EPA Proposal to
Ban the Intentional Poisoning by Pesticides of
Pregnant Women and Children

Federal Register v.70, n.175. p.53837 12sep2005

[Federal Register: September 12, 2005 (Volume 70, Number 175)]
[Proposed Rules]
[Page 53837-53866]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12se05-11]
[[Page 53838]]

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.

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 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 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: 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

[[Page 53839]]

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

[[Page 53840]]

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

[[Page 53841]]

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

[[Page 53842]]

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/5c50571a75df494485256
a95007a091e/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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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

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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 o