Protections for Subjects in Human Research, 53838-53866 [05-18010]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 70, Number 175 (Monday, September 12, 2005)]
[Proposed Rules]
[Pages 53838-53866]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-18010]



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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: https://www.regulations.gov/. 
Follow the on-line instructions for submitting comments.
     Agency Website: https://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 opp-
docket@epa.gov, 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 https://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 https://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: 
jordan.william@epa.gov.

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 (https://www.epa.gov/edocket/), you may 
access this Federal Register document electronically through the EPA 
Internet under the ``Federal Register'' listings at https://www.epa.gov/
fedrgstr/. A frequently updated electronic version of the Code of 
Federal Regulations (CFR) is available at https://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 https://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: https://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: https://
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: https://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: https://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