substances through guidance to IRBs to inform their
future consideration of covered studies.
    Based on this reasoning, EPA proposes to require submission of
protocols for review by EPA staff and the HSRB after approval of the
proposal by the local IRB(s). EPA welcomes comment on this issue.
    The proposal also specifies the range of information to be provided
with submitted protocols, and with the results of the research. This
list of topics is derived from the Common Rule criteria for IRB
approval of proposed research at 40 CFR 26.111. This information will
have been gathered for presentation to the IRB, and it should not be
any additional burden to provide the same range of information to the
Agency.
    As recommended by the NAS, EPA proposes to establish a Human
Studies Review Board (Board) to address in an integrated way the
scientific and ethical issues raised by such studies. Specifically, the
Agency proposes 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. After completing its initial
staff assessment of a research proposal, the Agency would send its
review, the proposal, and supporting materials to the Board for further
review and

comment. As recommended by the NAS, EPA intends to reexamine the
functions of the Human Studies Review Board after 5 years.

C. Topics for Public Comment

    The Agency has considered alternatives to the proposed rule and
invites public comment on whether EPA should adopt any of these
alternatives for the final rule:
    1. To what extent should EPA define by rule the range of functions
of the HSRB, its procedures, or how it should be constituted? What
should its functions be? How should it operate? Should it be formed
under the Federal Advisory Committee Act (FACA), or some other
authority? How best could its independence and integrity be protected
from improper influence?
    2. Should review of protocols for proposed research by EPA and the
HSRB precede (as recommended by the NAS) or follow (as proposed) review
by the local IRB?
    3. Should submission of protocols for EPA and HSRB review before
conduct of the research be made entirely voluntary?
    4. How much time should be allowed for review by EPA and HSRB of
submitted protocols? Should the rule establish a deadline for EPA's
response and define the consequence of missing such a deadline?
    5. Should more or less information be required about proposed
research than is specified in the proposed rule? For example, should
EPA specify elements of the protocol that must be contained in the
description of the ``research proposal''? Might the rule exempt from
submission certain types of correspondence between an investigator and
an IRB, such as correspondence concerning financial arrangements?
    6. Should more or less documentation of the ethical conduct of the
research be required than is specified in the proposed rule, when the
results of the research are submitted to the Agency? For example, might
the rule require additional information comparing the demographic
characteristics of the study subjects to the demographics of the larger
population from which the prospective participants were recruited? Or
might the rule exempt from submission with the report of completed
research documentation previously provided during the protocol review?
    7. Should the scope of the requirement to submit proposed protocols
be identical to the scope of third-party research covered by the
extension of EPA's Common Rule, as that might be expanded under some of
the alternatives listed for public comment in Unit IV.? For example, if
the scope of subpart A were expanded to cover all human research
intended for submission to EPA, should protocol submission be required
for the same range of research, or might protocol submission be limited
to human research involving intentional exposure?
    8. Should EPA establish, by rule, criteria identifying types of
protocols (e.g., skin irritation studies on products intended for use
involving long-term contact with human skin such as commercial
detergents and some consumer products) that may not warrant review by
the Human Studies Review Board and, if so, what should those criteria
be?

VI. Additional Protections for Children

    This unit concerns rulemaking to establish additional protections,
beyond the Common Rule, for children who may be subjects in research.
Summary of EPA Proposal
    EPA proposes to categorically prohibit third parties engaged in
research covered by the proposed extension of EPA's Common Rule from
conducting any study involving intentional dosing of children, and to
apply the same prohibition to human research that EPA conducts or
supports. EPA further proposes to prohibit its own reliance in its
decision-making under the pesticide laws on any research involving
intentional dosing of children. Finally, as recommended by NAS, EPA
proposes to adopt formally additional protections for children as
subjects of other than intentional dosing research--protections it has
long applied in practice in research which it conducts or supports.

A. Background

    EPA has never conducted or supported intentional dosing studies
with children, but EPA has both conducted and sponsored observational
studies in which some of the subjects were children. None of these
studies have involved intentional dosing. They were observational
studies that did not alter the children's exposure to substances
routinely experienced in their community. Many of these studies have
collected data on children's activity patterns (e.g., time spent
indoors, outdoors, sleeping, playing). Other research involving
children has measured their levels of exposure to environmental
substances in their daily lives--for example, monitoring pesticide
levels in the urine of children whose parents work on farms where
pesticides are used. Whenever the Agency conducts or supports
scientific studies involving children, EPA not only follows the
requirements of its Common Rule but also, as a matter of practice,
applies the additional protections established by HHS for research with
children.
    While it has not been common in recent years for third parties to
perform research on environmental substances with children, it should
be noted that EPA has received data from several previously conducted
third-party studies involving children. Most of these studies were
conducted in the last century, well before the Common Rule was adopted.
EPA cannot, of course, predict how many studies involving children that
third parties may conduct in the future, but based on recent
experience, the Agency thinks it likely there will be very few, if any.
    As part of its discussion of issues related to the selection of
research subjects, the NAS report specifically addressed whether and
when children could ethically be allowed to participate in human
research. Among other things, the NAS concluded that children, as
potential subjects in human research, raise special concerns. Not only
do children--particularly younger children--have less capacity to
understand the potential consequences from participation in a human
study, but they are also quite vulnerable to influence by adults. Both
factors make compliance with the principle of voluntary, informed
consent more difficult.
    While the NAS Report did not directly address whether it would ever
be ethical to conduct a study intentionally exposing children to
substances to determine their toxicity, we think the NAS did not
believe such testing could ever be justified. In 2004, when the NAS
released the report and panelists answered reporters' questions, the
panelists explained that they could not envision any situation in which
an investigator or the head of an agency could satisfy the ethical
standards for testing a pesticide on children to determine whether (or
at what level) it caused adverse effects. See http://www.nap.edu/webcast/
 webcast--detail.php? webcast--id=264.

    HHS has addressed these issues in a regulation promulgated in 1983.
Additional Protections for Children Involved as Subjects in Research,
48 FR 9814 (March 8, 1983). This regulation, codified at 45 CFR part
46, subpart D (Sec. Sec.  46.401 through 46.409), applies only to
research involving children as subjects which is conducted or supported
by HHS or conducted by third parties under a Federal-wide Assurance
(FWA) approved by OHRP. The HHS regulation greatly restricts the
enrollment of children in research involving greater than minimal risk.

    In 1997, the Education Department adopted similar rules to govern
research involving children as subjects that it conducts or supports.
See Additional ED Protections for Children Who Are Subjects in
Research, 62 FR 63221 (November 26, 1997), codified at 34 CFR part 97,
subpart D, Sec. Sec.  97.401 through 97.409. In 2001, the Food and Drug
Administration promulgated an interim final rule, codified at 21 CFR
50.51 through 50.56, establishing additional protections for children
participating in certain clinical investigations conducted by third
parties. Additional Safeguards for Children in Clinical Investigations
of FDA-Regulated Products, 66 FR 20589 (April 24, 2001). Although the
FDA and HHS rules are essentially equivalent in content, the FDA rule
applies only to research conducted by regulated third parties.
    In its Recommendation 5-2 the NAS Committee recommended:
    EPA should adopt Subpart D of the Regulations for the Protection
of Human Research Subjects. At a minimum, EPA should adhere to
Subpart D's requirements for research involving children.

B. Proposal

    EPA proposes to categorically prohibit third parties engaged in
research covered by the proposed extension of EPA's Common Rule from
conducting any study involving intentional dosing of children, and to
apply the same prohibition to human research that EPA conducts or
supports. EPA further proposes to prohibit its own reliance in its
decision-making under the pesticide laws on any research involving
intentional dosing of children. Finally, as recommended by NAS, EPA
proposes to adopt formally additional protections for children as
subjects of other than intentional dosing research--protections it has
long applied in practice in research which it conducts or supports.
    EPA is proposing to adopt and incorporate into a new subpart D of
40 CFR part 26 the essential content of subpart D of the HHS rule, 45
CFR part 46, with certain changes. EPA has made minor editorial changes
to the adopted language necessary to reflect that the proposed rule
would apply to third parties as well as to EPA, and would be
implemented by EPA. Substantive changes are limited to: (1) Making the
rule applicable to the same kinds of third-party research that would be
covered by the extension of EPA's Common Rule by proposed Sec.
26.101(j), (2) defining ``children'' as persons under the age of 18,
and (3) creating placeholders for (but not adopting) the provisions in
45 CFR 46.406, 46.407 and 46.409 by reserving 40 CFR 26.406, 26.407,
and 26.409. EPA does not consider these provisions applicable to
research with environmental substances.
    EPA opposes research involving intentional exposure of children,
and believes that prohibiting such research represents sound public
policy. With this in mind, EPA has chosen not to propose rule text
comparable to the HHS rules at 45 CFR 46.406 or 46.407, and has
identified those sections in the proposed EPA rule as ``Reserved.'' 45
CFR 46.409 has been reserved in the proposed EPA rule as well, since it
concerns only research approved under 45 CFR 46.406 or 46.407.
    EPA also proposes to add at the end of subpart D rules which would:
(1) Prohibit both EPA and third parties covered by proposed Sec.
26.101(j) from conducting or supporting an intentional dosing study
involving children, and (2) prohibit EPA itself from relying in its
decision-making under the pesticide laws on any research involving
intentional dosing of children with pesticides.
    EPA proposes to change the definition of ``children'' from the HHS
standard to define a finite upper age limit of 18. The HHS definition
in 45 CFR 46.402(a) defers to local standards:
    Children are persons who have not attained the legal age for
consent to treatments or procedures involved in the research, under
the applicable law of the jurisdiction in which the research will be
conducted.

EPA notes that 18 is the age of majority in the U.S. for essentially
all purposes except the purchase of alcohol. At 18 one can enlist in
the military or vote. Minor wards of the courts are discharged as
adults at age 18. Eighteen is also typically the minimum age for
participation in human research as an adult subject. Public comment is
invited on whether a finite upper age limit is needed in the definition
of ``children,'' and if so, whether it should be 18 or a different age.

C. Topics for Public Comment

    The Agency has considered a number of alternatives to the proposed
rule and invites public comment on whether EPA should adopt any of
these alternatives for the final rule:
    1. Should the proposed subpart D regulations apply to broader or
narrower categories of third-party research identified in Unit IV. of
this preamble, possibly covering all research intended for submission
to EPA involving intentional exposure of human subjects to any class of
environmental substance; or covering all research being considered by
EPA, etc.?
    2. Should the scope of the ban on conducting new intentional dosing
research involving children as subjects, proposed at Sec.  26.240 of
the regulatory text, be made broader or narrower?
    3. Should the scope of the ban on EPA's reliance in its decision-
making on intentional dosing research involving children as subjects,
proposed at Sec.  26.421 of the regulatory text, be made broader or
narrower?
    4. Should ``children'' be defined as persons under the age of 21,
or some other finite age than the age of 18 as proposed? Or should EPA
adopt unchanged the definition of ``children'' in the HHS regulation at
45 CFR 46.402(a)?
    5. Should EPA adopt the sections of the HHS subpart D regulation it
has proposed to reserve, including 45 CFR 46.406, addressing ``research
involving greater than minimal risk and no prospect of direct benefit
to individual subjects, but likely to yield generalizable knowledge
about the subject's disorder or condition''; 45 CFR 46.407, addressing
``research not otherwise approvable which presents an opportunity to
understand, prevent, or alleviate a serious problem affecting the
health or welfare of children''; and 45 CFR 46.409, addressing
inclusion of wards in research approved under 45 CFR 46.406 or 46.407?
    6. Under what circumstances, if any, should EPA be permitted to
rely in its decision-making under the pesticide laws on research
involving intentional dosing of children?

VII. Additional Protections for Pregnant Women, Fetuses, and Certain
Newborns

    This unit concerns rulemaking to establish additional protections,
beyond the Common Rule, for pregnant women, fetuses, and newborns who
may be subjects in research.
Summary of EPA Proposal
    EPA proposes to categorically prohibit third parties engaged in
research covered by the proposed extension of EPA's Common Rule from
conducting any study involving intentional dosing of pregnant women,
fetuses, or newborns, and to apply the same prohibition to human
research that EPA conducts or supports. EPA further proposes to
prohibit itself from relying in its decision-making under the pesticide
laws on research involving intentional dosing of pregnant women,
fetuses, or newborns. Finally EPA proposes to adopt formally additional
protections for pregnant women, fetuses, and newborns as subjects of
other than intentional dosing research--protections it has long applied
in

practice in research which it conducts or supports.

A. Background

    EPA has never conducted or supported intentional dosing studies
with pregnant women, but over the years, EPA has both conducted and
sponsored observational studies in which some of the subjects were
pregnant women. They were observational studies which did not involve
any intentional exposure, and participation in them as subjects did not
alter the exposure of the pregnant women to substances routinely
experienced in their daily lives. For example, EPA, through the STAR
(Science to Achieve Results) grant program, has awarded grants for both
urban and rural studies on pregnant women and children in partnership
with the National Institutes of Health as part of the Centers for
Children's Environmental Research and Disease Prevention. These
research centers are multi-disciplinary and foster community
participation in multiple aspects of the research process. The results
are directly relevant to the development of estimates of pesticide
exposure for pregnant women, fetuses, and very young children; to
assessment of genetic susceptibility to pesticide poisoning; and to
application of proposed EPA guidelines for cumulative risk assessment
of mixed exposures to multiple pesticides. These are the first
investigations of the potential health consequences of pesticide
exposures to young children to include in-depth assessments of
children's physical and neuro-behavioral development and respiratory
health. This research also characterizes pesticide and allergen levels
in the home environment, resident density, and child safety, and tests
the effectiveness of interventions aimed at reducing pesticide
exposures.
    It has not been common for third parties to perform research with
environmental substances involving pregnant women, fetuses, or
newborns. EPA is unaware of any such studies with any pesticide or
other environmental substance.
    As an essential precondition for approving any proposed research
with human subjects, the Common Rule requires that IRBs find that
subject selection is equitable. At 40 CFR 26.111(a)(3) EPA's
codification of the Common Rule explains:
    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
children, prisoners, pregnant women, mentally disabled persons, or
economically or educationally disadvantaged persons.

    HHS has taken further steps to provide additional protections
specific to pregnant women, fetuses, and newborns as subjects of
research. In a regulation initially promulgated on August 8, 1975 (40
FR 33526) and revised several times since, codified as 45 CFR part 46,
subpart B (45 CFR 46.201 through 46.207), HHS defines stringent
constraints on research with these particularly vulnerable populations.
The HHS subpart B does not rule out research with these groups when it
would involve direct benefit to them, but it requires an especially
high standard of justification and imposes many procedural and other
constraints on research which would not confer a direct benefit on the
subjects. The HHS subpart B regulation applies only to research
conducted or supported by HHS (or conducted under an applicable
assurance of compliance approved by OHRP and voluntarily extended to
cover other research). The FDA has neither proposed nor promulgated a
version of the HHS subpart B that would apply to research conducted by
third parties regulated by FDA.
    The NAS Report did not expressly address the topic of additional
protections for research involving pregnant women, fetuses, and
newborns. It did, however, discuss several general considerations
affecting the equitable selection of research subjects. Citing the
Belmont Report's principle of justice and the general requirement in
the Common Rule that ``selection of subjects is equitable,'' the NAS
identified a range of considerations:
    the study population needs to be representative of the target
population of interest in order for the research results to be
applicable (p. 114);
    the selection of research participants should be inclusive in
order to avoid the exploitation and appearance of exploitation of
any particular social group (p. 114);
    some persons may be vulnerable to coercion or undue influence
and hence may need additional safeguards (p.115); and
    some individuals are potentially more vulnerable to harm in
research protocols and therefore . . . investigators may need to
take steps to minimize risks, such as excluding those who would face
higher risks (p.115).

Based on these general considerations, in its Recommendation 5-2 the
NAS recommended in part:
    IRBs reviewing intentional human exposure studies should ensure
that the following conditions are met in selecting research
participants:
    a. Selection should be equitable.
    b. Selection of persons from vulnerable populations must be
convincingly justified in the protocol, which also must justify the
measures taken to protect those participants.
    c. Selection of individuals with conditions that put them at
increased risk for adverse effects in such studies must be
convincingly justified in the protocol, which must justify the
measures that investigators will use to decrease the risks to those
participants to an acceptable level.

    While the NAS Report did not directly address whether it would ever
be ethical to conduct a study intentionally exposing pregnant women or
fetuses to substances to determine their toxicity, we think the NAS did
not believe such testing could ever be justified. In 2004, when the NAS
released the report and panelists answered reporters' questions, the
panelists explained that they could not envision any situation in which
an investigator or the head of an agency could satisfy the ethical
standards for testing a pesticide on pregnant women to determine
whether (or at what level) it caused adverse effects. See http://www.nap.edu/webcast/
 webcast--detail.php? webcast--id=264.

B. Proposal

    EPA proposes to categorically prohibit third parties engaged in
research covered by the proposed extension of EPA's Common Rule from
conducting any study involving intentional dosing of pregnant women,
fetuses, or newborns, and to apply the same prohibition to human
research that EPA conducts or supports. EPA further proposes to
prohibit itself from relying in its decision-making under the pesticide
laws on research involving intentional dosing of pregnant women,
fetuses, or newborns. Finally EPA proposes to adopt formally additional
protections for pregnant women, fetuses, and newborns as subjects of
other than intentional dosing research--protections it has long applied
in practice in research which it conducts or supports.
    EPA is proposing to adopt and incorporate into a new subpart B of
40 CFR part 26 the essential content of subpart B of the HHS rule, 45
CFR part 46, with only a few changes. EPA has made minor editorial
changes to the language adopted necessary to reflect that the proposed
rule would apply to third parties as well as to EPA, and would be
implemented by EPA. Substantive changes are limited to: (1) Making the
rule applicable to the same kinds of third-party research that would be
covered by the proposed amendments to EPA's subpart A; and (2) creating
a placeholder for (but not

adopting) the provisions in 45 CFR 46.207 by reserving 40 CFR 26.207,
which EPA considers not to be appropriate for research with
environmental substances.
    EPA intends that the standards contained in proposed Sec. Sec.
26.204 and 26.205 of the regulatory text would preclude any research
with pregnant women, fetuses, or neonates who would not benefit
directly from the research. EPA further believes that no pregnant
woman, fetus, or neonate could possibly benefit directly from a study
involving their intentional exposure to a pesticide, and thus believes
such research could never be approved under the provisions of the
proposed rule.
    EPA opposes research involving intentional exposures to pregnant
women, fetuses, or newborns, and believes this to be sound public
policy. So as to eliminate even a theoretical possibility such research
could be approved, we have chosen not to propose adopting 45 CFR
46.207, which provides a procedure for approving in exceptional cases
research which does not meet the standards of 45 CFR 46.204 or 46.205.
    EPA is also proposing at Sec.  26.220 of the regulatory text to
prohibit both EPA and third parties covered by proposed Sec.  26.101(j)
from conducting or supporting an intentional dosing study involving as
subjects pregnant women, fetuses, or newborns. Finally, EPA is
proposing at Sec.  26.221 of the regulatory text to prohibit itself
from relying in its decision-making under the pesticide laws on
research involving intentional dosing of pregnant women, fetuses, or
newborns.

C. Topics for Public Comment

    The Agency has considered a number of alternatives to the proposed
rule and invites public comment on whether EPA should adopt any
alternatives for the final rule.
    1. Should the proposed subpart B regulations apply to any of the
broader or narrower categories of third-party research identified in
Unit IV. of this preamble, possibly covering all research intended for
submission to EPA involving intentional exposure of human subjects to
any class of environmental substance; or covering all research being
considered by EPA, etc.?
    2. Should the scope of the ban on conducting new intentional dosing
research involving pregnant women, fetuses, or newborns as subjects,
proposed at Sec.  26.220 of the regulatory text, be made broader or
narrower?
    3. Should the scope of the ban on EPA's reliance in its decision-
making on intentional dosing research involving pregnant women,
fetuses, or newborns as subjects, proposed at Sec.  26.221 of the
regulatory text, be made broader or narrower?
    4. Should EPA adopt the section of the HHS subpart B regulation it
has proposed to reserve, 45 CFR 46.207, addressing ``research not
otherwise approvable which presents an opportunity to understand,
prevent, or alleviate a serious problem affecting the health or welfare
of pregnant women, fetuses, or neonates''?
    5. Under what circumstances, if any, should EPA be permitted to
rely in its decision-making under the pesticide laws on research
involving intentional dosing of pregnant women, fetuses, or newborns?

VIII. Additional Protections for Prisoners

    This unit explains EPA's decision to defer at this time proposal of
rules providing additional protection for prisoners, comparable to
those adopted by HHS and codified at 45 CFR part 46, subpart C.

A. EPA Rationale for Deferral

    EPA has decided to defer adoption of the HHS subpart C rules at
this time for a number of reasons. First, many people in the ethics
community have concluded that these rules create as many problems as
they solve, providing inadequate protections for prisoners,
discouraging research on issues affecting prisoners, and sometimes
putting subjects of ongoing research at avoidable risk when they become
prisoners. HHS and its advisory committee, the Secretary's Advisory
Committee on Human Research Protections (SACHRP), are actively
considering revisions to the HHS subpart C, which has not been changed
since its adoption in 1978. EPA is monitoring the work of this
committee with interest, and will reconsider adopting additional
protections for prisoners as subjects of research when its
recommendations are known.
    In addition, EPA has never conducted or supported any human studies
with prisoner subjects, and has no intention to do so in the future.
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. We do not expect any to be submitted
to us in the future.
    Finally, if either EPA or third parties should consider performing
studies with prisoner subjects, the prisoners' participation would
still be governed by the provisions in EPA's Common Rule requiring
additional protections (40 CFR 26.111(a)(3) and 26.111(b)) and special
care in informed consent (40 CFR 26.116) when dealing with populations
vulnerable to coercion or undue influence.

B. Topics for Public Comment

    The Agency has considered a number of alternatives to the position
described and invites public comment on whether EPA should adopt any of
these alternatives for the final rule:
    1. Should EPA adopt an appropriately revised version of the HHS
subpart C regulation for application to research conducted or supported
by EPA or third parties, possibly including any of the types of
research or categories of third parties discussed in Unit IV.?
    2. Should EPA include in its final regulation an express
prohibition on any research involving intentional dosing of prisoners
with pesticides?

IX. Potential Consequences for Failure to Comply With the Requirements
of the Common Rule Within the Scope of Today's Proposed Rule

Summary of EPA Proposal
    To encourage compliance with the requirements of subparts A through
D of this action, EPA proposes, as circumstances warrant, to: (1)
Refuse to rely on the results of any research that does not comply with
these requirements; (2) seek withdrawal or suspension of a research
institution's Federal-wide Assurance; (3) disqualify a research
institution or its IRB; (4) debar an entity from receiving federal
funds for research; or (5) present 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.
These provisions in proposed Sec. Sec.  26.501 through 26.504 and Sec.
26.506 of the regulatory text closely follow FDA's existing regulations
in 21 CFR 56.120 through 56.124.

A. Background

    There are a number of options available to agencies seeking to
penalize first- or second-party researchers that fail to comply with
applicable provisions of the Common Rule. (See the NAS Report, pp. 60-
61). Funding or sponsoring agencies may: (1) Terminate or suspend the
offending research; (2) suspend funding for the research; (3) require
written responses regarding alleged deficiencies, or enactment of
specific changes to research protocols to address the problems; (4)
seek withdrawal of the OHRP-issued Federal-wide Assurance necessary to
conduct

the research; or (5) disqualify an IRB. With respect to third-party
human research that is not conducted or sponsored by a federal agency,
some or all of these options may be inapplicable.
    A potential consequence for the conduct of research by a third-
party that fails to comply with Common Rule requirements that EPA has,
by rule, made applicable is for the Agency to refuse to rely on the
data in regulatory decision-making. The NAS Report (p. 125)
specifically recommends that EPA ``not use data from ethically
problematic studies to inform its regulatory efforts.'' Recommendation
5-6 of the NAS (p. 127, italics in original) provides that EPA should
operate on the strong presumption that data obtained in studies
conducted after implementation of the new rules that do not meet the
ethical standards described in this report will not be considered in
its regulatory decisions. Similarly, a number of commenters have
suggested that EPA should not accept, consider, or rely upon any human
subjects studies that are ethically deficient. The NAS avers (p. 125)
that the question of addressing human subjects studies that are non-
compliant with ethical standards ``will rarely arise, especially after
EPA formulates its standards and procedures.'' EPA hopes such a
situation will never arise. Nonetheless, it is incumbent upon the
Agency to address the potential consequences should such non-compliance
occur.
    EPA is proposing to extend the requirements of its codification of
the Common Rule to third party intentional exposure studies intended to
be submitted under FIFRA or FFDCA. The Agency proposes to apply the
measures described in proposed subpart E of the regulatory text to this
research; the Agency would not apply any of these measures to research
falling outside this scope. In considering the issue of the appropriate
potential consequences for failure to comply with the requirements set
forth in this proposed rule for such studies submitted under FIFRA or
FFDCA, the Agency notes that FIFRA speaks specifically to ethical
considerations for human subjects research involving pesticides. FIFRA
section 12(a)(2)(P) expressly declares it unlawful for 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 consequences which are reasonably foreseeable
therefrom and (ii) freely volunteer to participate in the test.''
Violations of FIFRA section 12(a)(2)(P) are subject to civil and
criminal penalties under section 14 of FIFRA. Given that FIFRA
expressly requires that human subjects studies using pesticides include
specific protections for the human subjects in such studies, we believe
that, where these requirements have been violated, EPA is authorized to
refuse to rely on the data and other information resulting from such
studies. The Agency believes that, as a matter of policy, it would be
appropriate to decline, at least in some circumstances, to use in
regulatory decision-making under FIFRA the results of research that is
unlawful under FIFRA. Refusal to rely on data from completed human
studies which do not comply with applicable requirements of this part
is discussed further in Unit X.
    Thus, while EPA is proposing in some cases to refuse to rely on
data generated from ethically deficient human studies, we note that
refusal to rely on it is not the only possible response to the
discovery of ethical deficiencies in human research. The NAS Report
identifies a number of measures that HHS and FDA currently use to
encourage compliance. With respect to third-party research, possible
responses include declaring a particular entity ineligible to receive
future federal support to conduct human research; suspending or
withdrawing a ``Federal-wide Assurance'' (FWA) held by a research
institution or the approval of the IRB; disqualifying an IRB; and
addressing the ethical deficiencies of the research in a public notice
(which, however, would not necessarily preclude consideration of the
data in regulatory decision-making).
    The first two options described are among the most powerful
measures available to HHS for addressing problematic conduct under the
Common Rule. The Office for Human Research Protection (OHRP) of HHS
issues FWAs to institutions that commit to follow the Common Rule for
all federally funded human research performed at the institution, and
institutions may voluntarily commit to follow the Common Rule in all
their research, without regard to sources of funding or other support.
An FWA permits an institution to receive EPA contracts and grants to
perform human research. If OHRP determines that an institution is not
complying with the Common Rule, it may withdraw or suspend approval of
the FWA, thereby preventing the institution from conducting any
federally supported human research until HHS deems it deserves to have
the FWA reinstated. FDA also exercises a similar authority directed at
IRBs or institutions which fail to fulfill their responsibilities under
the FDA rules governing third-party human research. Currently, EPA
relies on OHRP's established mechanisms when EPA deems it necessary to
seek withdrawal of a FWA.
    In more egregious cases EPA might disqualify specific investigators
or institutions from eligibility to receive federal contracts or grants
through a process called ``debarment.'' Debarment proceedings follow a
common procedure throughout the Federal government, and debarment by
one federal agency would effect a government-wide ban on that entity's
receiving federal support for research.
    Finally, we are aware of no barriers to the Agency's publishing an
objective analysis of ethical conduct of any human research that it may
rely on in its regulatory decision-making. A candid public discussion
of any ethical shortcomings of such research accompanied by a
discussion of its scientific strengths, limitations, and findings, and
of the regulatory context of the Agency's decision can communicate both
why it was deemed necessary to consider the research, and the distaste
associated with relying on ethically deficient research. Full public
discussion of the ethical shortcomings of human research can contribute
a strong disincentive to repetition of such ethically deficient conduct
by the investigator and others.

B. Proposal

    To encourage compliance with the requirements of subparts A through
D of the regulatory text, EPA proposes, as circumstances warrant, to:
(1) Refuse to rely on the results of any research that does not comply
with these requirements; (2) seek withdrawal or suspension of a
research institution's FWA; (3) disqualify a research institution or
its IRB; (4) debar an entity from receiving federal funds for research;
or (5) present 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. These provisions in
proposed Sec. Sec.  26.501 through 26.504 and Sec.  26.506 of the
regulatory text closely follow FDA's existing regulations in 21 CFR
56.120 through 56.124.

C. Topics for Public Comment

    The Agency has considered a number of alternatives to the proposed
rule and invites public comment on whether EPA should adopt any
alternatives for the final rule.
    1. Are any additional measures available to enforce third-party

compliance with applicable provisions of proposed subparts A, B, and D?
    2. Should EPA define by rule criteria for determining the most
appropriate consequences for those who conduct or sponsor ethically
deficient human subjects. If so, what should those criteria be?
    3. If the scope of the extension of EPA's Common Rule were broader
or narrower than proposed in Sec.  26.101(j) of the regulatory text,
would the same or a different range of potential consequences for
failure to comply with Common Rule requirements apply?
    4. FDA has published at 21 CFR part 16 regulations establishing
procedures for deciding whether to disqualify an IRB or institution
that has failed to comply with applicable requirements. Should EPA
pursue rulemaking to establish procedural regulations similar to those
of FDA?

X. Ethical Standards for Determining Whether to Rely on Scientifically
Sound, Completed Human Studies with Ethical Deficiencies

    This unit concerns rulemaking to establish ethical standards EPA
would apply in deciding whether to rely on the results from a
scientifically sound completed human study deemed relevant to an EPA
action. Other parts of today's proposal address conduct of both EPA and
certain third parties in the roles of investigators or sponsors of
research with human subjects. It is in the capacity of investigators
that both EPA and covered third parties are prohibited by this proposal
from conducting or sponsoring intentional dosing studies involving
pregnant women, infants, or children as subjects of the research.
    By contrast, this part of the rulemaking would govern EPA's conduct
as a regulatory agency, as it makes decisions to consider or not to
consider reports of completed research with human subjects in its
scientific assessments, and to rely on or not to rely on such research
in its regulatory decisions. The Agency recognizes that the possibility
of EPA refusal to rely on the results of research that does not meet
appropriate ethical standards may influence the behavior of third
parties. The Agency hopes that such a prospect would, along with other
factors, be enough to encourage sponsors and investigators to conform
to high ethical standards when performing covered human research.
Summary of EPA Proposal
    In a new subpart F of 40 CFR part 26, EPA proposes ethical
standards for its decisions to rely on or not to rely on in its
decision-making reports of completed intentional-dosing research with
human subjects being considered under FIFRA or FFDCA. For covered types
of research conducted after the effective date of the rule, EPA
proposes to refuse to rely on data from scientifically sound and
relevant human research unless EPA has adequate information
demonstrating that the research complied with the Common Rule. For
covered types of research conducted before the effective date of the
rule, EPA proposes to rely on data from scientifically sound and
relevant human research unless there is clear evidence to show the
conduct of the research was fundamentally unethical or was
significantly deficient relative to the ethical standards prevailing at
the time the research was conducted. EPA also proposes a formal process
to make an 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.

A. Background

    The NAS Report specifically addressed the issue of what role, if
any, ethically deficient or unethical studies should play in EPA's
regulatory decisions. The NAS predicted that the problem would rarely
arise, especially once EPA formulated its standards and established
them though rulemaking or other means. Nonetheless, the NAS
acknowledged that, when it arises, the decision is ``ethically vexing''
(p. 125) because ``two important goals come into conflict: first, using
the best scientific data to protect the public and, second, avoiding
incentives for the conduct of unethical research involving humans and
undermining important ethical principles'' (p. 126). The NAS recognized
that different considerations could affect how this decision is made,
depending primarily on when the ethically problematic research was
performed in relation to EPA's articulation of its standards.
Accordingly, the NAS recommended two standards for acceptance, applying
respectively to research conducted after EPA establishes new standards,
and to research conducted before EPA establishes new standards.
    For research conducted after EPA establishes new standards i.e.,
after these proposed rules are promulgated in final form, the NAS
expected there to be relatively few deficiencies. The NAS assumed that
EPA and the HSRB would review both scientific and ethical aspects of
proposed human research before it is conducted. To the extent EPA
identified ethical issues, the NAS further assumed the Agency would
inform the researcher who, in turn, would make appropriate changes. In
its recommendation 5-6 NAS advised EPA as follows:
    EPA should operate on the strong presumption that data obtained
in studies conducted after implementation of the new rules* that do
not meet the ethical standards described in this report will not be
considered in its regulatory decisions. Under exceptional
circumstances, studies that fail to meet these ethical standards may
provide valid information to support a regulatory standard that
would provide greater protection for public health. Under these
circumstances, EPA should convene a special, outside panel,
consisting of relevant experts and members of the public, to examine
the cases for and against considering data from such studies.
[*Note: a footnote here in the text of NAS Recommendation 5-6 reads:
``The committee uses the term ``rules'' informally to mean guidance,
guidelines, policy, protocols, rules, or regulations.'']

    In explaining this recommendation, the NAS discussed and rejected
the position favoring a categorical refusal to rely on the results of
any ethically deficient study. The NAS began by noting that it is
critically important to deter unethical conduct in human research. The
NAS pointed out that many believe the refusal to rely on data from
ethically deficient studies has an additional purpose: to avoid
involving the government in ``a kind of symbolic approval of and
complicity in the unethical research, even after the fact, [and
instead] to express society's commitment to fundamental values in
research involving humans'' (p. 127). The NAS pointed out that this
position leads to an absolute renunciation of any benefits of knowledge
gained through the ethically deficient research, and that in some
instances that might compel a sacrifice in public health.
    Thus, the committee recommended that each case be judged
individually, to take into account the nature of the unethical behavior
and the importance of the information produced by the research. The NAS
indicated that EPA should use data from an unethical study only if a
special panel determined the data were ``crucially important for
protecting public health'' and could not otherwise be obtained with
reasonable certainty, within a reasonable time period, without exposing
additional subjects to additional risk of harm (pp. 126, 128). The
committee further advised that data from unethical studies should not
be used to justify relaxation of public health standards or to ``favor
the sponsor's interest'' (p. 128). Finally, the committee indicated its
view that

using the special procedure described in the recommendation would not
create ``an incentive for future breaches of the relevant ethical
rules'' (p. 126).
    The NAS Report also addressed what standard to apply in judging
studies completed before EPA's rulemaking becomes effective. (The
committee explained that this standard should also apply ``to studies
that EPA has retrieved from the public literature'' (pp. 129-30), but
did not say whether they intended this standard to apply only to
studies retrieved from the public literature that were conducted after
new EPA rules become effective.) The committee begins by pointing out
that the selection of a standard for determining the acceptability of
past research raises additional considerations, making the choice
``particularly vexing'' (p. 128). They noted in particular two issues:
``whether it is fair to judge past studies with humans by current
ethical standards'' (p. 128), and what evidentiary presumptions should
be used in applying the standard. Although the NAS did not devote much
discussion to whether to apply contemporary standards to past studies,
their recommendation 5-7 states clearly their conclusion that completed
research should be judged by the ethical standards prevailing at the
time the research was conducted.
    The NAS discussed at length alternative evidentiary presumptions
which could be used in applying the ethical standard, identifying two
broad choices. The first alternative would be to assume completed
research was conducted ethically unless clear evidence shows it was
unethical; the second would be to assume completed research was
conducted unethically unless clear evidence shows it was ethical. The
committee noted that documentation of the ethical attributes of a very
large proportion of past human studies is very limited, not only for
third-party research but also for government-conducted and government-
supported research. Applying the second alternative would mean,
effectively, that a substantial proportion of completed human research
would be rejected as unethical, solely because records were unavailable
to demonstrate that it was ethically conducted.
    The NAS recommended instead that, in the absence of information to
the contrary, EPA should assume completed research was performed
ethically. They favored this approach ``because of ethical concerns
about not considering scientifically valid data from completed
studies'' and because setting aside much or most completed research
could lead investigators ``to conduct additional research to obtain
similar data to protect the public, thus subjecting additional research
participants to risk'' (p. 129).
    Based on this discussion, NAS Recommendation 5-7 reads:
    EPA should accept scientifically valid studies conducted before
its new rules* are implemented unless there is clear and convincing
evidence that the conduct of those studies was fundamentally
unethical (e.g., the studies were intended to seriously harm
participants or failed to obtain informed consent) or that the
conduct was deficient relative to then-prevailing ethical standards.
Exceptional cases in which the Human Studies Review Board determines
that unethically conducted studies may provide valid information to
support a regulatory standard that would provide greater protection
for public health should be presented to a special outside panel,
described in Recommendation 5-6, for consideration. [* Note: a
footnote here in the text of NAS Recommendation 5-7 reads: ``See
footnote 1.'' The text of the NAS-referenced footnote 1 is provided
above in the note for Recommendation 5-6.]

B. Proposal

    In a new subpart F of 40 CFR part 26, EPA proposes ethical
standards for its decisions to rely on or not to rely on in its
decision-making reports of completed intentional-dosing research with
human subjects being considered under FIFRA or FFDCA. For covered types
of research conducted after the effective date of the rule, EPA
proposes to refuse to rely on data from scientifically sound and
relevant human research unless EPA has adequate information
demonstrating that the research complied with the Common Rule. For
covered types of research conducted before the effective date of the
rule, EPA proposes to rely on data from scientifically sound and
relevant human research unless there is clear evidence to show the
conduct of the research was fundamentally unethical or was
significantly deficient relative to the ethical standards prevailing at
the time the research was conducted. EPA also proposes a formal process
to make an 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.
    The provisions of EPA's proposed subpart F address intentional
exposure studies being considered under FIFRA or the FFDCA. The NAS
discussion of Recommendations 5-6 and 5-7 did not distinguish between
human studies involving intentional dosing and other types of human
research, although their report addressed ``intentional human dosing
studies.'' EPA has chosen to limit its proposal in subpart F to
intentional dosing human studies considered under FIFRA or FFDCA,
because the public debate about relying on data from human research has
focused primarily on that kind of testing. EPA expects to continue to
evaluate the ethical conduct of other types of human research outside
the scope of proposed subpart F on a case-by-case basis, guided by
statutory requirements, the Common Rule, and high ethical standards,
consistent with the approach described in its February 8, 2005, Federal
Register Notice.
    For human studies initiated before a final rule becomes effective,
we agree with the NAS committee that it is appropriate to measure the
conduct of human studies against the ethical standards prevailing when
the research was conducted. The history of the development and revision
of widely accepted standards of ethical research conduct such as the
Nuremberg Code, the Declaration of Helsinki, the Belmont Report, and
the Common Rule is well known. Although it is not always easy to
determine what standards prevailed where the research was conducted,
this history is adequate to identify an appropriate standard based on