[Federal Register Volume 70, Number 175 (Monday, September 12, 2005)]
[Proposed Rules]
[Pages 53837-53866]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-18010]



[[Page 53837]]

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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

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / 
Proposed Rules

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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 protected], 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 (703) 305-5805.

FOR FURTHER INFORMATION CONTACT: William L. Jordan, Mailcode 7501C, 
Office of Pesticide Programs, Environmental Protection Agency, 1200 
Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 
305-1049; fax number: (703) 308-4776; e-mail address: 
[email protected].

SUPPLEMENTARY INFORMATION: 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

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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

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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

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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

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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

[[Page 53843]]

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

[[Page 53844]]

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).


[[Page 53845]]


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.
BILLING CODE 6560-50-S

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[GRAPHIC] [TIFF OMITTED] TP12SE05.002

BILLING CODE 6560-50-C
    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

[[Page 53847]]

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

[[Page 53848]]

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

[[Page 53849]]

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.

[[Page 53850]]

    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

[[Page 53851]]

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

[[Page 53852]]

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

[[Page 53853]]

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

[[Page 53854]]

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

[[Page 53855]]

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 
when the research was conducted. This approach acknowledges that 
ethical standards have changed over time, and will surely change in the 
future. It would also be inequitable to apply contemporary ethical 
standards retroactively to research conducted in the past. Before the 
effective date of the rule, sponsors or investigators would have had no 
notice of the specific standard EPA would apply to their data. 
Moreover, they can be assumed to have regarded the ethical standards 
prevailing at the time the study was conducted as the most appropriate 
benchmark for guiding their conduct. While the proposed rule would, 
strictly speaking, only govern EPA's behavior, it provides the basis 
for judgment of others' past conduct. It seems inherently unfair to 
hold researchers to a standard about which they had no notice and 
which, after the fact, they would be unable to comply with through any 
further action. But it does seem reasonable and fair to judge their 
behavior against the standards of which they should have been aware. We 
believe this is the essence of NAS Recommendation 5-7.
    The Agency has refined the language of the standard in NAS 
Recommendation 5-7 in two ways. EPA has retained the evidentiary 
presumption recommended by the NAS committee, but has modified their 
suggested requirement for ``clear and convincing evidence'' to ``clear

[[Page 53856]]

evidence.'' The Agency simply cannot imagine ``clear but unconvincing'' 
evidence that research was fundamentally unethical, and has opted for 
brevity. EPA has further modified the recommended standard to specify 
that the Agency will consider refusing to rely on a past study when it 
is ``significantly deficient'' compared to prevailing ethical 
standards. This is intended to acknowledge that minor recordkeeping or 
administrative deficiencies with respect to the prevailing ethical 
standard should not in themselves force the Agency to set aside an 
otherwise ethically conducted and scientifically meritorious study.
    For judging the ethical acceptability of covered human studies 
initiated after a final rule becomes effective, EPA proposes the Common 
Rule as the primary standard. In general terms, the approach to human 
research covered under the extension of EPA's Common Rule would seem 
very straightforward. Once EPA completes rulemaking to extend to 
certain third-party research the requirements of EPA's Common Rule and 
these proposed additional subparts, it seems entirely appropriate to 
expect all research within the scope of these subparts and conducted 
after they take effect to comply with the rule. If the Agency were to 
become aware of covered research that does not comply, EPA should 
consider the measures in proposed subpart E of the regulatory text and 
discussed in Unit IX., including whether it would be appropriate to 
refuse to rely on the data. We believe this is the essence of NAS 
Recommendation 5-6.
    EPA is not, of course, proposing to establish FIFRA section 
12(a)(2)(P) as a standard. FIFRA section 12(a)(2)(P) was enacted in 
1972 and implementing regulations were promulgated in 1980. Thus FIFRA 
section 12(a)(2)(P) already applies to human subjects research with 
pesticides, and no additional rulemaking is necessary to make it 
applicable.
    EPA also agrees with the NAS Recommendation 5-6 that the researcher 
should bear the burden of demonstrating compliance with the standard. 
Proposed Sec.  26.602 of the regulatory text provides that the Agency 
would accept data from a study covered by the rule ``only if EPA has 
adequate information to determine that the research was conducted in a 
manner that substantially complies with subpart A and, as applicable, 
subparts B and D of this part.'' EPA has listed in proposed Sec.  
26.124(c) of the regulatory text the kinds of information documenting 
the ethical conduct of completed human research that EPA would expect 
to see in a submitted report of such research. (Note that this 
documentation would be additional to records required by 40 CFR 
169.2(j), implementing FIFRA section 12(a)(2)(P) recordkeeping 
requirements.) This range of documentation is derived from the Common 
Rule criteria for IRB approval of proposed research at 40 CFR 26.111. 
It will thus have been gathered for presentation to the IRB and for 
submission to EPA with the proposed protocol for the research, and it 
should not be a burden to provide the same information to the Agency 
with the report on the completed study.
    Today's proposal slightly modifies the standard in NAS 
recommendation 5-6 to make it clear that EPA would consider refusing to 
rely on a completed human study only if the study fails to 
``substantially'' comply with the applicable ethical standards. This 
addition reflects EPA's judgment that relatively minor administrative 
or recordkeeping deficiencies in a researcher's compliance with a rule 
as complex as the Common Rule would not in themselves justify rejecting 
otherwise scientifically valuable and ethically conducted research. The 
experience of HHS shows that many studies conducted under the Common 
Rule fail to meet every applicable provision of the Common Rule, yet 
many of these deficiencies are deemed minor. See ``Compliance Oversight 
in Human Subjects Protection'' by Dr. Kristina C. Borror, Director, 
Division of Compliance Oversight in the Office of Human Research 
Protections (February 1, 2005), available at: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg01-05/ present2/borror--files/frame.htm.
    EPA's proposed subpart F covers all intentional human dosing 
studies that EPA is considering under FIFRA or FFDCA. Some of these 
studies might not be covered by the proposed extension of EPA's Common 
Rule. The exceptions would include any intentional exposure human 
studies for pesticides that were not, at the time they were conducted, 
intended to be submitted to EPA under FIFRA or FFDCA. Such studies 
might be retrieved from the public literature by EPA, conducted by U.S. 
States or by foreign governments, or conducted by third parties for 
regulatory purposes in other countries. For studies like these, covered 
by proposed subpart F but not by the proposed extension of EPA's Common 
Rule, the question of what ethical standard to apply is more difficult.
    On the one hand, since the Agency proposes not to subject this 
research to the extension of EPA's Common Rule, it could be argued that 
it would be inconsistent and unfair to apply the standard of the Common 
Rule to the Agency's later decisions about whether to rely on that 
research. Sometimes the person submitting a report of research to EPA 
will have had no relationship with the sponsor or investigator of the 
research; a submitter in this situation could argue that they could be 
penalized for actions taken by someone else with no connection to them, 
who was not legally required to follow the Common Rule and who for 
whatever reason chose not to.
    On the other hand, once EPA promulgates a final rule, researchers 
would have notice of the ethical standards EPA would apply in deciding 
whether to rely on a completed intentional dosing human study. With 
such notice, researchers could make an informed decision whether or not 
to comply with the requirements of EPA's Common Rule. They would have 
adequate and timely warning about the consequences of noncompliance. 
Furthermore, it is EPA's judgment that it is fair to consider the 
``prevailing ethical standard'' for research conducted after the 
effective date of new rules to be the Common Rule or a foreign 
equivalent. These considerations argue for subjecting all research 
conducted after the effective date of the new rule to the more 
demanding ethical standards defined by that new rule. If EPA took this 
approach, its rules might influence the conduct of a larger universe of 
research and thereby provide greater protection for human subjects.
    EPA proposes therefore, in deciding whether to rely on data from a 
completed study, to apply the Common Rule to all studies conducted 
after a final rule becomes effective and which are covered by EPA's new 
subpart F, whether or not the research was required to comply with 
EPA's Common Rule under EPA's new subpart A. The primary argument 
against using the Common Rule as the ethical benchmark for all future 
intentional exposure human studies is that researchers will not have 
had adequate notice. EPA disagrees; publication of a final rule in the 
Federal Register will constitute adequate notice. Given the widespread 
awareness of and consensus on the Common Rule as the appropriate guide 
for ethical conduct of human research, EPA therefore expects that very 
few, if any, sponsors or investigators could credibly claim ignorance 
of their ethical responsibilities to protect human subjects. Finally, 
the Agency believes its use of the Common Rule as the ethical benchmark 
for deciding whether to rely

[[Page 53857]]

on a human study would provide additional incentive for researchers to 
act ethically.
    Finally, EPA proposes an extraordinary procedure applicable if 
scientifically sound but ethically deficient human research is found to 
be crucial to EPA's fulfilling its mission to protect public health. 
This procedure would also apply if a scientifically sound study covered 
by proposed Sec.  26.221 or Sec.  26.421--i.e., an intentional dosing 
study involving pregnant women or children as subjects--were found to 
be crucial to the protection of public health. The Agency accepts the 
NAS advice to make these decisions on a case-by-case basis, taking into 
account the particular circumstances of the study and the way it could 
affect the regulatory action, and seeking the best possible advice. EPA 
agrees such decisions should consider the importance of the research to 
a potential regulatory decision, and particularly whether it would 
support a regulatory position more protective of public health than 
would be justified without reliance on the data. Proposed Sec.  26.603 
would require EPA, before deciding not to rely on such data, to seek 
the advice of the Human Studies Review Board and comment from the 
public.

C. Topics for Public Comment

    The Agency has considered a number of alternatives to the positions 
described and invites public comment on whether EPA should adopt any of 
these alternatives for the final rule:
    1. Should EPA continue the case-by-case approach articulated in the 
February 8, 2005, Federal Register Notice, not adopting by rule ethical 
standards to guide decision-making with respect to completed, ethically 
problematic human studies?
    2. Should a final rule establish the standard that EPA would rely 
on all scientifically sound data from covered intentional exposure 
human studies relevant to EPA decision-making, without regard to any 
ethical deficiencies in the studies?
    3. Should a final rule establish a different criterion for 
acceptance of research conducted before the effective date of the rule 
than the criterion proposed in Sec.  26.601 of the regulatory text? 
Should a final rule identify specific factors to be considered or 
criteria to be applied in determining whether research was 
``fundamentally unethical'' or ``significantly deficient with respect 
to prevailing standards''?
    4. Should a final rule establish the standard that, in making 
decisions under FIFRA and FFDCA, EPA would never rely on data from a 
study involving intentional exposure of any human subject to a 
pesticide when a purpose of the study was to identify or measure toxic 
effects?
    5. Should a final rule establish the standard that EPA would not 
rely on an intentional exposure human study covered under proposed 
subpart F if the study did not comply with the Common Rule, without 
regard to when the research was conducted?
    6. Should a final rule establish the standard in NAS Recommendation 
5-7 for all three categories of completed research covered by proposed 
subpart F of the regulatory text--i.e., (1) Research conducted before 
the rule becomes effective; (2) research conducted after the rule 
becomes effective and required to comply with EPA's Common Rule; and 
(3) research conducted after the rule becomes effective but not 
required to comply with EPA's Common Rule?
    7. Should a final rule apply a different standard to research 
conducted after the effective date of the final rule, depending on 
whether the research was subject to the requirements of EPA's proposed 
subparts A through D?
    8. Should a final rule apply proposed subpart F to a different 
range of third-party human research, including any of the categories 
discussed in Unit IV., or apply different ethical standards to research 
in different categories within an altered scope?
    9. Should a final rule apply a standard other than ``substantial'' 
compliance with the requirements in EPA's proposed subparts A through 
D, perhaps requiring ``full'' or ``complete'' compliance with those 
requirements? How should minor, administrative deficiencies be treated 
under an alternative standard?
    10. Should a final rule permit use of the exception procedure in 
proposed Sec.  26.603 when research falling within the prohibitions of 
proposed Sec.  26.221 or Sec.  26.421--i.e., research involving 
intentional exposure of pregnant women or children--is deemed crucial 
to the protection of public health?
    11. Should a final rule identify additional factors EPA will 
consider in deciding whether to rely on a completed human study that 
does not meet the appropriate standard in proposed Sec.  26.601 or 
Sec.  26.602 of the regulatory text?

XI. EPA's 2006 Appropriations Act

    This unit discusses how this proposed rule meets the requirements 
of the Department of the Interior, Environment, and Related Agencies 
Appropriations Act, 2006, (Appropriations Act) relating to intentional 
dosing human toxicity studies for pesticides. This unit contains six 
sections. Section A reviews the provisions of the 2006 Appropriations 
Act and summarizes EPA's approach to implementation of its provisions. 
Section B addresses the proposed rule's prohibition of intentional 
dosing human studies for pesticides when the subjects are pregnant 
women, infants, or children. Section C addresses its consistency with 
the 2004 NAS report. Section D addresses its consistency with the 
Nuremberg Code. Section E addresses its establishment of an independent 
Human Studies Review Board. Section F identifies subjects on which EPA 
invites public comment.

A. Introduction

    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. Section 201 of the Appropriations Act 
addresses EPA activities regarding intentional dosing human toxicity 
studies for pesticides as follows:
    None of the funds made available by this Act may be used by the 
Administrator of the Environmental Protection Agency to accept, 
consider or rely on third-party intentional dosing human toxicity 
studies for pesticides, or to conduct intentional dosing human 
toxicity studies for pesticides until the Administrator issues a 
final rulemaking on this subject. The Administrator shall allow for 
a period of not less than 90 days for public comment on the Agency's 
proposed rule before issuing a final rule. Such rule shall not 
permit the use of pregnant women, infants or children as subjects; 
shall be consistent with the principles proposed in the 2004 report 
of the National Academy of Sciences on intentional human dosing and 
the principles of the Nuremberg Code with respect to human 
experimentation; and shall establish an independent Human Subjects 
Review Board. The final rule shall be issued no later than 180 days 
after enactment of this Act.

    Consistent with its interpretation of the intent of Congress, EPA 
has not waited for the beginning of FY 2006 to discontinue reliance on 
third-party intentional human dosing toxicity studies in its decision-
making under FIFRA and FFDCA. In addition, EPA is taking the necessary 
steps to ensure such studies will not be accepted or considered after 
the beginning of FY 2006 and before a final rule is promulgated. The 
Agency has not conducted or supported any intentional dosing human 
toxicity studies for pesticides in the past, and has no

[[Page 53858]]

intention to conduct them at any time in the future.
    The Agency will concentrate its attention on developing and 
promulgating a final rule. As required by the Appropriations Act, EPA 
is providing a period of 90 days for the public to comment on this 
proposed rule. Because the Appropriations Act directs the Agency to 
promulgate a final rule no later than 180 days after enactment (i.e., 
by January 29, 2006), the Agency does not expect to extend the comment 
period or to review public comments received after the close of the 
comment period.

B. Prohibition of Intentional Dosing Human Studies for Pesticides when 
the Subjects are Pregnant Women, Infants, or Children

    This proposed rule would ban third party intentional dosing human 
studies for pesticides when the subjects are pregnant women, infants or 
children, without regard to whether the studies were intended to 
identify or measure a toxic effect. Proposed Sec.  26.220 of the 
regulatory text would prohibit, without exception, any third party 
performing research covered by the proposed extension of EPA's Common 
Rule from ``conducting or supporting research involving intentional 
dosing of any pregnant woman, fetus, or newborn.'' Proposed Sec.  
26.420 of the regulatory text would prohibit, without exception, any 
third party performing research covered by the proposed extension of 
EPA's Common Rule from ``conducting or supporting research involving 
intentional dosing of any child.'' The same passages would apply the 
same prohibitions to EPA, similarly without exception, in any research 
it conducts or supports.
    The Agency interprets the phrase ``third-party intentional dosing 
human toxicity study for pesticides'' as used in the Appropriations Act 
to refer to a subset of all third-party intentional dosing studies 
intended for submission to EPA under the pesticide laws, and thus 
covered by proposed Sec.  26.101(j) of the regulatory text. Further, 
the Agency interprets the phrase ``pregnant women, infants or 
children'' as used in the Appropriations Act to have the same scope and 
meaning as the phrases ``any pregnant woman, fetus, or newborn'' and 
``any child'' in the sections cited above, when taken together. EPA 
also notes that the prohibitions in proposed Sec. Sec.  26.220 and 
26.420 of the regulatory text reference proposed Sec.  26.101(j), and 
therefore make the prohibitions applicable to research that was 
conducted with the intent to submit the results to EPA (or hold them 
for possible future inspection) under either of the pesticide laws, 
FIFRA or FFDCA. EPA interprets the phrase, ``for pesticides'' as used 
in the Appropriations Act to mean research that is intended for 
consideration by EPA under the pesticide laws, and thus which falls 
within the scope of proposed Sec.  26.101(j). EPA invites public 
comment on these interpretations of the meaning of the phrase 
``intentional dosing human toxicity studies for pesticides'' as it is 
used in the Appropriations Act, particularly as it relates to the scope 
of the requirement for a prohibition on such studies with subjects who 
are ``pregnant women, infants, or children.''

C. Consistency with the 2004 NAS Report

    The Appropriations Act directs EPA to promulgate a rule addressing 
third party intentional dosing human toxicity studies for pesticides 
that is ``consistent with the principles proposed in the 2004 report of 
the National Academy of Sciences on intentional human dosing.''
    Based on a careful review of the NAS report, EPA has concluded that 
the underlying principles intended by the NAS committee to be reflected 
in its recommendations are the three ``fundamental ethical principles'' 
identified by the National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (National Commission) in 
its report, Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research (the ``Belmont Report''). These three 
fundamental principles are respect for persons, beneficence, and 
justice. See NAS Report at pp. 49-50, 98, and 113-14.
    The NAS committee makes the point clearly that they did not propose 
new principles: ``the committee was not required to invent the basic 
standards that govern human research in the United States. These 
standards are already embodied in the Federal Policy for the Protection 
of Human Subjects (the Common Rule.)'' NAS Report pp. 4, 33.
    The NAS committee further stated that the fundamental principles 
articulated in the Belmont Report both undergird and are made 
operational by the procedural requirements of the Common Rule. The 
following quotations express this view:
    Federal regulations incorporate the obligation of beneficence by 
requiring IRBs to ensure that risks are minimized to the extent 
possible, given the research question, and are reasonable in 
relation to potential benefits to the participant or to the 
importance of the knowledge to be gained through the research (40 
CFR Sec.  26.111(a)(1)-(2)). NAS Report at 56.
    [D]etermining whether the principle of beneficence has been 
satisfied requires balancing the anticipated risks to study 
participants against the anticipated benefits of the study to 
society. The risks to participants must be reasonable in relation to 
the societal benefit. In the words of the Common Rule, the risks 
must be reasonable in relation to the importance of the knowledge 
that may reasonably be expected to result (40 CFR Sec.  26.111 
(a)(2)). NAS Report at 107.

    According to the Common Rule, IRBs should not approve a research 
protocol involving humans unless `selection of subjects is 
equitable' (40 CFR Sec.  26.111(3)). This requirement derives from 
the principle of justice identified in the Belmont Report. NAS 
Report at 114.
    Voluntary, informed consent by research participants . . . is a 
major element in the system of protection of research participants. 
The consent requirement expresses the principle of respect for 
persons, including respect for and promotion of autonomous choices. 
The Common Rule stresses this requirement, as do other codes of 
research ethics, including the Nuremberg Code (1949), the 
Declaration of Helsinki, and the Good Clinical Practice guidelines. 
NAS Report at 120.

    Accordingly, EPA concludes that the ``principles proposed in the 
2004 report of the National Academy of Sciences on intentional human 
dosing'' are, in fact, the ``three fundamental principles'' of respect 
for persons, beneficence, and justice articulated in the Belmont 
Report, and that the Common Rule rests on the foundation of those 
principles. This proposal to extend the coverage of EPA's Common Rule 
to additional categories of regulated third-party research is thus 
entirely consistent with those principles.

D. Consistency with the Nuremberg Code

    The Appropriations Act directs EPA to promulgate a rule addressing 
third-party intentional dosing human toxicity studies for pesticides 
that is ``consistent with . . . the principles of the Nuremberg Code 
with respect to human experimentation.''
    The NAS report (p. 47) explains the history of the Nuremberg Code 
as follows:
    Public policies regarding the ethical treatment of humans in 
research began forming in the late 1940s, largely in response to the 
atrocities committed by Nazi investigators who were tried before the 
Nuremberg Military Tribunal (United States v. Karl Brandt, et al.) 
In 1946, the American Medical Association adopted its first code of 
research ethics, which ultimately influenced the Nuremberg 
Tribunal's standards for ethical research, embodied in the ten 
``basic principles'' for human research now know as the Nuremberg 
Code. [footnotes and references omitted]


[[Page 53859]]


    The Agency has carefully reviewed this proposed rule, using the 10 
principles of the Nuremberg Code as a guide, and has concluded that it 
is consistent with them. A full report of this analysis has been placed 
in the docket for this proposal.

E. Establishment of a Human Studies Review Board

    The Appropriations Act directs EPA to promulgate a rule that 
``shall establish an independent Human Subjects Review Board.''
    EPA believes that the entity required by the Appropriations Act is 
intended to be substantially identical to the ``Human Studies Review 
Board'' recommended by the NAS in Recommendations 6-1, 6-2, and 6-3 of 
the NAS Report. (See discussion in Unit V. of this preamble.) 
Consistent with both the requirement of the Appropriations Act and the 
recommendations of the NAS, EPA proposes, in proposed Sec.  26.124(b) 
of the regulatory text, to establish an independent HSRB. Under this 
proposed rule, the review of proposed research by the HSRB would occur 
after review by a local IRB and EPA staff. This sequence would be 
consistent both with EPA's current practice for reviewing first- and 
second-party human research proposals and with the practice of FDA for 
reviewing third-party human research proposals. The NAS Report, 
however, recommended that the EPA and HSRB reviews come before the IRB 
review. EPA believes it has discretion to adopt an approach that 
differs in this respect from the NAS recommendation, but seeks public 
comment on whether HSRB review would be more effective before or after 
local IRB review.

F. Additional Topics for Public Comment

    Although EPA thinks that today's proposal satisfies the provisions 
in the Appropriations Act and, in particular, is consistent with the 
principles of both the Nuremberg Code and the 2004 NAS Report, the 
Agency recognizes that, as a matter of policy, it might be appropriate 
to include in the final rule additional provisions arising from either 
the Nuremberg Code or the 2004 NAS Report. Therefore, in addition to 
the topics identified above, the Agency invites the public to comment 
on any specific provisions of either the Nuremberg Code or the 2004 NAS 
report that may be appropriate for inclusion in the final rule.

XII. FIFRA Review Requirements

    Pursuant to FIFRA section 25(a), the Agency submitted a draft of 
this proposed regulation to the FIFRA Scientific Advisory Panel (SAP), 
the U.S. Department of Agriculture (USDA), the Committee on Agriculture 
in the House of Representatives, and the Committee on Agriculture, 
Nutrition, and Forestry in the United States Senate. In addition, the 
Agency submitted a draft of this proposed rule to the Department of 
Health and Human Services (HHS).
    The FIFRA SAP waived its review of this proposal because the 
significant scientific and ethical issues involved have already been 
reviewed by the SAP. (See the report of the SAB/SAP Data from Testing 
of Human Subjects Subcommittee in the docket for this proposal and on 
the web at: http://www.epa.gov/science1/pdf/ec0017.pdf.) The Agency met 
with the staff of the Congressional Committees, and where warranted, 
has made changes to the draft proposal based upon those discussions.
    USDA, the U.S. Department of Veterans Affairs, and HHS provided 
many helpful comments through the interagency review process, leading 
to numerous changes in the draft proposal. In addition, comments dated 
August 15, 2005, and August 26, 2005, which EPA received from Cristina 
V. Beato, M.D., Acting Assistant Secretary for Health at HHS, have been 
placed in the docket for this rulemaking, and are summarized here with 
EPA's responses.
    EPA thanks HHS for providing very helpful comments very quickly. In 
summary, HHS expressed strong support for EPA's effort to extend the 
protections of EPA's Common Rule to research regulated by EPA under 
FIFRA. HHS welcomes EPA's decision to adopt additional regulatory 
protections of pregnant women, fetuses, newborns, and children, 
formalizing EPA's longstanding practice. HHS also welcomes EPA's 
proposal to prohibit EPA involvement in or consideration of intentional 
exposure studies done to investigate toxic effects.
    HHS made four ``major'' comments. First, HHS stated that it could 
not support changes to the content of subpart A, the Common Rule, and 
recommended that EPA revise its proposal to incorporate all changes 
proposed to Sec. Sec.  26.101, 26.102, and 26.124 in a separate 
subpart. EPA appreciates and shares HHS's concern for maintaining 
uniformity in subpart A--the regulation common to all the Common Rule 
departments and agencies--and promises that the final rule will 
accomplish the extension of EPA's Common Rule without altering the 
common text. We have not made the requested change in this proposal 
because we want first to solicit public comment on how best to achieve 
clarity in our codification of these new requirements. Would the 
requirements applicable to regulated third parties be best expressed as 
HHS has suggested, in a separate subpart of 40 CFR part 26, or would it 
be clearer if all the requirements applying to regulated third parties 
were codified together in an entirely separate part, after the model of 
the FDA rules at 21 CFR parts 50 and 56?
    Second, HHS notes in their August 15 written comment that FDA may 
have additional comments, but did not have time to complete them in the 
greatly compressed scheduled imposed by the demands of the 
Appropriations Act. FDA's comments were received on August 26, and this 
proposal has been amended to reflect all their suggested clarifications 
and changes. The Agency would also welcome additional comments from HHS 
and FDA, and will address them in the final rule.
    Third, HHS recommends that EPA modify its proposal to incorporate a 
ban on research involving intentional exposure of prisoners, parallel 
to the bans proposed on similar research involving pregnant women, 
fetuses, newborns, and children. EPA has specifically requested public 
comment on this suggestion in Unit VIII., and will seriously consider 
adopting such a ban in the final rule.
    The final major HHS comment expresses concern that the ethical 
standard proposed in Sec.  26.601 of the regulatory text, to be applied 
to research conducted before the effective date of new EPA rules, may 
be too permissive, and ``fails to provide helpful guidance on what 
would separate an acceptable study from an unacceptable one.'' The 
standard EPA has proposed, as explained in Unit X., is based on the 
advice of the NAS committee, which thought long and hard about this 
issue. EPA, too, has thought a great deal about this criterion, and has 
identified several topics for public comment at the end of Unit X., 
including the specific points raised by HHS in this comment. We will 
consider all these comments in deciding on a standard for the final 
rule.
    In addition to the four ``major'' comments discussed above, HHS 
provided 23 additional ``specific'' comments. Although some of the 
passages HHS cited in the draft proposal they reviewed do not appear in 
this published proposal, EPA has adopted all the specific suggestions 
for clarifications and rewording suggested by HHS. The final HHS 
comment, however, questions whether submission to EPA of reports of 
completed research

[[Page 53860]]

should be made mandatory when the research proposal has been reviewed 
and approved by EPA. EPA has not proposed this, because FIFRA section 
6(a)(2) already requires any applicant for registration or registrant 
of a pesticide to provide to EPA any ``additional factual information 
concerning adverse effects of a pesticide'' that it becomes aware of. 
It is EPA's interpretation that it would be a violation of this 
provision for a regulated third party to refuse to submit a report upon 
completion of research which EPA had approved as a proposal in order to 
suppress ``additional factual information concerning adverse effects.''

XIII. Statutory and Executive Order Reviews

A. Executive Order 12866

    Under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993), the Office of Management and 
Budget (OMB) determined that this proposed rule is a ``significant 
regulatory action'' under section 3(f) of the Executive Order because 
this action might raise novel legal or policy issues. Accordingly, EPA 
submitted this proposed rulemaking to OMB for review under Executive 
Order 12866 and any changes made in response to OMB comments have been 
documented in the public docket for this rulemaking as required by 
section 6(a)(3)(E) of the Executive Order.
    In addition, EPA has prepared an economic analysis of the potential 
costs and benefits associated with this proposed action, which is 
contained in a document entitled Economic Analysis of Proposed Human 
Studies Rule. A copy of this document is available in the public docket 
for this proposed rule and is briefly summarized here.
    The analysis describes the benefits of the proposed rulemaking in 
qualitative terms. These benefits included greater protections for test 
subjects, and a corresponding reduction in their risks, to the extent 
that affected researchers are not already following the Common Rule. 
The benefits to sponsors of third-party human research include a better 
understanding of the standards that EPA will apply in determining 
whether to rely on the results of their studies, and thus, the 
opportunity to design and perform studies that are more likely to meet 
EPA standards, leading to more efficient Agency reviews. The Agency 
believes the general public will benefit from the proposed rule because 
the rule will strengthen the protections for human subjects and 
reinforce the Agency's strong commitment to base its decisions on 
scientifically sound information.
    The analysis also estimates the costs of the proposed rule by 
focusing on the costs to third parties of complying with the new 
requirements and the costs to EPA of implementing the new requirements. 
In general, EPA believes that most, if not all, third-party research 
intended for submission to EPA that involves intentional exposure of 
human subjects already complies with the Common Rule or an equivalent 
foreign standard. For purposes of this analysis, EPA assumed that 
current practice was in full compliance with the Common Rule. In 
contrast, EPA assumed that other types of third-party human research do 
not comply with the Common Rule, although it is likely that many 
responsible for such research are aware of and do follow Common Rule 
principles relating to informed consent and IRB review.
    After reviewing the history of EPA's consideration of research 
involving human subjects in its various program offices, EPA estimates 
that the proposed rule would affect only a limited number of third-
party studies involving human subjects each year. EPA also collected 
data on the cost per study of compliance with the Common Rule. These 
costs include preparing documents to support review by an IRB and the 
expense associated with the IRB review. These costs are very minor 
relative to the overall cost of conducting the studies. For EPA, the 
costs are associated with the review of protocols and the review of 
completed human studies by EPA staff and the Human Studies Review 
Board.
    EPA evaluated a range of options, from no action to an expansive 
rule. The first option was not to promulgate any rule, thereby 
continuing the current practice. All other options evaluated would 
apply to third-party human research that was conducted with the intent 
to submit the results to EPA under either FIFRA or FFDCA. The second 
option consisted of extending the requirements of EPA's Common Rule to 
such third-party human research only when it involved intentional 
exposure studies for the purpose of identifying or quantifying a toxic 
effect. The third option, which reflects the rule being proposed, would 
extend the requirements of EPA's Common Rule to all third-party 
intentional exposure human studies intended for submission under FIFRA 
or FFDCA. Option 4 would extend the requirements of EPA's Common Rule 
to all third-party human research intended for submission under the 
pesticide laws. All of the latter three options include a requirement 
for third parties to submit protocols for review prior to initiating 
the types of human research covered by the Common Rule. Finally, 
options 2-4 include a provision prohibiting the Agency and third 
parties from conducting covered human research with pregnant women or 
children as subjects.
    For all of the options, the potential costs of the proposed rule to 
third-party researchers and EPA are estimated to be very low, both 
because the number of affected studies is relatively small and because 
the costs of compliance with the Common Rule are low. Where the option 
simply reflects the current practice (option 1) the added total 
incremental costs to third-party sponsors of human research are zero. 
EPA assumes that currently the pesticide industry is already spending 
$159,000 to $196,000 annually to comply with the Common Rule for 
intentional exposure human studies and the Agency is currently spending 
$113,000 a year to review, on a case-by-case basis, the ethical aspects 
of such studies. Option 2 would add an estimated total annual 
incremental cost to third parties of $7,532, and an estimated annual 
cost to EPA of $220,894. Option 3 would add an estimated total annual 
incremental cost to third parties of $16,140, and an estimated annual 
cost to EPA of $327,630. Option 4 would add an estimated total annual 
incremental cost to third parties of $202,700 to $242,796, and an 
estimated annual cost to EPA of $601,134. The higher estimated costs 
for option 4 reflect the Common Rule compliance burden on third-party 
researchers who perform human studies not involving intentional 
exposure of human subjects, and the costs for EPA to review such 
completed studies and protocols for intentional exposure studies.
    The proposed rule, if finalized as proposed, is estimated to result 
in a total annual incremental cost to third parties of approximately 
$16,000, and an estimated annual cost to EPA of approximately $328,000.

B. Paperwork Reduction Act

    The information collection requirements in this proposed rule have 
been submitted to the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act, 44 U.S.C. 3501 et seq. The Information 
Collection Request (ICR) document prepared by EPA has been assigned EPA 
ICR No. 2195.01, and a copy of the ICR has been placed in the public 
docket for this proposed rule.
    This new information collection activity is planned to ensure that 
sound

[[Page 53861]]

and appropriate scientific data are available to EPA when making 
regulatory decisions, and to protect the interests, rights and safety 
of those individuals that are participants in the type of research 
activity that is the subject of this proposed rule. Specifically, this 
new information collection activity consists of proposed reporting and 
recordkeeping requirements. Whenever respondents intend to conduct 
research for submission to EPA under the pesticide laws that involves 
intentional dosing of human subjects, they will be required to submit 
study protocols to EPA and a cognizant local IRB before such research 
is initiated so that the scientific design and ethical standards that 
will be employed during the proposed study may be reviewed and 
approved. Respondents will also be required to submit information about 
the ethical conduct of completed research that involved intentional 
dosing of human subjects when such research is submitted to EPA.
    Some responses to this collection of information will be required 
in order to obtain or retain a benefit (i.e., a pesticide 
registration). Other responses will be voluntarily submitted at the 
initiative of the regulated entity. The information collection activity 
described in the ICR will be initiated by respondents as a condition of 
EPA's consideration of the research when it is subsequently submitted 
to EPA.
    FIFRA sections 3(c)(1)(F) and 3(c)(2)(B) authorize EPA to require 
various data in support of a pesticide's continued registration or an 
application for a new or amended pesticide registration. FIFRA section 
12(a)(2)(P) forbids any person ``to use any pesticide in tests on human 
beings unless such human beings (i) are fully informed of the nature 
and purposes of the test and of any physical and mental health 
consequences which are reasonably foreseeable therefrom, and (ii) 
freely volunteer to participate in the test.''
    An agency may not conduct or sponsor, and a person is not required 
to respond to an information collection request unless it displays a 
currently valid OMB control number. The OMB control numbers for EPA's 
regulations codified in Chapter 40 of the CFR, after appearing in the 
preamble of the final rule, are listed in 40 CFR part 9 for display 
purposes, and are also included on any related collection instrument 
(e.g., the form or survey instrument).
    EPA anticipates that respondents will submit 30 studies that 
involve intentional dosing of human subjects under FIFRA or FFDCA to 
EPA per year and that the preparation of the required information will 
require about 32 hours per study for a total estimated annual burden 
hours for affected entities of 960 hours, representing a total 
estimated annual paperwork cost of $440,160. It is important to note 
that this total annual paperwork burden and cost estimate includes 
activities related to initial rule familiarization, as well as 
activities that researchers already perform and would continue to 
perform even without the Agency's rulemaking in this area (i.e., 
developing a protocol and maintaining records). The average annual 
burden on EPA for reviewing this information for each study submission 
is estimated to be 80 hours per study, representing a paperwork related 
labor cost of about $14,672 per response and a total annual cost of 
$440,160.
    Under the PRA, ``burden'' means the total time, effort, or 
financial resources expended by persons to generate, maintain, retain, 
or disclose or provide information to or for a Federal agency. This 
includes the time needed to review instructions; develop, acquire, 
install, and utilize technology and systems for the purposes of 
collecting, validating, and verifying information, processing and 
maintaining information, and disclosing and providing information; 
adjust the existing ways to comply with any previously applicable 
instructions and requirements; train personnel to be able to respond to 
a collection of information; search data sources; complete and review 
the collection of information; and transmit or otherwise disclose the 
information.
    Direct your comments on the Agency's need for this information, the 
accuracy of the provided burden estimates, and any suggested methods 
for minimizing respondent burden, including the use of automated 
collection techniques, to EPA using the public docket that has been 
established for this proposed rule (docket ID number OPP-2003-0132) at 
http://www.epa.gov/edocket/. In addition, send a copy of your comments 
about the ICR to OMB at: Office of Information and Regulatory Affairs, 
Office of Management and Budget, 725 17th St., NW., Washington, DC 
20503, Attention: Desk Office for EPA ICR No. 2195.01. Since OMB is 
required to complete its review of the ICR between 30 and 60 days after 
September 12, 2005, please submit your ICR comments for OMB 
consideration to OMB by October 12, 2005.
    The Agency will consider and address comments received on the 
information collection requirements contained in this proposal when it 
develops the final rule.

C. Regulatory Flexibility Act

    Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA), 
5 U.S.C. 601 et seq., after considering the potential economic impacts 
of today's proposed rule on small entities, the Agency hereby certifies 
that this proposal will not have a significant adverse economic impact 
on a substantial number of small entities. This determination is based 
on the Agency's economic analysis performed for this rulemaking, which 
is summarized in Unit XIII.A., and a copy of which is available in the 
public docket for this rulemaking. The following is a brief summary of 
the factual basis for this certification.
    Small entities include small businesses, small organizations, and 
small governmental jurisdictions. For purposes of assessing the impacts 
of today's proposed rule on small entities, small entity is defined in 
accordance with the RFA as: (1) A small business as defined by the 
Small Business Administration's (SBA) regulations at 13 CFR 121.201; 
(2) a small governmental jurisdiction that is a government of a city, 
county, town, school district, or special district with a population of 
less than 50,000; and (3) a small organization that is any not-for-
profit enterprise which is independently owned and operated and is not 
dominant in its field.
    As discussed in Unit XIII.A., the total annual cost to researchers 
covered by this proposed rule is estimated to be $16,000, or under $600 
per study. This is a trivially small portion of the overall cost of 
performing such studies, each of which is estimated to cost from 
$125,000 to $500,000. After reviewing the history of EPA's 
consideration on human research in its various program offices, EPA 
estimates that the proposed rule would affect only a limited number of 
third-party human studies each year. Because both the number of 
affected studies is relatively small and the costs of compliance with 
the Common Rule are low, the potential overall costs to third parties 
are also small. Although we cannot predict whether or how many small 
entities might engage in the subject matter research in the future, the 
Agency expects that there will be no or minimal impact from this 
proposed rule on small entities.
    We continue to be interested in the potential impacts of the 
proposed rule on small entities and welcome comments on all aspects 
related to such impacts.

[[Page 53862]]

D. Unfunded Mandates Reform Act

    Under Title II of the Unfunded Mandates Reform Act of 1995 (UMRA) 
(Public Law 104-4), EPA has determined that this action does not 
contain a Federal mandate that may result in expenditures of $100 
million or more for State, local, and tribal governments, in the 
aggregate, or the private sector in any one year. As described in Unit 
XIII.A., the estimated total costs associated with this action are 
approximately $16,000 per year. This cost represents the incremental 
cost to researchers attributed to the additional procedural 
requirements contained in this proposal. Based on historical 
submissions, EPA has determined that State, local, and tribal 
governments rarely perform human research intended for submission to 
EPA under FIFRA or FFDCA. In addition, the proposed rule is not 
expected to significantly or uniquely affect small governments. 
Accordingly, this action is not subject to the requirements of sections 
202 and 205 of UMRA.

E. Executive Order 13132

    Pursuant to Executive Order 13132, entitled Federalism (64 FR 
43255, August 10, 1999), EPA has determined that this proposed rule 
does not have ``federalism implications,'' because it will not have 
substantial direct effects on the states, on the relationship between 
the national government and the states, or on the distribution of power 
and responsibilities among the various levels of government, as 
specified in the Order. As indicated earlier, instances where a state 
performs human research intended for submission to EPA under FIFRA or 
FFDCA are extremely rare. Therefore, this proposed rule may seldom 
affect a state government. Thus, Executive Order 13132 does not apply 
to this proposed rule. In the spirit of the Order, and consistent with 
EPA policy to promote communications between the Agency and State and 
local governments, EPA specifically solicits comment on this proposed 
rule from State and local officials.

F. Executive Order 13175

    As required by Executive Order 13175, entitled Consultation and 
Coordination with Indian Tribal Governments (59 FR 22951, November 6, 
2000), EPA has determined that this proposed rule does not have tribal 
implications because it will not have substantial direct effects on 
tribal governments, on the relationship between the Federal government 
and the Indian tribes, or on the distribution of power and 
responsibilities between the Federal government and Indian tribes, as 
specified in the Order. As indicated previously, instances where a 
tribal government performs human research intended for submission to 
EPA under FIFRA or FFDCA are extremely rare. Thus, Executive Order 
13175 does not apply to this proposed rule. In the spirit of the Order, 
and consistent with EPA policy to promote communications between the 
Agency and State and local governments, EPA specifically solicits 
comment on this proposed rule from tribal officials.

G. Executive Order 13045

    Executive Order 13045, entitled Protection of Children from 
Environmental Health Risks and Safety Risks (62 FR 19885, April 23, 
1997) does not apply to this proposed rule because this action is not 
designated as an ``economically significant'' regulatory action as 
defined by Executive Order 12866 (see Unit XIII.A.). Further, this 
proposal does not establish an environmental standard that is intended 
to have a negatively disproportionate effect on children. To the 
contrary, this action will provide added protections for children who 
may participate in the research covered by the proposed rule.

H. Executive Order 13211

    This proposed rule is not subject to Executive Order 13211, 
entitled Actions Concerning Regulations that Significantly Affect 
Energy Supply, Distribution, or Use (66 FR 28355, May 22, 2001) because 
it is not likely to have any significant adverse effect on the supply, 
distribution, or use of energy.

I. National Technology Transfer and Advancement Act

    Section 12(d) of the National Technology Transfer and Advancement 
Act of 1995 (NTTAA), 15 U.S.C. 272 note) directs EPA to use voluntary 
consensus standards in its regulatory activities unless to do so would 
be inconsistent with applicable law or impractical. Voluntary consensus 
standards are technical standards (e.g., materials specifications, test 
methods, sampling procedures) that are developed or adopted by 
voluntary consensus standards bodies. NTTAA directs EPA to provide 
Congress, through OMB, with explanations when the Agency decides not to 
use available and applicable voluntary consensus standards. This action 
does not propose to require specific methods or standards to generate 
those data. Therefore, this proposed rule does not impose any technical 
standards that would require Agency consideration of voluntary 
consensus standards. The Agency invites comment on its conclusion 
regarding the applicability of voluntary consensus standards to this 
proposed rulemaking.

J. Executive Order 12898

    This proposed rule does not have an adverse impact on the 
environmental and health conditions in low-income and minority 
communities. Therefore, under Executive Order 12898, entitled Federal 
Actions to Address Environmental Justice in Minority Populations and 
Low-Income Populations (59 FR 7629, February 16, 1994), the Agency has 
not considered environmental justice-related issues. Although not 
directly impacting environmental justice-related concerns, the 
provisions of the proposed rule would require researchers to use 
procedures to ensure equitable selection of test subjects in covered 
human research.

XIV. Effective Date

    EPA considers the expeditious application of these new protections 
to be in the public interest and accordingly proposes to provide no 
longer period than is essential between publication of a final rule and 
its effective date. The Agency believes a longer transition period is 
not likely to be necessary in light of the relatively few studies 
affected by this proposal.
    FIFRA section 25(a)(4), 7 U.S.C. 136w(a)(4), provides that:
    Simultaneously with the promulgation of any rule or regulation 
under this Act, the Administrator shall transmit a copy thereof to 
the Secretary of the Senate and the Clerk of the House of 
Representatives. The rule or regulation shall not become effective 
until the passage of 60 calendar days after the rule or regulation 
is so transmitted.

    Since this regulation would be issued under the authority of FIFRA, 
this requirement defines the minimum time lapse after promulgation 
before a final rule could become effective. EPA thus proposes that the 
final rule would be effective 60 days after its promulgation and 
transmittal to Congress. EPA invites public comment on the timing of 
the effective date of the final rule.

List of Subjects in 40 CFR Part 26

    Environmental protection, Human research subjects, Reporting and 
recordkeeping requirements.


    Dated: September 6, 2005.
Stephen L. Johnson,
Administrator.

    Therefore, it is proposed that 40 CFR chapter I be amended as 
follows:

[[Page 53863]]

PART 26--[AMENDED]

    1. By revising the authority citation for part 26 to read as 
follows:

    Authority: 5 U.S.C. 301; 7 U.S.C. 136w(a)(1); 21 U.S.C. 
346a(e)(1)(C); and 42 U.S.C. 300v-1(b).

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

Subpart A--Basic Federal Policy for Protection of Human Research 
Subjects

    3. By amending Sec.  26.101 by adding paragraphs (j) and (k) to 
read as follows:


Sec.  26.101  To what does this policy apply?

* * * * *
    (j) Except as provided in paragraphs (a) and (b) of this section, 
this policy applies to all research involving intentional exposure of a 
human subject if, at any time prior to initiating such research, any 
person who conducted or supported such research intended:
    (1) To submit results of the research to EPA for consideration in 
connection with any regulatory action that may be performed by EPA 
under the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 
136 et seq.) or section 408 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 346a); or
    (2) To hold the results of the research for later inspection by EPA 
under the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 
136 et seq.) or section 408 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 346a).
    (k) 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 FIFRA or the FFDCA 
and, at the time the research was initiated, the results of the 
research would be relevant to EPA's exercise of its authority under 
FIFRA or the FFDCA with respect to that class of people, products, or 
activities.
    4. By amending Sec.  26.102 by adding paragraph (k) to read as 
follows:


Sec.  26.102  Definitions.

* * * * *
    (k) Research involving intentional exposure of a human subject 
means 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.
    5. By revising Sec.  26.124 to read as follows:


Sec.  26.124  Conditions.

    (a) With respect to any research project or any class of research 
projects the department or agency head may impose additional conditions 
prior to or at the time of approval when in the judgment of the 
department or agency head additional conditions are necessary for the 
protection of human subjects.
    (b) Prior submission and review of proposed human research. Any 
person who intends to conduct human research covered by Sec.  26.101(j) 
shall, after receiving approval from all appropriate IRBs, submit to 
EPA at least 90 days prior to initiating such research all information 
relevant to the proposed research specified by Sec.  26.115(a) to be 
prepared and maintained by an IRB, and the following additional 
information, to the extent not otherwise covered:
    (1) A discussion of:
    (i) The potential risks to human subjects;
    (ii) The measures proposed to minimize risks to the human subjects;
    (iii) The expected benefits of such research, and to whom they 
would accrue;
    (iv) Alternative means of obtaining information comparable to what 
would be collected through the proposed research; and
    (v) The distribution and balance of risks and benefits of the 
proposed research.
    (2) The information for subjects and written informed consent 
agreements as provided to the IRB, and as approved by the IRB.
    (3) Information about how subjects will be recruited, including any 
advertisements proposed to be used.
    (4) All correspondence between the IRB and the investigators or 
sponsors.
    (5) Following initial evaluation of the protocol by Agency staff, 
EPA shall submit the protocol and all supporting materials, together 
with the staff evaluation, to the Human Studies Review Board. This 
Board shall consist of members who are not employed by the Agency, who 
meet the ethics requirements for special government employees, and who 
have expertise in fields appropriate for review of human research. The 
Board shall review and comment on the scientific and ethical aspects of 
research proposals and reports of completed intentional dosing research 
with human subjects which EPA intends to rely on in its decision-making 
under FIFRA or FFDCA, and, on request, advise EPA on ways to strengthen 
its programs for protection of human subjects of research.
    (c) Submission of information pertaining to ethical conduct of 
completed human research. Any person who submits to EPA data derived 
from human research covered by this subpart shall also provide to EPA 
information documenting compliance with the requirements of this 
subpart. Such information should include:
    (1) Copies of all of the records relevant to the research specified 
by Sec.  26.115(a) to be prepared and maintained by an IRB.
    (2) Copies of sample records used to document informed consent as 
specified by Sec.  26.117, but not identifying any subjects of the 
research.
    (3) Copies of all correspondence, if any, between EPA and the 
researcher or sponsor pursuant to paragraph (b) of this section.
    6. By adding new subparts B through F to read as follows:
Subpart B--Additional Protections for Pregnant Women, Fetuses, and 
Newborns Involved in Research
Sec.
Sec.  26.201 To what do these regulations apply?
Sec.  26.202 Definitions.
Sec.  26.203 Duties of IRBs in connection with research involving 
pregnant women, fetuses, and neonates.
Sec.  26.204 Research involving pregnant women or fetuses.
Sec.  26.205 Research involving neonates.
Sec.  26.206 Research involving, after delivery, the placenta, the 
dead fetus, or fetal material.
Sec.  26.207-26.219 [Reserved]
Sec.  26.220 Prohibition of research involving intentional dosing of 
pregnant women, fetuses, or newborns.
Sec.  26.221 Prohibition of EPA reliance on research involving 
intentional dosing of pregnant women, fetuses, or newborns.
Subpart C--Additional Protections Pertaining to Research Involving 
Prisoners as Subjects [Reserved]
Subpart D--Additional Protections for Children Involved as Subjects in 
Research
Sec.  26.401 To what do these regulations apply?
Sec.  26.402 Definitions.
Sec.  26.403 IRB duties.
Sec.  26.404 Research not involving greater than minimal risk.
Sec.  26.405 Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the individual 
subjects.
Sec.  26.406 [Reserved]
Sec.  26.407 [Reserved]

[[Page 53864]]

Sec.  26.408 Requirements for permission by parents or guardians and 
for assent by children.
Sec.  26.409-26.419 [Reserved]
Sec.  26.420 Prohibition of research involving intentional dosing of 
children.
Sec.  26.421 Prohibition of EPA reliance on research involving 
intentional dosing of children.
Subpart E--Administrative Actions for Noncompliance
Sec.  26.501 Lesser administrative actions.
Sec.  26.502 Disqualification of an IRB or an institution.
Sec.  26.503 Public disclosure of information regarding revocation.
Sec.  26.504 Reinstatement of an IRB or an institution.
Sec.  26.505 Debarment.
Sec.  26.506 Actions alternative or additional to disqualification.
Subpart F--Ethical Standards for Assessing Whether to Rely on the 
Results of Human Research in EPA Regulatory Decisions
Sec.  26.601 Human research conducted prior to [effective date of 
the final rule].
Sec.  26.602 Human research conducted after [effective date of the 
final rule].
Sec.  26.603 Exceptions for human research.

Subpart B--Additional Protections for Pregnant Women, Fetuses, and 
Newborns Involved in Research


Sec.  26.201  To what do these regulations apply?

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


Sec.  26.202  Definitions.

    The definitions in Sec.  26.102 shall be applicable to this subpart 
as well. In addition, the definitions at 45 CFR 46.202(a) through (f) 
and at 45 CFR 46.202(h) are applicable to this subpart. For purposes of 
this part, Administrator means the Administrator of the Environmental 
Protection Agency and any other officer or employee of the 
Environmental Protection Agency to whom authority has been delegated.


Sec.  26.203  Duties of IRBs in connection with research involving 
pregnant women, fetuses, and neonates.

    The provisions of 45 CFR 46.203 are applicable to this section.


Sec.  26.204   Research involving pregnant women or fetuses.

    The provisions of 45 CFR 46.204 are applicable to this section.


Sec.  26.205  Research involving neonates.

    The provisions of 45 CFR 46.205 are applicable to this section.


Sec.  26.206  Research involving, after delivery, the placenta, the 
dead fetus, or fetal material.

    The provisions of 45 CFR 46.206 are applicable to this section.


Sec.  26.207-26.219  [Reserved]


Sec.  26.220  Prohibition of research involving intentional dosing of 
pregnant women, fetuses, or newborns.

    Notwithstanding any other provision of this part, under no 
circumstances shall EPA or a person when covered by Sec.  26.101(j) 
conduct or support research involving intentional dosing of any 
pregnant woman, fetus, or newborn.


Sec.  26.221  Prohibition of EPA reliance on research involving 
intentional dosing of pregnant women, fetuses, or newborns.

    In its regulatory decision-making under the Federal Insecticide, 
Fungicide, and Rodenticide Act (7 U.S.C. 136 et seq.) or section 408 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 346a), EPA shall 
not rely on any research involving intentional dosing of any pregnant 
women, fetuses, or newborns, except when such research is deemed 
scientifically sound and crucial to the protection of public health, 
under the procedure defined in Sec.  26.603.

Subpart C--Additional Protections Pertaining to Research Involving 
Prisoners as Subjects [Reserved]

Subpart D--Additional Protections for Children Involved as Subjects 
in Research


Sec.  26.401  To what do these regulations apply?

    (a) This subpart applies to all research involving children as 
subjects, conducted or supported by EPA. This subpart also applies to 
all research involving children covered by Sec.  26.101(j).
    (1) This includes research conducted by EPA employees, except that 
each head of an Office of the Agency may adopt such nonsubstantive, 
procedural modifications as may be appropriate from an administrative 
standpoint.
    (2) It also includes research conducted or supported by EPA outside 
the United States, but in appropriate circumstances, the Administrator 
may, under Sec.  26.101(e), waive the applicability of some or all of 
the requirements of these regulations for research of this type.
    (b) Exemptions at Sec.  26.101(b)(1) and (b)(3) through (b)(6) are 
applicable to this subpart. The exemption at Sec.  26.101(b)(2) 
regarding educational tests is also applicable to this subpart. 
However, the exemption at Sec.  26.101(b)(2) for research involving 
survey or interview procedures or observations of public behavior does 
not apply to research covered by this subpart, except for research 
involving observation of public behavior when the investigator(s) do 
not participate in the activities being observed.
    (c) The exceptions, additions, and provisions for waiver as they 
appear in Sec.  26.101(c) through (i) are applicable to this subpart.


Sec.  26.402  Definitions.

    The definitions in Sec.  26.102 shall be applicable to this subpart 
as well. In addition, as used in this subpart:
    (a) Children are persons who have not attained the age of 18.
    (b) Assent means a child's affirmative agreement to participate in 
research. Mere failure to object should not, absent affirmative 
agreement, be construed as assent.
    (c) Permission means the agreement of parent(s) or guardian to the 
participation of their child or ward in research.
    (d) Parent means a child's biological or adoptive parent.
    (e) Guardian means an individual who is authorized under applicable 
State, Tribal, or local law to consent on behalf of a child to general 
medical care.


Sec.  26.403  IRB duties.

    The provisions of 45 CFR 46.403 are applicable to this section.


Sec.  26.404  Research not involving greater than minimal risk.

    EPA will conduct or fund research in which the IRB finds that no 
greater than minimal risk to children is presented, only if the IRB 
finds that adequate provisions are made for soliciting the assent of 
the children and the

[[Page 53865]]

permission of their parents or guardians, as set forth in Sec.  26.408.


Sec.  26.405  Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the individual subjects.

    EPA will conduct or fund research in which the IRB finds that more 
than minimal risk to children is presented by an intervention or 
procedure that holds out the prospect of direct benefit for the 
individual subject, or by a monitoring procedure that is likely to 
contribute to the subject's well-being, only if the IRB finds and 
documents that:
    (a) The risk is justified by the anticipated benefit to the 
subjects.
    (b) The relation of the anticipated benefit to the risk is at least 
as favorable to the subjects as that presented by available alternative 
approaches.
    (c) Adequate provisions are made for soliciting the assent of the 
children and permission of their parents or guardians, as set forth in 
Sec.  26.408.


Sec.  26.406  [Reserved]


Sec.  26.407  [Reserved]


Sec.  26.408  Requirements for permission by parents or guardians and 
for assent by children.

    (a) In addition to the determinations required under other 
applicable sections of this subpart, the IRB shall determine that 
adequate provisions are made for soliciting the assent of the children, 
when in the judgment of the IRB the children are capable of providing 
assent. In determining whether children are capable of assenting, the 
IRB shall take into account the ages, maturity, and psychological state 
of the children involved. This judgment may be made for all children to 
be involved in research under a particular protocol, or for each child, 
as the IRB deems appropriate. If the IRB determines that the capability 
of some or all of the children is so limited that they cannot 
reasonably be consulted or that the intervention or procedure involved 
in the research holds out a prospect of direct benefit that is 
important to the health or well-being of the children and is available 
only in the context of the research, the assent of the children is not 
a necessary condition for proceeding with the research. Even where the 
IRB determines that the subjects are capable of assenting, the IRB may 
still waive the assent requirement under circumstances in which consent 
may be waived in accord with Sec.  26.116(d).
    (b) In addition to the determinations required under other 
applicable sections of this subpart, the IRB shall determine, in 
accordance with and to the extent that consent is required by Sec.  
26.116, that adequate provisions are made for soliciting the permission 
of each child's parents or guardian. Where parental permission is to be 
obtained, the IRB may find that the permission of one parent is 
sufficient for research to be conducted under Sec. 26.404 or 
Sec. 26.405.
    (c) In addition to the provisions for waiver contained in Sec.  
26.116, if the IRB determines that a research protocol is designed for 
conditions or for a subject population for which parental or guardian 
permission is not a reasonable requirement to protect the subjects (for 
example, neglected or abused children), it may waive the consent 
requirements in subpart A of this part and paragraph (b) of this 
section, provided an appropriate mechanism for protecting the children 
who will participate as subjects in the research is substituted, and 
provided further that the waiver is not inconsistent with Federal, 
State or local law. The choice of an appropriate mechanism would depend 
upon the nature and purpose of the activities described in the 
protocol, the risk and anticipated benefit to the research subjects, 
and their age, maturity, status, and condition.
    (d) Permission by parents or guardians shall be documented in 
accordance with and to the extent required by Sec.  26.117.
    (e) When the IRB determines that assent is required, it shall also 
determine whether and how assent must be documented.


Sec. Sec.  26.409-26.419  [Reserved]


Sec.  26.420  Prohibition of research involving intentional dosing of 
children.

    Notwithstanding any other provision of this part, under no 
circumstances shall EPA or a person when covered by Sec.  26.101(j) 
conduct or support research involving intentional dosing of any child.


Sec.  26.421  Prohibition of EPA reliance on research involving 
intentional dosing of children.

    In its regulatory decision-making under the Federal Insecticide, 
Fungicide, and Rodenticide Act (7 U.S.C. 136 et seq.) or section 408 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 346a), EPA shall 
not rely on any research involving intentional dosing of any child, 
except when such research is deemed scientifically sound and crucial to 
the protection of public health, under the procedure defined in Sec.  
26.603.

Subpart E--Administrative Actions for Noncompliance


Sec.  26.501  Lesser administrative actions.

    (a) If apparent noncompliance with the applicable regulations in 
subparts A through D of this part concerning the operation of an IRB is 
observed by a duly authorized investigator during an inspection, the 
inspector will present an oral or written summary of observations to an 
appropriate representative of the IRB. EPA may subsequently send a 
letter describing the noncompliance to the IRB and to the parent 
institution. The agency will require that the IRB or the parent 
institution respond to this letter within a time period specified by 
EPA and describe the corrective actions that will be taken by the IRB, 
the institution, or both to achieve compliance with these regulations.
    (b) On the basis of the IRB's or the institution's response, EPA 
may schedule a reinspection to confirm the adequacy of corrective 
actions. In addition, until the IRB or the parent institution takes 
appropriate corrective action, the Agency may:
    (1) Withhold approval of new studies subject to the requirements of 
this part that are conducted at the institution or reviewed by the IRB;
    (2) Direct that no new subjects be added to ongoing studies subject 
to this part;
    (3) Terminate ongoing studies subject to this part when doing so 
would not endanger the subjects; or
    (4) When the apparent noncompliance creates a significant threat to 
the rights and welfare of human subjects, notify relevant State and 
Federal regulatory agencies and other parties with a direct interest in 
the agency's action of the deficiencies in the operation of the IRB.
    (c) The parent institution is presumed to be responsible for the 
operation of an IRB, and EPA will ordinarily direct any administrative 
action under this subpart against the institution. However, depending 
on the evidence of responsibility for deficiencies, determined during 
the investigation, EPA may restrict its administrative actions to the 
IRB or to a component of the parent institution determined to be 
responsible for formal designation of the IRB.


Sec.  26.502  Disqualification of an IRB or an institution.

    (a) Whenever the IRB or the institution has failed to take adequate 
steps to correct the noncompliance stated in the letter sent by the 
Agency under Sec.  26.501(a) and the EPA Administrator determines that 
this noncompliance may justify the

[[Page 53866]]

disqualification of the IRB or of the parent institution, the 
Administrator may institute appropriate proceedings.
    (b) The Administrator may disqualify an IRB or the parent 
institution if the Administrator determines that:
    (1) The IRB has refused or repeatedly failed to comply with any of 
the regulations set forth in this part, and
    (2) The noncompliance adversely affects the rights or welfare of 
the human subjects of research.
    (c) If the Administrator determines that disqualification is 
appropriate, the Administrator will issue an order that explains the 
basis for the determination and that prescribes any actions to be taken 
with regard to ongoing human research, covered by subparts A through D 
of this part, conducted under the review of the IRB. EPA will send 
notice of the disqualification to the IRB and the parent institution. 
Other parties with a direct interest, such as sponsors and 
investigators, may also be sent a notice of the disqualification. In 
addition, the agency may elect to publish a notice of its action in the 
Federal Register.
    (d) EPA may refuse to consider in support of a regulatory decision 
the data from human research, covered by subparts A through D of this 
part, that was reviewed by a disqualified IRB or conducted at a 
disqualified institution, unless the IRB or the parent institution is 
reinstated as provided in Sec.  26.504, or unless such research is 
deemed scientifically sound and crucial to the protection of public 
health, under the procedure defined in Sec.  26.603.


Sec.  26.503  Public disclosure of information regarding revocation.

    A determination that EPA has disqualified an institution and the 
administrative record regarding that determination are disclosable to 
the public under 40 CFR part 2.


Sec.  26.504  Reinstatement of an IRB or an institution.

    An IRB or an institution may be reinstated if the Administrator 
determines, upon an evaluation of a written submission from the IRB or 
institution that explains the corrective action that the institution or 
IRB plans to take, that the IRB or institution has provided adequate 
assurance that it will operate in compliance with the standards set 
forth in this part. Notification of reinstatement shall be provided to 
all persons notified under Sec.  26.501(c).


Sec.  26.505  Debarment.

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


Sec.  26.506  Actions alternative or additional to disqualification.

    Disqualification of an IRB or of an institution is independent of, 
and neither in lieu of nor a precondition to, other statutorily 
authorized proceedings or actions. EPA may, at any time, on its own 
initiative or through the Department of Justice, institute any 
appropriate judicial proceedings (civil or criminal) and any other 
appropriate regulatory action, in addition to or in lieu of, and 
before, at the time of, or after, disqualification. The Agency may also 
refer pertinent matters to another Federal, State, or local government 
agency for any action that that agency determines to be appropriate.

Subpart F--Ethical Standards for Assessing Whether to Rely on the 
Results of Human Research in EPA Regulatory Decisions


Sec.  26.601  Human research conducted prior to [effective date of the 
final rule].

    Unless there is clear evidence that the conduct of that research 
was fundamentally unethical (e.g., the research was intended to 
seriously harm participants or failed to obtain informed consent), or 
was significantly deficient relative to the ethical standards 
prevailing at the time the research was conducted, EPA will generally 
accept and rely on relevant, scientifically valid data from research 
that:
    (a) Was initiated prior to [effective date of the final rule],
    (b) Involved intentional exposure of a human subject,
    (c) Did not involve intentional exposure of a pregnant woman, 
fetus, newborn, or child, and
    (d) Is being considered under the Federal Insecticide, Fungicide, 
and Rodenticide Act or the Federal Food, Drug, and Cosmetic Act.


Sec.  26.602  Human research conducted after [effective date of the 
final rule].

    EPA will generally accept and rely on relevant, scientifically 
valid data from research that:
    (a) Was initiated after [effective date of the final rule],
    (b) Involved intentional exposure of a human subject,
    (c) Did not involve intentional exposure of a pregnant woman, 
fetus, newborn, or child, and
    (d) Is being considered under the Federal Insecticide, Fungicide, 
and Rodenticide Act or the Federal Food, Drug, and Cosmetic Act only if 
EPA has adequate information to determine that the research was 
conducted in a manner that substantially complies with subparts A 
through D of this part.


Sec.  26.603  Exceptions for human research.

    (a) Before reaching a decision not to rely on scientifically useful 
and relevant data derived from research that does not meet the 
applicable standards of Sec. Sec.  26.601 through 26.602, or that 
involves intentional exposure of a pregnant woman, fetus, newborn, or 
child, EPA will consider whether the data are crucial to a regulatory 
decision that would be more protective of public health than could be 
justified without relying on the data.
    (b) Before making a decision under this section, EPA will solicit 
the views of the Human Studies Review Board and provide an opportunity 
for public comment.
    (c) If EPA decides to rely on data derived from a study that does 
not meet the applicable standards of Sec. Sec.  26.601 through 26.602, 
EPA will include in the explanation of its decision a thorough 
discussion of the significant ethical deficiencies of the study, as 
well as the full rationale for concluding that relying on the study is 
crucial to protection of public health.
[FR Doc. 05-18010 Filed 9-8-05; 9:19 am]
BILLING CODE 6560-50-S