[Federal Register Volume 70, Number 25 (Tuesday, February 8, 2005)]
[Pages 6661-6667]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-2371]



RIN: 2070-AD57
[OPP-2003-0132; FRL-7695-4]

Human Testing; Proposed Plan and Description of Review Process

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.


SUMMARY: This notice announces EPA's plan to establish a comprehensive 
framework for making decisions about the extent to which it will 
consider or rely on certain types of research with human participants. 
Among other actions the plan provides for: Issuing proposed and final 
rules, and providing in this Notice a description of the Agency's case-
by-case process for evaluating human studies, which is to

[[Page 6662]]

remain in effect until superseded by rulemaking. This Notice invites 
public comments on the overall plan and particularly on the current 
case-by-case process.

DATES: Comments must be received on or before May 9, 2005.

ADDRESSES: Submit your comments, identified by docket identification 
(ID) number OPP-2003-0132, by one of the following methods:
     Agency website: http://www.epa.gov/edocket/. EDOCKET, 
EPA's electronic public docket and comment system, is EPA's preferred 
method for receiving comments. Follow the on-line instructions for 
submitting comments.
     E-mail: Comments may be sent by e-mail to [email protected], Attention: Docket ID Number OPP-2003-0132.
     Mail: Public Information and Records Integrity Branch 
(PIRIB) (7502C), Office of Pesticide Programs (OPP), Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001, Attention: Docket ID Number OPP-2003-0132.
     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 or see the Federal Register of May 31, 
2002 (67 FR 38102) (FRL-7181-7).
    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) 

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

SUPPLEMENTARY INFORMATION: This Notice is organized into five Units. 
Unit I. contains ``General Information'' about the applicability of 
this Notice, how to obtain additional information, how to submit 
comments in response to the request for comments, and certain other 
related matters. Unit II. provides background and historic information 
pertaining to human subject research. Unit III. describes the 
activities that EPA is planning to pursue to establish a framework 
within which it will address the broad range of issues related to the 
Agency's consideration of or reliance on research with human 
participants. Unit IV. describes the current case-by-case process that 
EPA will continue to follow pending completion of the rulemaking 
efforts described in its plan. The last unit describes procedures 
followed in the development of this Notice and certain statutes and 
Executive Orders that the public may wish to consider in preparing 

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 testing of 
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/.

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

    1. Submitting CBI. Do not submit this information to EPA through 
EDOCKET, regulations.gov, or e-mail. Clearly mark the part or all of 
the information that you claim to be CBI. For CBI information in a disk 
or CD ROM that you mail to EPA, mark the outside of the disk or CD ROM 
as CBI and then identify electronically within the disk or CD ROM the 
specific information that is claimed as CBI. In addition to one 
complete version of the comment that includes information claimed as 
CBI, a copy of the comment that does not contain the information 
claimed as CBI must be submitted for inclusion in the public docket. 
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.

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    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 
    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. Introduction

A. Background on Federal Standards for Conducting Human Research

    Over the years, scientific research with human subjects has 
provided much 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 1979 The 
Belmont Report: Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research. This document can be found on the web at 
http://www.hhs.gov/ohrp/humansubjects/ guidance/belmont.htm. For many 
Federal agencies and departments in the United States, the principles 
of the Belmont Report are implemented through the Federal Policy for 
the Protection of Human Subjects (also known as the Common Rule). The 
Common Rule, which was 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.
    More broadly, the international medical research community has 
developed and maintains ethical standards documented in the Declaration 
of Helsinki, first issued by the World Medical Association 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 to research on matters relating to the diagnosis and treatment of 
human disease, and to research that adds to understanding of the causes 
of disease and the biological mechanisms that explain the relationships 
between human exposures to environmental agents and 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. governmental 
organizations, have their own specific policies related to the 
protection of human participants in research.
    Much of the scientific information supporting EPA's actions is 
generated by researchers who are not part of or supported by a Federal 
agency, including 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 
for federalwide use by the Department of Health and Human Services' 
(HHS) Office for Human Research Protections and the institution has 
voluntarily extended the applicability of the assurance to such 
research. In some instances, research is reported in such a manner that 
EPA cannot readily determine whether institutional policies are 
consistent with or as protective of human subjects as the Common Rule, 
or even the extent to which such policies or standards have been 
followed in the conduct of any particular study. Thus, even well-
conducted third-party human studies may raise difficult questions for 
the Agency when it seeks to determine their acceptability for 
consideration. Unit IV. of this Notice contains a description of EPA's 
case-by-case process for review of third-party human studies.

B. Human Research Issues in EPA's Pesticide Program

    Although data from human studies has 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), EPA is 
authorized to require pesticide companies to conduct studies with human 
subjects, for example, to measure potential exposure to pesticide users 
or to workers and others who re-enter areas treated with pesticides, or 
to evaluate the effectiveness of pesticide products intended to repel 
insects and other pests from human skin. In addition, EPA sometimes 
encourages other research with human subjects, including tests of the 
potential for some pesticides--generally those designed for prolonged 
contact with human skin--to irritate or sensitize human skin, and tests 
of the metabolic fate of pesticides in the human body. These latter 
studies typically precede monitoring studies of agricultural workers 
and others to protect them from exposure to potentially dangerous 
levels of pesticide residues.
    In addition to these kinds of research which have been required or 
encouraged by EPA, other kinds of studies involving human subjects 
intentionally exposed to pesticides have occasionally been submitted to 
the agency voluntarily. Among these voluntarily submitted studies have 
been tests involving intentional dosing of human subjects to establish 
a No Observed Adverse Effect Level (NOAEL) or No Observed Effect Level 
(NOEL) for systemic toxicity of certain pesticides to humans. (Often 
the researchers reported observing no treatment-related responses in 
test participants.) For some two decades before passage of the Food 
Quality Protection Act (FQPA) in 1996, submission of such studies was 
rare. EPA considered and relied on human NOAEL/NOEL studies in a few 
regulatory decisions on pesticides made prior to 1996. After passage of 
FQPA, submission of these types of studies to EPA's Office of Pesticide 
Programs increased; the Agency has received some 20 studies of this 
kind since 1996.
    In response to concerns about human testing expressed in a report 
of a non-governmental advocacy organization, the Environmental Working 
Group, in July 1998, the Agency began a systematic review of its policy 
and practice. In a press statement on July 28, 1998, EPA noted that it 
had not relied on any such studies in any final decisions made under 
    In further response to growing public concern over pesticide 
research with human subjects, EPA convened an advisory committee under 
the joint auspices of the EPA Science Advisory

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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 cited above in this Notice, 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. No clear consensus emerged from the advisory 
committee process on the acceptability of NOAEL or NOEL studies of 
systemic toxicity of pesticides to human subjects, and significant 
differences of opinion remained on both their scientific merit and 
ethical acceptability. A vigorous public debate continued about the 
extent to which EPA should accept, consider, or rely on third-party 
intentional dosing human toxicity studies with pesticides.
    In December 2001, EPA asked the advice of the National Academy of 
Sciences (NAS) on the many difficult scientific and ethical issues 
raised in this debate, and also stated the Agency's interim approach on 
third-party intentional dosing human subjects studies. The Agency's 
press release on this subject is on the web at http://yosemite.epa.gov/opa/admpress.nsf/ b1ab9f485b098972852562e7004dc686/ c232a45f5473 
717085256b2200740ad4? OpenDocument. At that time the Agency committed 
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 rulemaking 
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 filed a 
petition with the U. S. Court of Appeals for the District of Columbia 
for review of EPA's December 2001 press release. These parties argued 
that the Agency's interim approach 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 of Appeals concluded that:
    For the reasons enumerated above, 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 Crop Life America v. Environmental Protection Agency, 329 F.3d 876, 
884 - 85 (D.C. Cir. 2003) (referred to as the Crop Life America case).
    In the meantime, under a contract with EPA, 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/5c50571a75df49 4485256a95007a091e/ 
9303f725c15902f685256c44005d8931? OpenDocument&Highlight=0,EPA. The 
committee issued its final report, ``Intentional Human Dosing Studies 
for EPA Regulatory Purposes: Scientific and Ethical Issues,'' in 
February 2004. That 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 (68 FR 24410) in which EPA announced its 
intention to undertake notice-and-comment rulemaking on the subject of 
its consideration of or reliance on research involving human 
participants. The ANPR also invited public comment on a broad range of 
issues related to this subject. EPA received over 600 submissions in 
response to the ANPR. 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 for EPA by third parties. 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 EPA's consideration of results from 
human testing, especially those involving intentional dosing of test 
participants with pesticides, on ethical grounds. 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 sent 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 Agency-wide Focus on Human Research Issues

    Human research issues affect all programs in EPA. In its Office of 
Research and Development, EPA conducts research with human subjects to 
provide critical information on environmental risks, exposures, and 
effects in humans. This is referred to as first-party research. In both 
its Office of Research and Development and its program offices 
(including the Office of Air and Radiation, the Office of Water, the 
Office of Solid Waste and Emergency Response, and the Office of 
Prevention, Pesticides and Toxic Substances), EPA also supports 
research with human subjects conducted by others. This is referred to 
as second-party research. In all this work EPA has been and remains 
committed to full compliance with the Common Rule. This research has 
provided many important insights and has contributed to the protection 
of human health. The Agency will continue to conduct and support such 
research, and to consider and rely on its results in Agency assessments 
and decisions.
    EPA also remains committed to scientifically sound assessments of 
the hazards of environmental agents, taking into consideration all 
available, relevant, and appropriate scientific research. In at least 
some cases, some of the available, relevant, and appropriate scientific 
research is conducted with human subjects by third parties, without 
Federal government support. EPA programs have on occasion relied on 
such studies to more completely characterize and understand 
environmental risks to humans; the Agency will continue to do so when 
it is appropriate.
    EPA recognizes that its approach to the issues surrounding human 
research needs to be consistent across the Agency. EPA is interested in 
addressing the broad range of issues involving the consideration of and 
reliance on data from human subjects studies, particularly tests 
conducted by third

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parties. After consideration of the Court of Appeals' decision in the 
Crop Life America case, the public comments on the ANPR, and the report 
from the NAS, EPA has concluded that it should undertake a number of 
activities to address these issues fully. The Agency's plan is 
described in Unit III. of this Notice.

D. Legal Authority

    The actions described below are authorized under a variety of 
provisions of the different environmental statutes EPA administers. 
Section 25(a) of the Federal Insecticide, Fungicide, and Rodenticide 
Act (FIFRA) gives the Administrator authority to ``prescribe 
regulations to carry out the purposes of [FIFRA].'' Such a rule would 
implement EPA's authority to require data in support of registration of 
pesticides (see, for example, FIFRA sections 3(c)(1)(F) and 3(c)(2)(B)) 
and to interpret the provision making 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 health consequences which are reasonably 
foreseeable therefrom, and (ii) freely volunteer to participate in the 
test.'' (FIFRA section 12(a)(2)(P)). In addition, 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 this section.''
    The Clean Air Act authorizes the Administrator to promulgate 
regulations necessary to carry out the Agency's functions under that 
Act at 42 U.S.C. 7601(a). The Clean Water Act contains a comparable 
provision at 33 U.S.C. 1361. Section 42 U.S.C. 9615 in the 
Comprehensive Environmental Response, Compensation, and Liability Act 
authorizes the President to establish regulations to implement the 
statute; this authority has been delegated to EPA by Executive Order 
12580. The Emergency Planning and Community Right-to-Know Act also 
contains a general rulemaking provision, 42 U.S.C. 11048, authorizing 
the Administrator to promulgate rules necessary to carry out the Act. 
The Resource Conservation and Recovery Act specifically authorizes the 
Administrator to prescribe regulations necessary to carry out EPA's 
functions under the Act, 42 U.S.C. 6912. The Safe Drinking Water Act 
contains similar language, authorizing the Administrator to prescribe 
such regulations ``as are necessary and appropriate'' to carry out 
EPA's functions under the Act, 42 U.S.C. 300j-9. In addition, EPA has 
broad authority under 5 U.S.C. 301 and 42 U.S.C. 300v-1(b).

III. EPA's Proposed Plan for Addressing Issues Relating to Human 

    As a consequence of the public debate over whether it is 
appropriate to consider or rely on data from intentional dosing of 
humans, EPA recognizes that it is essential that the Agency state its 
positions on these issues so that the public can understand under what 
circumstances the Agency would take particular actions. The public 
debate has made clear that a number of aspects of EPA's policy and 
procedures are affected and that changes should be considered. Thus, 
EPA has identified a number of activities including the issuance of a 
clarifying description of the current case-by-case approach, 
rulemakings, and administrative/organizational changes that appear 
appropriate. EPA's overall goals for these activities are: That human 
participants in any research required by, conducted for, or considered 
by EPA are treated ethically; and that all scientifically sound data 
relevant to EPA decision-making is considered and used appropriately in 
reaching decisions under our authorities.
    EPA has identified a variety of activities that, collectively, will 
establish a comprehensive framework to address the broad range of 
issues relating to the consideration of or reliance on data from human 
studies, particularly when conducted by third parties. EPA has drawn 
heavily on the recommendations contained in the NAS report in designing 
this framework.
    1. Publication of a clarifying description of the current case-by-
case review of completed third-party human studies. Consistent with the 
Court's opinion in the Crop Life America case, EPA will continue to 
evaluate third-party human studies on a case-by-case basis, applying 
statutory requirements, the Common Rule, and high ethical standards as 
a guide, until such time as this practice is replaced by a rulemaking. 
EPA is issuing a clarifying description of its current process in Unit 
IV. of this Notice. EPA intends to continue this process until such 
time as it is superseded by rulemaking. EPA, however, welcomes public 
comment on the description of its current process, and after reviewing 
comments, EPA may choose to publish additional clarification.
    2. Intent to publish a policy statement to third parties 
encouraging them to submit protocols for proposed human studies to EPA 
for review. EPA intends to develop and make public a policy statement 
that encourages, but does not require, ``third-party'' researchers, 
i.e., researchers who are not part of or supported by a Federal agency, 
who are planning to conduct studies involving human participants to 
support an EPA regulatory decision, to submit a proposed protocol to 
EPA prior to conducting the research. The policy statement would 
explain EPA's intent to review and provide comments to the researcher 
concerning the ethical and scientific attributes of the proposal.
    3. Intent to publish guidance concerning compliance with the Common 
Rule for any future human studies specifically required by EPA. EPA 
intends to publish non-binding guidance reflecting its plans to extend 
the Common Rule to specifically cover third-party human subject studies 
that are intended to be submitted to the Agency either voluntarily or 
in response to an Agency-imposed requirement and setting forth its 
expectation that any such study intended to be submitted in the interim 
should endeavor to include protections such as those included in the 
Common Rule.
    Additionally, in the interim, the Agency intends to utilize 
existing authority, where appropriate, to require that test sponsors 
and testing facilities and personnel adhere to the Common Rule in 
conducting human studies if such studies are submitted to the Agency to 
satisfy specific data requirements, for example, studies with human 
participants that may be submitted to the Agency to satisfy data 
requirements under FIFRA section 3(c)(2)(B) or pursuant to a TSCA 
section 4 testing rule.
    4. Intent to conduct outreach to scientific journals encouraging 
improved reporting of the ethics of published human studies. Many 
biomedical journals have adopted voluntary, uniform requirements for 
submitted manuscripts. These requirements include reporting on the 
protection of human subjects, through indicating whether the procedures 
followed were in accordance with the ethical standards of the 
responsible institution and with the Declaration of Helsinki or other, 
comparable, ethics codes. EPA intends to conduct outreach to these 
journals to determine the extent of coverage and compliance, and to 
encourage the reporting of this ethics information in connection with 
publication of the results of research conducted with human 
    5. Intent to expand the functions of the EPA Human Subjects 
Research Review Official and to relocate the HSRRO office. Within EPA, 
the Human Subjects Research Review Official (HSRRO) has responsibility 
for assuring

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that all human subjects research that is conducted or supported by EPA 
complies with the requirements of the Common Rule. The HSRRO's specific 
responsibilities are described in EPA Order 1000.17 Change A1. See 
http://www.epa.gov/oamrtpnc/forms/ 1000--17a.pdf. These 
responsibilities, in effect, entail addressing the scientific and 
ethical issues raised by human studies. The HSRRO reviews and approves 
about 50 projects a year, of which only a few involve intentional 
dosing of human participants with environmental pollutants. Currently, 
the HSRRO is located within EPA's Office of Research & Development, 
which is the Office within EPA that conducts or sponsors most of the 
research programs reviewed by the HSRRO.
    The NAS report included the recommendation that ``[t]o ensure 
intentional dosing human 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.'' The NAS further 
recommended that the Human Studies Review Board ``should report 
directly to the Office of the [EPA] Administrator.'' Consistent with 
the NAS recommendation, EPA intends to expand the functions of the 
HSRRO and is looking at where to relocate those functions. In addition 
to the existing function of ensuring compliance with the Common Rule 
for human subjects research conducted or supported by EPA, the Agency 
intends that the HSRRO will have responsibility for overseeing 
implementation of the ethics screening of completed studies (see Unit 
IV.), overseeing the review of proposals to conduct new human studies, 
identifying emerging ethical issues for research not subject to the 
Common Rule, and developing additional policies, training, and best 
practices guidance. The Agency welcomes public comment on this part of 
its plan.
    6. Intent to pursue rulemaking. EPA intends to publish a proposed 
rule to make the provisions of the Common Rule, 40 CFR part 26, 
applicable to certain newly conducted third-party human studies and may 
propose to adopt some or all of the HHS regulations that provide 
additional protections for certain populations of vulnerable subjects. 
These HHS regulations are contained in HHS regulations at 45 CFR part 
46, subpart B (Additional Protections for Pregnant Women, Human Fetuses 
and Neonates Involved in Research), subpart C (Additional Protections 
Pertaining to Biomedical and Behavioral Research Involving Prisoners as 
Subjects), and subpart D (Additional Protections for Children Involved 
as Subjects in Research), and apply to all research involving these 
respective vulnerable subject groups that is conducted or supported by 
HHS. This proposal may also require a sponsor or investigator to 
provide to EPA, for prior review and approval, the protocol for certain 
human studies. EPA will also consider whether to propose a rule 
applying to certain previously conducted human studies. In developing 
its proposals, EPA will consider both the report from the NAS and 
public comments on the ANPR and this Notice.

IV. Description of EPA's Current Case-by-Case Review Process for Third-
Party Human Studies

    This unit describes the Agency's process for reviewing and relying 
on completed, third-party studies that involve intentional dosing of 
human participants to identify or quantify a toxic endpoint. It is 
important to note that this is a case-by-case process. As such, it 
binds no one to a particular process or result--not the regulated 
community, not advocacy groups, not the public, and not EPA. Therefore, 
in any decision before EPA, any stakeholder may urge EPA to: (1) 
Conclude that this process is inapplicable; (2) consider factors other 
than those described here; or (3) make an exception to the process as 
described. EPA notes that it may determine, based on individual 
circumstances to act at variance from the review process as described. 
Thus, affected parties should not assume that EPA will follow a 
prescribed method of reviewing a particular human study in each and 
every instance. In any action involving consideration and review of a 
third-party, intentional dosing human study, EPA will explicitly state 
the basis upon which such a study has been evaluated.
    As mandated by the D.C. Circuit in the Crop Life 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. The 
Agency notes that this approach is consistent with Recommendation 5-7 
of the February 2004, NAS report.
    Primary responsibility for conducting case-by-case science and 
ethics reviews of third-party, intentional dosing human studies for 
toxic effects is vested in the EPA Office responsible for the relevant 
Agency action or risk assessment. To maintain high ethical standards 
the Agency screens all ``priority'' studies involving intentional 
dosing of human participants for toxic effects for existing ethics and 
scientific review information, and the responsible Office documents 
such reviews. A priority study is one which is expected to 
significantly affect the assessment, either by itself or as a 
substantial component of the weight of evidence, in determining: A 
regulatory standard, decision, or risk assessment value; determining an 
uncertainty factor or safety factor; or defining exposure or effects. 
The Agency also reviews as a ``priority'' study any study which was not 
relied on but which, if considered, arguably would change the outcome 
of the Agency's risk assessment or regulatory judgement or 
significantly affect the record underlying the Agency's conclusions. In 
addition, an Office may selectively review the ethics of any non-
priority study, as it deems appropriate.
    If a study raises potential ethical concerns or if there is 
uncertainty, the primary Office consults with the Human Subjects 
Research Review Official (HSRRO) and they jointly develop an evaluation 
plan for the study, which may include soliciting outside ethics advice. 
Senior Agency officials decide the appropriate action to take 
concerning ethically problematic studies on a case-by-case basis. 
Depending on the context, senior officials could include senior 
executives in the program office of concern, the Agency's HSRRO, and/or 
the Agency Science Advisor. If appropriate, the senior Agency officials 
may seek independent advice from an external peer review group such as 
the Science Advisory Board or the FIFRA Scientific Advisory Panel.

V. Statutory and Executive Order Reviews

    Since this Notice does not impose any requirements, and instead 
describes EPA's current case-by-case approach for reviewing certain 
human studies, and seeks comments on EPA's plans for amending that 
process and any suggestions for the Agency to consider in developing a 
subsequent notice of proposed rulemaking, the various other

[[Page 6667]]

review requirements that apply when an agency imposes requirements do 
not apply to this action.
    As part of your comments on this Notice you may include any 
comments or information that you have regarding these requirements. In 
particular, any comments or information that would help the Agency to 
assess the potential impact of a rule on small entities pursuant to the 
Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et seq.); to consider 
voluntary consensus standards pursuant to section 12(d) of the National 
Technology Transfer and Advancement Act of 1995 (NTTAA), Public Law 
104-113, section 12(d) (15 U.S.C. 272 note); or to consider 
environmental health or safety effects on children pursuant to 
Executive Order 13045, titled Protection of Children from Environmental 
Health Risks and Safety Risks (62 FR 19885, April 23, 1997). The Agency 
will consider such comments during the development of any subsequent 
notice of proposed rulemaking as it takes appropriate steps to address 
any applicable requirements.

List of Subjects

    Environmental protection, Protection of human research subjects.

    Dated: February 2, 2005.
Susan B. Hazen,
Acting Assistant Administrator, Office of Prevention, Pesticides and 
Toxic Substances.

[FR Doc. 05-2371 Filed 2-3-05; 11:43 am]