53838 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 online 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 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 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 ‘‘firstparty’’ 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 thirdparty 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 

53840 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 

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

53842 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 

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

In early 2002, various parties from the 

pesticide industry petitioned the U. S. 

Court of Appeals for the D. C. Circuit for 

review of EPA’s December 2001 press 

release. These parties argued that the 

interim approach announced in the 

Agency’s December 2001 Press Release 

constituted a ‘‘rule’’ promulgated in 

violation of the procedural requirements 

of the Administrative Procedure Act and 

the Federal Food, Drug, and Cosmetic 

Act. On June 3, 2003, the Court found 

for the petitioners and vacated EPA’s 

interim approach, stating: 

For the reasons enumerated previously, we 

vacate the directive articulated in EPA’s 

December 14, 2001 Press Release for a failure 

to engage in the requisite notice and 

comment rulemaking. The consequence is 

that the agency’s previous practice of 

considering third-party human studies on a 

case-by-case basis, applying statutory 

requirements, the Common Rule, and high 

ethical standards as a guide, is reinstated and 

remains in effect unless and until it is 

replaced by a lawfully promulgated 

regulation. See CropLife America v. 

Environmental Protection Agency, 329 F.3d 

876, 884 - 85 (D.C. Cir. 2003) (referred to as 

the CropLife America case). 

At EPA’s request, the NAS convened 

a committee to provide the requested 

advice. The committee met publicly in 

December 2002, and again in January 

and March 2003. The membership, 

meeting schedule, and other 

information about the work of this 

committee can be found on the NAS 

website at: http://www4.nas.edu/ 

webcr.nsf/ 5c50571a75df494485256a 

95007a 091e/ 

9303f725c15902f685256c44005d8931 

?OpenDocument. The committee issued 

its final report, ‘‘Intentional Human 

Dosing Studies for EPA Regulatory 

Purposes: Scientific and Ethical Issues,’’

in February 2004. Their report is 

available at: http://www.nap.edu/books/ 

0309091721/html/. 

On May 7, 2003, EPA issued an 

advance notice of proposed rulemaking 

(ANPR) on Human Testing announcing 

its intention to undertake notice-andcomment 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 

53844 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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-effectlevel (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-observedadverse-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 thirdparty 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). 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 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 thirdparty 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 thirdparty 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 § 26.102(j) of the 

regulatory text. 

BILLING CODE 6560–50–S 

53846 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 

§ 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 


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

53848 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 

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

(§§ 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. 

53850 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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, §§ 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 § 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 § 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 § 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 

§ 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 

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

53852 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 §§ 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 § 26.220 of 

the regulatory text to prohibit both EPA 

and third parties covered by proposed 

§ 26.101(j) from conducting or 

supporting an intentional dosing study 

involving as subjects pregnant women, 

fetuses, or newborns. Finally, EPA is 

proposing at § 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 § 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 § 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 §§ 26.501 through 26.504 and 

§ 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 Federalwide Assurance necessary to conduct 

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

§§ 26.501 through 26.504 and § 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 

53854 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

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 § 26.101(j) of 

the regulatory text, would the same or 

a different range of potential 

consequences for failure to comply with 

Common Rule requirements apply? 

4. FDA has published at 21 CFR part 

16 regulations establishing procedures 

for deciding whether to disqualify an 

IRB or institution that has failed to 

comply with applicable requirements. 

Should EPA pursue rulemaking to 

establish procedural regulations similar 

to those of FDA? 

X. Ethical Standards for Determining 

Whether to Rely on Scientifically 

Sound, Completed Human Studies with 

Ethical Deficiencies 

This unit concerns rulemaking to 

establish ethical standards EPA would 

apply in deciding whether to rely on the 

results from a scientifically sound 

completed human study deemed 

relevant to an EPA action. Other parts 

of today’s proposal address conduct of 

both EPA and certain third parties in the 

roles of investigators or sponsors of 

research with human subjects. It is in 

the capacity of investigators that both 

EPA and covered third parties are 

prohibited by this proposal from 

conducting or sponsoring intentional 

dosing studies involving pregnant 

women, infants, or children as subjects 

of the research. 

By contrast, this part of the 

rulemaking would govern EPA’s 

conduct as a regulatory agency, as it 

makes decisions to consider or not to 

consider reports of completed research 

with human subjects in its scientific 

assessments, and to rely on or not to 

rely on such research in its regulatory 

decisions. The Agency recognizes that 

the possibility of EPA refusal to rely on 

the results of research that does not 

meet appropriate ethical standards may 

influence the behavior of third parties. 

The Agency hopes that such a prospect 

would, along with other factors, be 

enough to encourage sponsors and 

investigators to conform to high ethical 

standards when performing covered 

human research. 

Summary of EPA Proposal 

In a new subpart F of 40 CFR part 26, 

EPA proposes ethical standards for its 

decisions to rely on or not to rely on in 

its decision-making reports of 

completed intentional-dosing research 

with human subjects being considered 

under FIFRA or FFDCA. For covered 

types of research conducted after the 

effective date of the rule, EPA proposes 

to refuse to rely on data from 

scientifically sound and relevant human 

research unless EPA has adequate 

information demonstrating that the 

research complied with the Common 

Rule. For covered types of research 

conducted before the effective date of 

the rule, EPA proposes to rely on data 

from scientifically sound and relevant 

human research unless there is clear 

evidence to show the conduct of the 

research was fundamentally unethical 

or was significantly deficient relative to 

the ethical standards prevailing at the 

time the research was conducted. EPA 

also proposes a formal process to make 

an exception to these standards when to 

rely on scientifically sound but ethically 

deficient research would give crucial 

support to a regulatory action more 

protective of public health than could 

be justified without relying on the 

ethically deficient research. 

A. Background 

The NAS Report specifically 

addressed the issue of what role, if any, 

ethically deficient or unethical studies 

should play in EPA’s regulatory 

decisions. The NAS predicted that the 

problem would rarely arise, especially 

once EPA formulated its standards and 

established them though rulemaking or 

other means. Nonetheless, the NAS 

acknowledged that, when it arises, the 

decision is ‘‘ethically vexing’’ (p. 125) 

because ‘‘two important goals come into 

conflict: first, using the best scientific 

data to protect the public and, second, 

avoiding incentives for the conduct of 

unethical research involving humans 

and undermining important ethical 

principles’’ (p. 126). The NAS 

recognized that different considerations 

could affect how this decision is made, 

depending primarily on when the 

ethically problematic research was 

performed in relation to EPA’s 

articulation of its standards. 

Accordingly, the NAS recommended 

two standards for acceptance, applying 

respectively to research conducted after 

EPA establishes new standards, and to 

research conducted before EPA 

establishes new standards. 

For research conducted after EPA 

establishes new standards i.e., after 

these proposed rules are promulgated in 

final form, the NAS expected there to be 

relatively few deficiencies. The NAS 

assumed that EPA and the HSRB would 

review both scientific and ethical 

aspects of proposed human research 

before it is conducted. To the extent 

EPA identified ethical issues, the NAS 

further assumed the Agency would 

inform the researcher who, in turn, 

would make appropriate changes. In its 

recommendation 5-6 NAS advised EPA 

as follows: 

EPA should operate on the strong 

presumption that data obtained in studies 

conducted after implementation of the new 

rules* that do not meet the ethical standards 

described in this report will not be 

considered in its regulatory decisions. Under 

exceptional circumstances, studies that fail to 

meet these ethical standards may provide 

valid information to support a regulatory 

standard that would provide greater 

protection for public health. Under these 

circumstances, EPA should convene a 

special, outside panel, consisting of relevant 

experts and members of the public, to 

examine the cases for and against considering 

data from such studies. [*Note: a footnote 

here in the text of NAS Recommendation 5- 

6 reads: ‘‘The committee uses the term 

‘‘rules’’ informally to mean guidance, 

guidelines, policy, protocols, rules, or 

regulations.’’] 

In explaining this recommendation, 

the NAS discussed and rejected the 

position favoring a categorical refusal to 

rely on the results of any ethically 

deficient study. The NAS began by 

noting that it is critically important to 

deter unethical conduct in human 

research. The NAS pointed out that 

many believe the refusal to rely on data 

from ethically deficient studies has an 

additional purpose: to avoid involving 

the government in ‘‘a kind of symbolic 

approval of and complicity in the 

unethical research, even after the fact, 

[and instead] to express society’s 

commitment to fundamental values in 

research involving humans’’ (p. 127). 

The NAS pointed out that this position 

leads to an absolute renunciation of any 

benefits of knowledge gained through 

the ethically deficient research, and that 

in some instances that might compel a 

sacrifice in public health. 

Thus, the committee recommended 

that each case be judged individually, to 

take into account the nature of the 

unethical behavior and the importance 

of the information produced by the 

research. The NAS indicated that EPA 

should use data from an unethical study 

only if a special panel determined the 

data were ‘‘crucially important for 

protecting public health’’ and could not 

otherwise be obtained with reasonable 

certainty, within a reasonable time 

period, without exposing additional 

subjects to additional risk of harm (pp. 

126, 128). The committee further 

advised that data from unethical studies 

should not be used to justify relaxation 

of public health standards or to ‘‘favor 

the sponsor’s interest’’ (p. 128). Finally, 

the committee indicated its view that 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 53855 

using the special procedure described in 

the recommendation would not create 

‘‘an incentive for future breaches of the 

relevant ethical rules’’ (p. 126). 

The NAS Report also addressed what 

standard to apply in judging studies 

completed before EPA’s rulemaking 

becomes effective. (The committee 

explained that this standard should also 

apply ‘‘to studies that EPA has retrieved 

from the public literature’’ (pp. 129–30), 

but did not say whether they intended 

this standard to apply only to studies 

retrieved from the public literature that 

were conducted after new EPA rules 

become effective.) The committee begins 

by pointing out that the selection of a 

standard for determining the 

acceptability of past research raises 

additional considerations, making the 

choice ‘‘particularly vexing’’ (p. 128). 

They noted in particular two issues: 

‘‘whether it is fair to judge past studies 

with humans by current ethical 

standards’’ (p. 128), and what 

evidentiary presumptions should be 

used in applying the standard. Although 

the NAS did not devote much 

discussion to whether to apply 

contemporary standards to past studies, 

their recommendation 5-7 states clearly 

their conclusion that completed 

research should be judged by the ethical 

standards prevailing at the time the 

research was conducted. 

The NAS discussed at length 

alternative evidentiary presumptions 

which could be used in applying the 

ethical standard, identifying two broad 

choices. The first alternative would be 

to assume completed research was 

conducted ethically unless clear 

evidence shows it was unethical; the 

second would be to assume completed 

research was conducted unethically 

unless clear evidence shows it was 

ethical. The committee noted that 

documentation of the ethical attributes 

of a very large proportion of past human 

studies is very limited, not only for 

third-party research but also for 

government-conducted and governmentsupported research. Applying the 

second alternative would mean, 

effectively, that a substantial proportion 

of completed human research would be 

rejected as unethical, solely because 

records were unavailable to demonstrate 

that it was ethically conducted. 

The NAS recommended instead that, 

in the absence of information to the 

contrary, EPA should assume completed 

research was performed ethically. They 

favored this approach ‘‘because of 

ethical concerns about not considering 

scientifically valid data from completed 

studies’’ and because setting aside much 

or most completed research could lead 

investigators ‘‘to conduct additional 

research to obtain similar data to protect 

the public, thus subjecting additional 

research participants to risk’’ (p. 129). 

Based on this discussion, NAS 

Recommendation 5-7 reads: 

EPA should accept scientifically valid 

studies conducted before its new rules* are 

implemented unless there is clear and 

convincing evidence that the conduct of 

those studies was fundamentally unethical 

(e.g., the studies were intended to seriously 

harm participants or failed to obtain 

informed consent) or that the conduct was 

deficient relative to then-prevailing ethical 

standards. Exceptional cases in which the 

Human Studies Review Board determines 

that unethically conducted studies may 

provide valid information to support a 

regulatory standard that would provide 

greater protection for public health should be 

presented to a special outside panel, 

described in Recommendation 5-6, for 

consideration. [* Note: a footnote here in the 

text of NAS Recommendation 5-7 reads: ‘‘See 

footnote 1.’’ The text of the NAS-referenced 

footnote 1 is provided above in the note for 

Recommendation 5-6.] 

B. Proposal 

In a new subpart F of 40 CFR part 26, 

EPA proposes ethical standards for its 

decisions to rely on or not to rely on in 

its decision-making reports of 

completed intentional-dosing research 

with human subjects being considered 

under FIFRA or FFDCA. For covered 

types of research conducted after the 

effective date of the rule, EPA proposes 

to refuse to rely on data from 

scientifically sound and relevant human 

research unless EPA has adequate 

information demonstrating that the 

research complied with the Common 

Rule. For covered types of research 

conducted before the effective date of 

the rule, EPA proposes to rely on data 

from scientifically sound and relevant 

human research unless there is clear 

evidence to show the conduct of the 

research was fundamentally unethical 

or was significantly deficient relative to 

the ethical standards prevailing at the 

time the research was conducted. EPA 

also proposes a formal process to make 

an exception to these standards when to 

rely on scientifically sound but ethically 

deficient research would give crucial 

support to a regulatory action more 

protective of public health than could 

be justified without relying on the 

ethically deficient research. 

The provisions of EPA’s proposed 

subpart F address intentional exposure 

studies being considered under FIFRA 

or the FFDCA. The NAS discussion of 

Recommendations 5-6 and 5-7 did not 

distinguish between human studies 

involving intentional dosing and other 

types of human research, although their 

report addressed ‘‘intentional human 

dosing studies.’’ EPA has chosen to 

limit its proposal in subpart F to 

intentional dosing human studies 

considered under FIFRA or FFDCA, 

because the public debate about relying 

on data from human research has 

focused primarily on that kind of 

testing. EPA expects to continue to 

evaluate the ethical conduct of other 

types of human research outside the 

scope of proposed subpart F on a caseby-case basis, guided by statutory 

requirements, the Common Rule, and 

high ethical standards, consistent with 

the approach described in its February 

8, 2005, Federal Register Notice. 

For human studies initiated before a 

final rule becomes effective, we agree 

with the NAS committee that it is 

appropriate to measure the conduct of 

human studies against the ethical 

standards prevailing when the research 

was conducted. The history of the 

development and revision of widely 

accepted standards of ethical research 

conduct such as the Nuremberg Code, 

the Declaration of Helsinki, the Belmont 

Report, and the Common Rule is well 

known. Although it is not always easy 

to determine what standards prevailed 

where the research was conducted, this 

history is adequate to identify an 

appropriate standard based on when the 

research was conducted. This approach 

acknowledges that ethical standards 

have changed over time, and will surely 

change in the future. It would also be 

inequitable to apply contemporary 

ethical standards retroactively to 

research conducted in the past. Before 

the effective date of the rule, sponsors 

or investigators would have had no 

notice of the specific standard EPA 

would apply to their data. Moreover, 

they can be assumed to have regarded 

the ethical standards prevailing at the 

time the study was conducted as the 

most appropriate benchmark for guiding 

their conduct. While the proposed rule 

would, strictly speaking, only govern 

EPA’s behavior, it provides the basis for 

judgment of others’ past conduct. It 

seems inherently unfair to hold 

researchers to a standard about which 

they had no notice and which, after the 

fact, they would be unable to comply 

with through any further action. But it 

does seem reasonable and fair to judge 

their behavior against the standards of 

which they should have been aware. We 

believe this is the essence of NAS 

Recommendation 5-7. 

The Agency has refined the language 

of the standard in NAS 

Recommendation 5-7 in two ways. EPA 

has retained the evidentiary 

presumption recommended by the NAS 

committee, but has modified their 

suggested requirement for ‘‘clear and 

convincing evidence’’ to ‘‘clear 

53856 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

evidence.’’ The Agency simply cannot 

imagine ‘‘clear but unconvincing’’

evidence that research was 

fundamentally unethical, and has opted 

for brevity. EPA has further modified 

the recommended standard to specify 

that the Agency will consider refusing 

to rely on a past study when it is 

‘‘significantly deficient’’ compared to 

prevailing ethical standards. This is 

intended to acknowledge that minor 

recordkeeping or administrative 

deficiencies with respect to the 

prevailing ethical standard should not 

in themselves force the Agency to set 

aside an otherwise ethically conducted 

and scientifically meritorious study. 

For judging the ethical acceptability 

of covered human studies initiated after 

a final rule becomes effective, EPA 

proposes the Common Rule as the 

primary standard. In general terms, the 

approach to human research covered 

under the extension of EPA’s Common 

Rule would seem very straightforward. 

Once EPA completes rulemaking to 

extend to certain third-party research 

the requirements of EPA’s Common 

Rule and these proposed additional 

subparts, it seems entirely appropriate 

to expect all research within the scope 

of these subparts and conducted after 

they take effect to comply with the rule. 

If the Agency were to become aware of 

covered research that does not comply, 

EPA should consider the measures in 

proposed subpart E of the regulatory 

text and discussed in Unit IX., including 

whether it would be appropriate to 

refuse to rely on the data. We believe 

this is the essence of NAS 

Recommendation 5-6. 

EPA is not, of course, proposing to 

establish FIFRA section 12(a)(2)(P) as a 

standard. FIFRA section 12(a)(2)(P) was 

enacted in 1972 and implementing 

regulations were promulgated in 1980. 

Thus FIFRA section 12(a)(2)(P) already 

applies to human subjects research with 

pesticides, and no additional 

rulemaking is necessary to make it 

applicable. 

EPA also agrees with the NAS 

Recommendation 5-6 that the researcher 

should bear the burden of 

demonstrating compliance with the 

standard. Proposed § 26.602 of the 

regulatory text provides that the Agency 

would accept data from a study covered 

by the rule ‘‘only if EPA has adequate 

information to determine that the 

research was conducted in a manner 

that substantially complies with subpart 

A and, as applicable, subparts B and D 

of this part.’’ EPA has listed in proposed 

§ 26.124(c) of the regulatory text the 

kinds of information documenting the 

ethical conduct of completed human 

research that EPA would expect to see 

in a submitted report of such research. 

(Note that this documentation would be 

additional to records required by 40 

CFR 169.2(j), implementing FIFRA 

section 12(a)(2)(P) recordkeeping 

requirements.) This range of 

documentation is derived from the 

Common Rule criteria for IRB approval 

of proposed research at 40 CFR 26.111. 

It will thus have been gathered for 

presentation to the IRB and for 

submission to EPA with the proposed 

protocol for the research, and it should 

not be a burden to provide the same 

information to the Agency with the 

report on the completed study. 

Today’s proposal slightly modifies the 

standard in NAS recommendation 5-6 to 

make it clear that EPA would consider 

refusing to rely on a completed human 

study only if the study fails to 

‘‘substantially’’ comply with the 

applicable ethical standards. This 

addition reflects EPA’s judgment that 

relatively minor administrative or 

recordkeeping deficiencies in a 

researcher’s compliance with a rule as 

complex as the Common Rule would 

not in themselves justify rejecting 

otherwise scientifically valuable and 

ethically conducted research. The 

experience of HHS shows that many 

studies conducted under the Common 

Rule fail to meet every applicable 

provision of the Common Rule, yet 

many of these deficiencies are deemed 

minor. See ‘‘Compliance Oversight in 

Human Subjects Protection’’ by Dr. 

Kristina C. Borror, Director, Division of 

Compliance Oversight in the Office of 

Human Research Protections (February 

1, 2005), available at: http:// 

www.hhs.gov/ohrp/sachrp/mtgings/ 

mtg01-05/ present2/borror_files/ 

frame.htm. 

EPA’s proposed subpart F covers all 

intentional human dosing studies that 

EPA is considering under FIFRA or 

FFDCA. Some of these studies might not 

be covered by the proposed extension of 

EPA’s Common Rule. The exceptions 

would include any intentional exposure 

human studies for pesticides that were 

not, at the time they were conducted, 

intended to be submitted to EPA under 

FIFRA or FFDCA. Such studies might be 

retrieved from the public literature by 

EPA, conducted by U.S. States or by 

foreign governments, or conducted by 

third parties for regulatory purposes in 

other countries. For studies like these, 

covered by proposed subpart F but not 

by the proposed extension of EPA’s 

Common Rule, the question of what 

ethical standard to apply is more 

difficult. 

On the one hand, since the Agency 

proposes not to subject this research to 

the extension of EPA’s Common Rule, it 

could be argued that it would be 

inconsistent and unfair to apply the 

standard of the Common Rule to the 

Agency’s later decisions about whether 

to rely on that research. Sometimes the 

person submitting a report of research to 

EPA will have had no relationship with 

the sponsor or investigator of the 

research; a submitter in this situation 

could argue that they could be 

penalized for actions taken by someone 

else with no connection to them, who 

was not legally required to follow the 

Common Rule and who for whatever 

reason chose not to. 

On the other hand, once EPA 

promulgates a final rule, researchers 

would have notice of the ethical 

standards EPA would apply in deciding 

whether to rely on a completed 

intentional dosing human study. With 

such notice, researchers could make an 

informed decision whether or not to 

comply with the requirements of EPA’s 

Common Rule. They would have 

adequate and timely warning about the 

consequences of noncompliance. 

Furthermore, it is EPA’s judgment that 

it is fair to consider the ‘‘prevailing 

ethical standard’’ for research 

conducted after the effective date of new 

rules to be the Common Rule or a 

foreign equivalent. These considerations 

argue for subjecting all research 

conducted after the effective date of the 

new rule to the more demanding ethical 

standards defined by that new rule. If 

EPA took this approach, its rules might 

influence the conduct of a larger 

universe of research and thereby 

provide greater protection for human 

subjects. 

EPA proposes therefore, in deciding 

whether to rely on data from a 

completed study, to apply the Common 

Rule to all studies conducted after a 

final rule becomes effective and which 

are covered by EPA’s new subpart F, 

whether or not the research was 

required to comply with EPA’s Common 

Rule under EPA’s new subpart A. The 

primary argument against using the 

Common Rule as the ethical benchmark 

for all future intentional exposure 

human studies is that researchers will 

not have had adequate notice. EPA 

disagrees; publication of a final rule in 

the Federal Register will constitute 

adequate notice. Given the widespread 

awareness of and consensus on the 

Common Rule as the appropriate guide 

for ethical conduct of human research, 

EPA therefore expects that very few, if 

any, sponsors or investigators could 

credibly claim ignorance of their ethical 

responsibilities to protect human 

subjects. Finally, the Agency believes its 

use of the Common Rule as the ethical 

benchmark for deciding whether to rely 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 53857 

on a human study would provide 

additional incentive for researchers to 

act ethically. 

Finally, EPA proposes an 

extraordinary procedure applicable if 

scientifically sound but ethically 

deficient human research is found to be 

crucial to EPA’s fulfilling its mission to 

protect public health. This procedure 

would also apply if a scientifically 

sound study covered by proposed 

§ 26.221 or § 26.421--i.e., an intentional 

dosing study involving pregnant women 

or children as subjects--were found to be 

crucial to the protection of public 

health. The Agency accepts the NAS 

advice to make these decisions on a 

case-by-case basis, taking into account 

the particular circumstances of the 

study and the way it could affect the 

regulatory action, and seeking the best 

possible advice. EPA agrees such 

decisions should consider the 

importance of the research to a potential 

regulatory decision, and particularly 

whether it would support a regulatory 

position more protective of public 

health than would be justified without 

reliance on the data. Proposed § 26.603 

would require EPA, before deciding not 

to rely on such data, to seek the advice 

of the Human Studies Review Board and 

comment from the public. 

C. Topics for Public Comment 

The Agency has considered a number 

of alternatives to the positions described 

and invites public comment on whether 

EPA should adopt any of these 

alternatives for the final rule: 

1. Should EPA continue the case-bycase approach articulated in the 

February 8, 2005, Federal Register 

Notice, not adopting by rule ethical 

standards to guide decision-making 

with respect to completed, ethically 

problematic human studies? 

2. Should a final rule establish the 

standard that EPA would rely on all 

scientifically sound data from covered 

intentional exposure human studies 

relevant to EPA decision-making, 

without regard to any ethical 

deficiencies in the studies? 

3. Should a final rule establish a 

different criterion for acceptance of 

research conducted before the effective 

date of the rule than the criterion 

proposed in § 26.601 of the regulatory 

text? Should a final rule identify 

specific factors to be considered or 

criteria to be applied in determining 

whether research was ‘‘fundamentally 

unethical’’ or ‘‘significantly deficient 

with respect to prevailing standards’’? 

4. Should a final rule establish the 

standard that, in making decisions 

under FIFRA and FFDCA, EPA would 

never rely on data from a study 

involving intentional exposure of any 

human subject to a pesticide when a 

purpose of the study was to identify or 

measure toxic effects? 

5. Should a final rule establish the 

standard that EPA would not rely on an 

intentional exposure human study 

covered under proposed subpart F if the 

study did not comply with the Common 

Rule, without regard to when the 

research was conducted? 

6. Should a final rule establish the 

standard in NAS Recommendation 5-7 

for all three categories of completed 

research covered by proposed subpart F 

of the regulatory text--i.e., (1) Research 

conducted before the rule becomes 

effective; (2) research conducted after 

the rule becomes effective and required 

to comply with EPA’s Common Rule; 

and (3) research conducted after the rule 

becomes effective but not required to 

comply with EPA’s Common Rule? 

7. Should a final rule apply a different 

standard to research conducted after the 

effective date of the final rule, 

depending on whether the research was 

subject to the requirements of EPA’s 

proposed subparts A through D? 

8. Should a final rule apply proposed 

subpart F to a different range of thirdparty human research, including any of 

the categories discussed in Unit IV., or 

apply different ethical standards to 

research in different categories within 

an altered scope? 

9. Should a final rule apply a standard 

other than ‘‘substantial’’ compliance 

with the requirements in EPA’s 

proposed subparts A through D, perhaps 

requiring ‘‘full’’ or ‘‘complete’’

compliance with those requirements? 

How should minor, administrative 

deficiencies be treated under an 

alternative standard? 

10. Should a final rule permit use of 

the exception procedure in proposed 

§ 26.603 when research falling within 

the prohibitions of proposed § 26.221 or 

§ 26.421--i.e., research involving 

intentional exposure of pregnant women 

or children--is deemed crucial to the 

protection of public health? 

11. Should a final rule identify 

additional factors EPA will consider in 

deciding whether to rely on a completed 

human study that does not meet the 

appropriate standard in proposed 

§ 26.601 or § 26.602 of the regulatory 

text? 

XI. EPA’s 2006 Appropriations Act 

This unit discusses how this proposed 

rule meets the requirements of the 

Department of the Interior, 

Environment, and Related Agencies 

Appropriations Act, 2006, 

(Appropriations Act) relating to 

intentional dosing human toxicity 

studies for pesticides. This unit contains 

six sections. Section A reviews the 

provisions of the 2006 Appropriations 

Act and summarizes EPA’s approach to 

implementation of its provisions. 

Section B addresses the proposed rule’s 

prohibition of intentional dosing human 

studies for pesticides when the subjects 

are pregnant women, infants, or 

children. Section C addresses its 

consistency with the 2004 NAS report. 

Section D addresses its consistency with 

the Nuremberg Code. Section E 

addresses its establishment of an 

independent Human Studies Review 

Board. Section F identifies subjects on 

which EPA invites public comment. 

A. Introduction 

On August 2, 2005, the President 

signed into law the Department of the 

Interior, Environment, and Related 

Agencies Appropriations Act, 2006, 

Public Law No. 109–54 (Appropriations 

Act), which provides appropriated 

funds for the Environmental Protection 

Agency and other federal departments 

and agencies. Section 201 of the 

Appropriations Act addresses EPA 

activities regarding intentional dosing 

human toxicity studies for pesticides as 

follows: 

None of the funds made available by this 

Act may be used by the Administrator of the 

Environmental Protection Agency to accept, 

consider or rely on third-party intentional 

dosing human toxicity studies for pesticides, 

or to conduct intentional dosing human 

toxicity studies for pesticides until the 

Administrator issues a final rulemaking on 

this subject. The Administrator shall allow 

for a period of not less than 90 days for 

public comment on the Agency’s proposed 

rule before issuing a final rule. Such rule 

shall not permit the use of pregnant women, 

infants or children as subjects; shall be 

consistent with the principles proposed in 

the 2004 report of the National Academy of 

Sciences on intentional human dosing and 

the principles of the Nuremberg Code with 

respect to human experimentation; and shall 

establish an independent Human Subjects 

Review Board. The final rule shall be issued 

no later than 180 days after enactment of this 

Act. 

Consistent with its interpretation of 

the intent of Congress, EPA has not 

waited for the beginning of FY 2006 to 

discontinue reliance on third-party 

intentional human dosing toxicity 

studies in its decision-making under 

FIFRA and FFDCA. In addition, EPA is 

taking the necessary steps to ensure 

such studies will not be accepted or 

considered after the beginning of FY 

2006 and before a final rule is 

promulgated. The Agency has not 

conducted or supported any intentional 

dosing human toxicity studies for 

pesticides in the past, and has no 

53858 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

intention to conduct them at any time 

in the future. 

The Agency will concentrate its 

attention on developing and 

promulgating a final rule. As required 

by the Appropriations Act, EPA is 

providing a period of 90 days for the 

public to comment on this proposed 

rule. Because the Appropriations Act 

directs the Agency to promulgate a final 

rule no later than 180 days after 

enactment (i.e., by January 29, 2006), 

the Agency does not expect to extend 

the comment period or to review public 

comments received after the close of the 

comment period. 

B. Prohibition of Intentional Dosing 

Human Studies for Pesticides when the 

Subjects are Pregnant Women, Infants, 

or Children 

This proposed rule would ban third 

party intentional dosing human studies 

for pesticides when the subjects are 

pregnant women, infants or children, 

without regard to whether the studies 

were intended to identify or measure a 

toxic effect. Proposed § 26.220 of the 

regulatory text would prohibit, without 

exception, any third party performing 

research covered by the proposed 

extension of EPA’s Common Rule from 

‘‘conducting or supporting research 

involving intentional dosing of any 

pregnant woman, fetus, or newborn.’’

Proposed § 26.420 of the regulatory text 

would prohibit, without exception, any 

third party performing research covered 

by the proposed extension of EPA’s 

Common Rule from ‘‘conducting or 

supporting research involving 

intentional dosing of any child.’’ The 

same passages would apply the same 

prohibitions to EPA, similarly without 

exception, in any research it conducts or 

supports. 

The Agency interprets the phrase 

‘‘third-party intentional dosing human 

toxicity study for pesticides’’ as used in 

the Appropriations Act to refer to a 

subset of all third-party intentional 

dosing studies intended for submission 

to EPA under the pesticide laws, and 

thus covered by proposed § 26.101(j) of 

the regulatory text. Further, the Agency 

interprets the phrase ‘‘pregnant women, 

infants or children’’ as used in the 

Appropriations Act to have the same 

scope and meaning as the phrases ‘‘any 

pregnant woman, fetus, or newborn’’

and ‘‘any child’’ in the sections cited 

above, when taken together. EPA also 

notes that the prohibitions in proposed 

§§ 26.220 and 26.420 of the regulatory 

text reference proposed § 26.101(j), and 

therefore make the prohibitions 

applicable to research that was 

conducted with the intent to submit the 

results to EPA (or hold them for possible 

future inspection) under either of the 

pesticide laws, FIFRA or FFDCA. EPA 

interprets the phrase, ‘‘for pesticides’’ as 

used in the Appropriations Act to mean 

research that is intended for 

consideration by EPA under the 

pesticide laws, and thus which falls 

within the scope of proposed § 26.101(j). 

EPA invites public comment on these 

interpretations of the meaning of the 

phrase ‘‘intentional dosing human 

toxicity studies for pesticides’’ as it is 

used in the Appropriations Act, 

particularly as it relates to the scope of 

the requirement for a prohibition on 

such studies with subjects who are 

‘‘pregnant women, infants, or children.’’

C. Consistency with the 2004 NAS 

Report 

The Appropriations Act directs EPA 

to promulgate a rule addressing third 

party intentional dosing human toxicity 

studies for pesticides that is ‘‘consistent 

with the principles proposed in the 

2004 report of the National Academy of 

Sciences on intentional human dosing.’’

Based on a careful review of the NAS 

report, EPA has concluded that the 

underlying principles intended by the 

NAS committee to be reflected in its 

recommendations are the three 

‘‘fundamental ethical principles’’

identified by the National Commission 

for the Protection of Human Subjects of 

Biomedical and Behavioral Research 

(National Commission) in its report, 

Ethical Principles and Guidelines for the 

Protection of Human Subjects of 

Research (the ‘‘Belmont Report’’). These 

three fundamental principles are respect 

for persons, beneficence, and justice. 

See NAS Report at pp. 49–50, 98, and 

113–14. 

The NAS committee makes the point 

clearly that they did not propose new 

principles: ‘‘the committee was not 

required to invent the basic standards 

that govern human research in the 

United States. These standards are 

already embodied in the Federal Policy 

for the Protection of Human Subjects 

(the Common Rule.)’’ NAS Report pp. 4, 

33. 

The NAS committee further stated 

that the fundamental principles 

articulated in the Belmont Report both 

undergird and are made operational by 

the procedural requirements of the 

Common Rule. The following quotations 

express this view: 

Federal regulations incorporate the 

obligation of beneficence by requiring IRBs to 

ensure that risks are minimized to the extent 

possible, given the research question, and are 

reasonable in relation to potential benefits to 

the participant or to the importance of the 

knowledge to be gained through the research 

(40 CFR § 26.111(a)(1)–(2)). NAS Report at 

56. 

[D]etermining whether the principle of 

beneficence has been satisfied requires 

balancing the anticipated risks to study 

participants against the anticipated benefits 

of the study to society. The risks to 

participants must be reasonable in relation to 

the societal benefit. In the words of the 

Common Rule, the risks must be reasonable 

in relation to the importance of the 

knowledge that may reasonably be expected 

to result (40 CFR § 26.111 (a)(2)). NAS Report 

at 107. 

According to the Common Rule, IRBs 

should not approve a research protocol 

involving humans unless ‘selection of 

subjects is equitable’ (40 CFR § 26.111(3)). 

This requirement derives from the principle 

of justice identified in the Belmont Report. 

NAS Report at 114. 

Voluntary, informed consent by research 

participants . . . is a major element in the 

system of protection of research participants. 

The consent requirement expresses the 

principle of respect for persons, including 

respect for and promotion of autonomous 

choices. The Common Rule stresses this 

requirement, as do other codes of research 

ethics, including the Nuremberg Code (1949), 

the Declaration of Helsinki, and the Good 

Clinical Practice guidelines. NAS Report at 

120. 

Accordingly, EPA concludes that the 

‘‘principles proposed in the 2004 report 

of the National Academy of Sciences on 

intentional human dosing’’ are, in fact, 

the ‘‘three fundamental principles’’ of 

respect for persons, beneficence, and 

justice articulated in the Belmont 

Report, and that the Common Rule rests 

on the foundation of those principles. 

This proposal to extend the coverage of 

EPA’s Common Rule to additional 

categories of regulated third-party 

research is thus entirely consistent with 

those principles. 

D. Consistency with the Nuremberg 

Code 

The Appropriations Act directs EPA 

to promulgate a rule addressing thirdparty intentional dosing human toxicity 

studies for pesticides that is ‘‘consistent 

with . . . the principles of the 

Nuremberg Code with respect to human 

experimentation.’’

The NAS report (p. 47) explains the 

history of the Nuremberg Code as 

follows: 

Public policies regarding the ethical 

treatment of humans in research began 

forming in the late 1940s, largely in response 

to the atrocities committed by Nazi 

investigators who were tried before the 

Nuremberg Military Tribunal (United States 

v. Karl Brandt, et al.) In 1946, the American 

Medical Association adopted its first code of 

research ethics, which ultimately influenced 

the Nuremberg Tribunal’s standards for 

ethical research, embodied in the ten ‘‘basic 

principles’’ for human research now know as 

the Nuremberg Code. [footnotes and 

references omitted] 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 53859 

The Agency has carefully reviewed 

this proposed rule, using the 10 

principles of the Nuremberg Code as a 

guide, and has concluded that it is 

consistent with them. A full report of 

this analysis has been placed in the 

docket for this proposal. 

E. Establishment of a Human Studies 

Review Board 

The Appropriations Act directs EPA 

to promulgate a rule that ‘‘shall 

establish an independent Human 

Subjects Review Board.’’

EPA believes that the entity required 

by the Appropriations Act is intended to 

be substantially identical to the ‘‘Human 

Studies Review Board’’ recommended 

by the NAS in Recommendations 6-1, 6- 

2, and 6-3 of the NAS Report. (See 

discussion in Unit V. of this preamble.) 

Consistent with both the requirement of 

the Appropriations Act and the 

recommendations of the NAS, EPA 

proposes, in proposed § 26.124(b) of the 

regulatory text, to establish an 

independent HSRB. Under this 

proposed rule, the review of proposed 

research by the HSRB would occur after 

review by a local IRB and EPA staff. 

This sequence would be consistent both 

with EPA’s current practice for 

reviewing first- and second-party 

human research proposals and with the 

practice of FDA for reviewing thirdparty human research proposals. The 

NAS Report, however, recommended 

that the EPA and HSRB reviews come 

before the IRB review. EPA believes it 

has discretion to adopt an approach that 

differs in this respect from the NAS 

recommendation, but seeks public 

comment on whether HSRB review 

would be more effective before or after 

local IRB review. 

F. Additional Topics for Public 

Comment 

Although EPA thinks that today’s 

proposal satisfies the provisions in the 

Appropriations Act and, in particular, is 

consistent with the principles of both 

the Nuremberg Code and the 2004 NAS 

Report, the Agency recognizes that, as a 

matter of policy, it might be appropriate 

to include in the final rule additional 

provisions arising from either the 

Nuremberg Code or the 2004 NAS 

Report. Therefore, in addition to the 

topics identified above, the Agency 

invites the public to comment on any 

specific provisions of either the 

Nuremberg Code or the 2004 NAS report 

that may be appropriate for inclusion in 

the final rule. 

XII. FIFRA Review Requirements 

Pursuant to FIFRA section 25(a), the 

Agency submitted a draft of this 

proposed regulation to the FIFRA 

Scientific Advisory Panel (SAP), the 

U.S. Department of Agriculture (USDA), 

the Committee on Agriculture in the 

House of Representatives, and the 

Committee on Agriculture, Nutrition, 

and Forestry in the United States 

Senate. In addition, the Agency 

submitted a draft of this proposed rule 

to the Department of Health and Human 

Services (HHS). 

The FIFRA SAP waived its review of 

this proposal because the significant 

scientific and ethical issues involved 

have already been reviewed by the SAP. 

(See the report of the SAB/SAP Data 

from Testing of Human Subjects 

Subcommittee in the docket for this 

proposal and on the web at: http:// 

www.epa.gov/science1/pdf/ec0017.pdf.) 

The Agency met with the staff of the 

Congressional Committees, and where 

warranted, has made changes to the 

draft proposal based upon those 

discussions. 

USDA, the U.S. Department of 

Veterans Affairs, and HHS provided 

many helpful comments through the 

interagency review process, leading to 

numerous changes in the draft proposal. 

In addition, comments dated August 15, 

2005, and August 26, 2005, which EPA 

received from Cristina V. Beato, M.D., 

Acting Assistant Secretary for Health at 

HHS, have been placed in the docket for 

this rulemaking, and are summarized 

here with EPA’s responses. 

EPA thanks HHS for providing very 

helpful comments very quickly. In 

summary, HHS expressed strong 

support for EPA’s effort to extend the 

protections of EPA’s Common Rule to 

research regulated by EPA under FIFRA. 

HHS welcomes EPA’s decision to adopt 

additional regulatory protections of 

pregnant women, fetuses, newborns, 

and children, formalizing EPA’s 

longstanding practice. HHS also 

welcomes EPA’s proposal to prohibit 

EPA involvement in or consideration of 

intentional exposure studies done to 

investigate toxic effects. 

HHS made four ‘‘major’’ comments. 

First, HHS stated that it could not 

support changes to the content of 

subpart A, the Common Rule, and 

recommended that EPA revise its 

proposal to incorporate all changes 

proposed to §§ 26.101, 26.102, and 

26.124 in a separate subpart. EPA 

appreciates and shares HHS’s concern 

for maintaining uniformity in subpart A- 

-the regulation common to all the 

Common Rule departments and 

agencies--and promises that the final 

rule will accomplish the extension of 

EPA’s Common Rule without altering 

the common text. We have not made the 

requested change in this proposal 

because we want first to solicit public 

comment on how best to achieve clarity 

in our codification of these new 

requirements. Would the requirements 

applicable to regulated third parties be 

best expressed as HHS has suggested, in 

a separate subpart of 40 CFR part 26, or 

would it be clearer if all the 

requirements applying to regulated third 

parties were codified together in an 

entirely separate part, after the model of 

the FDA rules at 21 CFR parts 50 and 

56? 

Second, HHS notes in their August 15 

written comment that FDA may have 

additional comments, but did not have 

time to complete them in the greatly 

compressed scheduled imposed by the 

demands of the Appropriations Act. 

FDA’s comments were received on 

August 26, and this proposal has been 

amended to reflect all their suggested 

clarifications and changes. The Agency 

would also welcome additional 

comments from HHS and FDA, and will 

address them in the final rule. 

Third, HHS recommends that EPA 

modify its proposal to incorporate a ban 

on research involving intentional 

exposure of prisoners, parallel to the 

bans proposed on similar research 

involving pregnant women, fetuses, 

newborns, and children. EPA has 

specifically requested public comment 

on this suggestion in Unit VIII., and will 

seriously consider adopting such a ban 

in the final rule. 

The final major HHS comment 

expresses concern that the ethical 

standard proposed in § 26.601 of the 

regulatory text, to be applied to research 

conducted before the effective date of 

new EPA rules, may be too permissive, 

and ‘‘fails to provide helpful guidance 

on what would separate an acceptable 

study from an unacceptable one.’’ The 

standard EPA has proposed, as 

explained in Unit X., is based on the 

advice of the NAS committee, which 

thought long and hard about this issue. 

EPA, too, has thought a great deal about 

this criterion, and has identified several 

topics for public comment at the end of 

Unit X., including the specific points 

raised by HHS in this comment. We will 

consider all these comments in deciding 

on a standard for the final rule. 

In addition to the four ‘‘major’’

comments discussed above, HHS 

provided 23 additional ‘‘specific’’

comments. Although some of the 

passages HHS cited in the draft proposal 

they reviewed do not appear in this 

published proposal, EPA has adopted 

all the specific suggestions for 

clarifications and rewording suggested 

by HHS. The final HHS comment, 

however, questions whether submission 

to EPA of reports of completed research 

53860 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

should be made mandatory when the 

research proposal has been reviewed 

and approved by EPA. EPA has not 

proposed this, because FIFRA section 

6(a)(2) already requires any applicant 

for registration or registrant of a 

pesticide to provide to EPA any 

‘‘additional factual information 

concerning adverse effects of a 

pesticide’’ that it becomes aware of. It is 

EPA’s interpretation that it would be a 

violation of this provision for a 

regulated third party to refuse to submit 

a report upon completion of research 

which EPA had approved as a proposal 

in order to suppress ‘‘additional factual 

information concerning adverse effects.’’

XIII. Statutory and Executive Order 

Reviews 

A. Executive Order 12866 

Under Executive Order 12866, 

entitled Regulatory Planning and 

Review (58 FR 51735, October 4, 1993), 

the Office of Management and Budget 

(OMB) determined that this proposed 

rule is a ‘‘significant regulatory action’’

under section 3(f) of the Executive 

Order because this action might raise 

novel legal or policy issues. 

Accordingly, EPA submitted this 

proposed rulemaking to OMB for review 

under Executive Order 12866 and any 

changes made in response to OMB 

comments have been documented in the 

public docket for this rulemaking as 

required by section 6(a)(3)(E) of the 

Executive Order. 

In addition, EPA has prepared an 

economic analysis of the potential costs 

and benefits associated with this 

proposed action, which is contained in 

a document entitled Economic Analysis 

of Proposed Human Studies Rule. A 

copy of this document is available in the 

public docket for this proposed rule and 

is briefly summarized here. 

The analysis describes the benefits of 

the proposed rulemaking in qualitative 

terms. These benefits included greater 

protections for test subjects, and a 

corresponding reduction in their risks, 

to the extent that affected researchers 

are not already following the Common 

Rule. The benefits to sponsors of thirdparty human research include a better 

understanding of the standards that EPA 

will apply in determining whether to 

rely on the results of their studies, and 

thus, the opportunity to design and 

perform studies that are more likely to 

meet EPA standards, leading to more 

efficient Agency reviews. The Agency 

believes the general public will benefit 

from the proposed rule because the rule 

will strengthen the protections for 

human subjects and reinforce the 

Agency’s strong commitment to base its 

decisions on scientifically sound 

information. 

The analysis also estimates the costs 

of the proposed rule by focusing on the 

costs to third parties of complying with 

the new requirements and the costs to 

EPA of implementing the new 

requirements. In general, EPA believes 

that most, if not all, third-party research 

intended for submission to EPA that 

involves intentional exposure of human 

subjects already complies with the 

Common Rule or an equivalent foreign 

standard. For purposes of this analysis, 

EPA assumed that current practice was 

in full compliance with the Common 

Rule. In contrast, EPA assumed that 

other types of third-party human 

research do not comply with the 

Common Rule, although it is likely that 

many responsible for such research are 

aware of and do follow Common Rule 

principles relating to informed consent 

and IRB review. 

After reviewing the history of EPA’s 

consideration of research involving 

human subjects in its various program 

offices, EPA estimates that the proposed 

rule would affect only a limited number 

of third-party studies involving human 

subjects each year. EPA also collected 

data on the cost per study of compliance 

with the Common Rule. These costs 

include preparing documents to support 

review by an IRB and the expense 

associated with the IRB review. These 

costs are very minor relative to the 

overall cost of conducting the studies. 

For EPA, the costs are associated with 

the review of protocols and the review 

of completed human studies by EPA 

staff and the Human Studies Review 

Board. 

EPA evaluated a range of options, 

from no action to an expansive rule. The 

first option was not to promulgate any 

rule, thereby continuing the current 

practice. All other options evaluated 

would apply to third-party human 

research that was conducted with the 

intent to submit the results to EPA 

under either FIFRA or FFDCA. The 

second option consisted of extending 

the requirements of EPA’s Common 

Rule to such third-party human research 

only when it involved intentional 

exposure studies for the purpose of 

identifying or quantifying a toxic effect. 

The third option, which reflects the rule 

being proposed, would extend the 

requirements of EPA’s Common Rule to 

all third-party intentional exposure 

human studies intended for submission 

under FIFRA or FFDCA. Option 4 

would extend the requirements of EPA’s 

Common Rule to all third-party human 

research intended for submission under 

the pesticide laws. All of the latter three 

options include a requirement for third 

parties to submit protocols for review 

prior to initiating the types of human 

research covered by the Common Rule. 

Finally, options 2–4 include a provision 

prohibiting the Agency and third parties 

from conducting covered human 

research with pregnant women or 

children as subjects. 

For all of the options, the potential 

costs of the proposed rule to third-party 

researchers and EPA are estimated to be 

very low, both because the number of 

affected studies is relatively small and 

because the costs of compliance with 

the Common Rule are low. Where the 

option simply reflects the current 

practice (option 1) the added total 

incremental costs to third-party 

sponsors of human research are zero. 

EPA assumes that currently the 

pesticide industry is already spending 

$159,000 to $196,000 annually to 

comply with the Common Rule for 

intentional exposure human studies and 

the Agency is currently spending 

$113,000 a year to review, on a case-bycase basis, the ethical aspects of such 

studies. Option 2 would add an 

estimated total annual incremental cost 

to third parties of $7,532, and an 

estimated annual cost to EPA of 

$220,894. Option 3 would add an 

estimated total annual incremental cost 

to third parties of $16,140, and an 

estimated annual cost to EPA of 

$327,630. Option 4 would add an 

estimated total annual incremental cost 

to third parties of $202,700 to $242,796, 

and an estimated annual cost to EPA of 

$601,134. The higher estimated costs for 

option 4 reflect the Common Rule 

compliance burden on third-party 

researchers who perform human studies 

not involving intentional exposure of 

human subjects, and the costs for EPA 

to review such completed studies and 

protocols for intentional exposure 

studies. 

The proposed rule, if finalized as 

proposed, is estimated to result in a 

total annual incremental cost to third 

parties of approximately $16,000, and 

an estimated annual cost to EPA of 

approximately $328,000. 

B. Paperwork Reduction Act 

The information collection 

requirements in this proposed rule have 

been submitted to the Office of 

Management and Budget (OMB) under 

the Paperwork Reduction Act, 44 U.S.C. 

3501 et seq. The Information Collection 

Request (ICR) document prepared by 

EPA has been assigned EPA ICR No. 

2195.01, and a copy of the ICR has been 

placed in the public docket for this 

proposed rule. 

This new information collection 

activity is planned to ensure that sound 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 53861 

and appropriate scientific data are 

available to EPA when making 

regulatory decisions, and to protect the 

interests, rights and safety of those 

individuals that are participants in the 

type of research activity that is the 

subject of this proposed rule. 

Specifically, this new information 

collection activity consists of proposed 

reporting and recordkeeping 

requirements. Whenever respondents 

intend to conduct research for 

submission to EPA under the pesticide 

laws that involves intentional dosing of 

human subjects, they will be required to 

submit study protocols to EPA and a 

cognizant local IRB before such research 

is initiated so that the scientific design 

and ethical standards that will be 

employed during the proposed study 

may be reviewed and approved. 

Respondents will also be required to 

submit information about the ethical 

conduct of completed research that 

involved intentional dosing of human 

subjects when such research is 

submitted to EPA. 

Some responses to this collection of 

information will be required in order to 

obtain or retain a benefit (i.e., a 

pesticide registration). Other responses 

will be voluntarily submitted at the 

initiative of the regulated entity. The 

information collection activity 

described in the ICR will be initiated by 

respondents as a condition of EPA’s 

consideration of the research when it is 

subsequently submitted to EPA. 

FIFRA sections 3(c)(1)(F) and 

3(c)(2)(B) authorize EPA to require 

various data in support of a pesticide’s 

continued registration or an application 

for a new or amended pesticide 

registration. FIFRA section 12(a)(2)(P) 

forbids any person ‘‘to use any pesticide 

in tests on human beings unless such 

human beings (i) are fully informed of 

the nature and purposes of the test and 

of any physical and mental health 

consequences which are reasonably 

foreseeable therefrom, and (ii) freely 

volunteer to participate in the test.’’

An agency may not conduct or 

sponsor, and a person is not required to 

respond to an information collection 

request unless it displays a currently 

valid OMB control number. The OMB 

control numbers for EPA’s regulations 

codified in Chapter 40 of the CFR, after 

appearing in the preamble of the final 

rule, are listed in 40 CFR part 9 for 

display purposes, and are also included 

on any related collection instrument 

(e.g., the form or survey instrument). 

EPA anticipates that respondents will 

submit 30 studies that involve 

intentional dosing of human subjects 

under FIFRA or FFDCA to EPA per year 

and that the preparation of the required 

information will require about 32 hours 

per study for a total estimated annual 

burden hours for affected entities of 960 

hours, representing a total estimated 

annual paperwork cost of $440,160. It is 

important to note that this total annual 

paperwork burden and cost estimate 

includes activities related to initial rule 

familiarization, as well as activities that 

researchers already perform and would 

continue to perform even without the 

Agency’s rulemaking in this area (i.e., 

developing a protocol and maintaining 

records). The average annual burden on 

EPA for reviewing this information for 

each study submission is estimated to 

be 80 hours per study, representing a 

paperwork related labor cost of about 

$14,672 per response and a total annual 

cost of $440,160. 

Under the PRA, ‘‘burden’’ means the 

total time, effort, or financial resources 

expended by persons to generate, 

maintain, retain, or disclose or provide 

information to or for a Federal agency. 

This includes the time needed to review 

instructions; develop, acquire, install, 

and utilize technology and systems for 

the purposes of collecting, validating, 

and verifying information, processing 

and maintaining information, and 

disclosing and providing information; 

adjust the existing ways to comply with 

any previously applicable instructions 

and requirements; train personnel to be 

able to respond to a collection of 

information; search data sources; 

complete and review the collection of 

information; and transmit or otherwise 

disclose the information. 

Direct your comments on the 

Agency’s need for this information, the 

accuracy of the provided burden 

estimates, and any suggested methods 

for minimizing respondent burden, 

including the use of automated 

collection techniques, to EPA using the 

public docket that has been established 

for this proposed rule (docket ID 

number OPP–2003–0132) at http:// 

www.epa.gov/edocket/. In addition, 

send a copy of your comments about the 

ICR to OMB at: Office of Information 

and Regulatory Affairs, Office of 

Management and Budget, 725 17th St., 

NW., Washington, DC 20503, Attention: 

Desk Office for EPA ICR No. 2195.01. 

Since OMB is required to complete its 

review of the ICR between 30 and 60 

days after September 12, 2005, please 

submit your ICR comments for OMB 

consideration to OMB by October 12, 

2005. 

The Agency will consider and address 

comments received on the information 

collection requirements contained in 

this proposal when it develops the final 

rule. 

C. Regulatory Flexibility Act 

Pursuant to section 605(b) of the 

Regulatory Flexibility Act (RFA), 5 

U.S.C. 601 et seq., after considering the 

potential economic impacts of today’s 

proposed rule on small entities, the 

Agency hereby certifies that this 

proposal will not have a significant 

adverse economic impact on a 

substantial number of small entities. 

This determination is based on the 

Agency’s economic analysis performed 

for this rulemaking, which is 

summarized in Unit XIII.A., and a copy 

of which is available in the public 

docket for this rulemaking. The 

following is a brief summary of the 

factual basis for this certification. 

Small entities include small 

businesses, small organizations, and 

small governmental jurisdictions. For 

purposes of assessing the impacts of 

today’s proposed rule on small entities, 

small entity is defined in accordance 

with the RFA as: (1) A small business 

as defined by the Small Business 

Administration’s (SBA) regulations at 13 

CFR 121.201; (2) a small governmental 

jurisdiction that is a government of a 

city, county, town, school district, or 

special district with a population of less 

than 50,000; and (3) a small 

organization that is any not-for-profit 

enterprise which is independently 

owned and operated and is not 

dominant in its field. 

As discussed in Unit XIII.A., the total 

annual cost to researchers covered by 

this proposed rule is estimated to be 

$16,000, or under $600 per study. This 

is a trivially small portion of the overall 

cost of performing such studies, each of 

which is estimated to cost from 

$125,000 to $500,000. After reviewing 

the history of EPA’s consideration on 

human research in its various program 

offices, EPA estimates that the proposed 

rule would affect only a limited number 

of third-party human studies each year. 

Because both the number of affected 

studies is relatively small and the costs 

of compliance with the Common Rule 

are low, the potential overall costs to 

third parties are also small. Although 

we cannot predict whether or how many 

small entities might engage in the 

subject matter research in the future, the 

Agency expects that there will be no or 

minimal impact from this proposed rule 

on small entities. 

We continue to be interested in the 

potential impacts of the proposed rule 

on small entities and welcome 

comments on all aspects related to such 

impacts. 

53862 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

D. Unfunded Mandates Reform Act 

Under Title II of the Unfunded 

Mandates Reform Act of 1995 (UMRA) 

(Public Law 104–4), EPA has 

determined that this action does not 

contain a Federal mandate that may 

result in expenditures of $100 million or 

more for State, local, and tribal 

governments, in the aggregate, or the 

private sector in any one year. As 

described in Unit XIII.A., the estimated 

total costs associated with this action 

are approximately $16,000 per year. 

This cost represents the incremental 

cost to researchers attributed to the 

additional procedural requirements 

contained in this proposal. Based on 

historical submissions, EPA has 

determined that State, local, and tribal 

governments rarely perform human 

research intended for submission to 

EPA under FIFRA or FFDCA. In 

addition, the proposed rule is not 

expected to significantly or uniquely 

affect small governments. Accordingly, 

this action is not subject to the 

requirements of sections 202 and 205 of 

UMRA. 

E. Executive Order 13132 

Pursuant to Executive Order 13132, 

entitled Federalism (64 FR 43255, 

August 10, 1999), EPA has determined 

that this proposed rule does not have 

‘‘federalism implications,’’ because it 

will not have substantial direct effects 

on the states, on the relationship 

between the national government and 

the states, or on the distribution of 

power and responsibilities among the 

various levels of government, as 

specified in the Order. As indicated 

earlier, instances where a state performs 

human research intended for 

submission to EPA under FIFRA or 

FFDCA are extremely rare. Therefore, 

this proposed rule may seldom affect a 

state government. Thus, Executive 

Order 13132 does not apply to this 

proposed rule. In the spirit of the Order, 

and consistent with EPA policy to 

promote communications between the 

Agency and State and local 

governments, EPA specifically solicits 

comment on this proposed rule from 

State and local officials. 

F. Executive Order 13175 

As required by Executive Order 

13175, entitled Consultation and 

Coordination with Indian Tribal 

Governments (59 FR 22951, November 

6, 2000), EPA has determined that this 

proposed rule does not have tribal 

implications because it will not have 

substantial direct effects on tribal 

governments, on the relationship 

between the Federal government and 

the Indian tribes, or on the distribution 

of power and responsibilities between 

the Federal government and Indian 

tribes, as specified in the Order. As 

indicated previously, instances where a 

tribal government performs human 

research intended for submission to 

EPA under FIFRA or FFDCA are 

extremely rare. Thus, Executive Order 

13175 does not apply to this proposed 

rule. In the spirit of the Order, and 

consistent with EPA policy to promote 

communications between the Agency 

and State and local governments, EPA 

specifically solicits comment on this 

proposed rule from tribal officials. 

G. Executive Order 13045 

Executive Order 13045, entitled 

Protection of Children from 

Environmental Health Risks and Safety 

Risks (62 FR 19885, April 23, 1997) does 

not apply to this proposed rule because 

this action is not designated as an 

‘‘economically significant’’ regulatory 

action as defined by Executive Order 

12866 (see Unit XIII.A.). Further, this 

proposal does not establish an 

environmental standard that is intended 

to have a negatively disproportionate 

effect on children. To the contrary, this 

action will provide added protections 

for children who may participate in the 

research covered by the proposed rule. 

H. Executive Order 13211 

This proposed rule is not subject to 

Executive Order 13211, entitled Actions 

Concerning Regulations that 

Significantly Affect Energy Supply, 

Distribution, or Use (66 FR 28355, May 

22, 2001) because it is not likely to have 

any significant adverse effect on the 

supply, distribution, or use of energy. 

I. National Technology Transfer and 

Advancement Act 

Section 12(d) of the National 

Technology Transfer and Advancement 

Act of 1995 (NTTAA), 15 U.S.C. 272 

note) directs EPA to use voluntary 

consensus standards in its regulatory 

activities unless to do so would be 

inconsistent with applicable law or 

impractical. Voluntary consensus 

standards are technical standards (e.g., 

materials specifications, test methods, 

sampling procedures) that are 

developed or adopted by voluntary 

consensus standards bodies. NTTAA 

directs EPA to provide Congress, 

through OMB, with explanations when 

the Agency decides not to use available 

and applicable voluntary consensus 

standards. This action does not propose 

to require specific methods or standards 

to generate those data. Therefore, this 

proposed rule does not impose any 

technical standards that would require 

Agency consideration of voluntary 

consensus standards. The Agency 

invites comment on its conclusion 

regarding the applicability of voluntary 

consensus standards to this proposed 

rulemaking. 

J. Executive Order 12898 

This proposed rule does not have an 

adverse impact on the environmental 

and health conditions in low-income 

and minority communities. Therefore, 

under Executive Order 12898, entitled 

Federal Actions to Address 

Environmental Justice in Minority 

Populations and Low-Income 

Populations (59 FR 7629, February 16, 

1994), the Agency has not considered 

environmental justice-related issues. 

Although not directly impacting 

environmental justice-related concerns, 

the provisions of the proposed rule 

would require researchers to use 

procedures to ensure equitable selection 

of test subjects in covered human 

research. 

XIV. Effective Date 

EPA considers the expeditious 

application of these new protections to 

be in the public interest and accordingly 

proposes to provide no longer period 

than is essential between publication of 

a final rule and its effective date. The 

Agency believes a longer transition 

period is not likely to be necessary in 

light of the relatively few studies 

affected by this proposal. 

FIFRA section 25(a)(4), 7 U.S.C. 

136w(a)(4), provides that: 

Simultaneously with the promulgation of 

any rule or regulation under this Act, the 

Administrator shall transmit a copy thereof 

to the Secretary of the Senate and the Clerk 

of the House of Representatives. The rule or 

regulation shall not become effective until 

the passage of 60 calendar days after the rule 

or regulation is so transmitted. 

Since this regulation would be issued 

under the authority of FIFRA, this 

requirement defines the minimum time 

lapse after promulgation before a final 

rule could become effective. EPA thus 

proposes that the final rule would be 

effective 60 days after its promulgation 

and transmittal to Congress. EPA invites 

public comment on the timing of the 

effective date of the final rule. 

List of Subjects in 40 CFR Part 26 

Environmental protection, Human 

research subjects, Reporting and 

recordkeeping requirements. 

Dated: September 6, 2005. 

Stephen L. Johnson, 

Administrator. 

Therefore, it is proposed that 40 CFR 

chapter I be amended as follows: 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 53863 

PART 26—[AMENDED] 

1. By revising the authority citation 

for part 26 to read as follows: 

Authority: 5 U.S.C. 301; 7 U.S.C. 

136w(a)(1); 21 U.S.C. 346a(e)(1)(C); and 42 

U.S.C. 300v-1(b). 

2. By redesignating §§ 26.101 through 

26.124 as subpart A and adding a new 

subpart heading to read as follows: 

Subpart A—Basic Federal Policy for 

Protection of Human Research 

Subjects 

3. By amending § 26.101 by adding 

paragraphs (j) and (k) to read as follows: 

§ 26.101 To what does this policy apply? 

* * * * * 

(j) Except as provided in paragraphs 

(a) and (b) of this section, this policy 

applies to all research involving 

intentional exposure of a human subject 

if, at any time prior to initiating such 

research, any person who conducted or 

supported such research intended: 

(1) To submit results of the research 

to EPA for consideration in connection 

with any regulatory action that may be 

performed by EPA under the Federal 

Insecticide, Fungicide, and Rodenticide 

Act (7 U.S.C. 136 et seq.) or section 408 

of the Federal Food, Drug, and Cosmetic 

Act (21 U.S.C. 346a); or 

(2) To hold the results of the research 

for later inspection by EPA under the 

Federal Insecticide, Fungicide, and 

Rodenticide Act (7 U.S.C. 136 et seq.) or 

section 408 of the Federal Food, Drug, 

and Cosmetic Act (21 U.S.C. 346a). 

(k) For purposes of determining a 

person’s intent under paragraph (j) of 

this section, EPA may consider any 

available information relevant to 

determining the intent of a person who 

conducts or supports research with 

human subjects after the effective date 

of the rule. EPA shall rebuttably 

presume such intent existed if: 

(1) The person or the person’s agent 

has submitted or made available for 

inspection the results of such research 

to EPA; or 

(2) The person is a member of a class 

of people who, or whose products or 

activities, are regulated by EPA under 

FIFRA or the FFDCA and, at the time 

the research was initiated, the results of 

the research would be relevant to EPA’s 

exercise of its authority under FIFRA or 

the FFDCA with respect to that class of 

people, products, or activities. 

4. By amending § 26.102 by adding 

paragraph (k) to read as follows: 

§ 26.102 Definitions. 

* * * * * 

(k) Research involving intentional 

exposure of a human subject means a 

study of an environmental substance in 

which the exposure to the substance 

experienced by a human subject 

participating in the study would not 

have occurred but for the human 

subject’s participation in the study. 

5. By revising § 26.124 to read as 

follows: 

§ 26.124 Conditions. 

(a) With respect to any research 

project or any class of research projects 

the department or agency head may 

impose additional conditions prior to or 

at the time of approval when in the 

judgment of the department or agency 

head additional conditions are 

necessary for the protection of human 

subjects. 

(b) Prior submission and review of 

proposed human research. Any person 

who intends to conduct human research 

covered by § 26.101(j) shall, after 

receiving approval from all appropriate 

IRBs, submit to EPA at least 90 days 

prior to initiating such research all 

information relevant to the proposed 

research specified by § 26.115(a) to be 

prepared and maintained by an IRB, and 

the following additional information, to 

the extent not otherwise covered: 

(1) A discussion of: 

(i) The potential risks to human 

subjects; 

(ii) The measures proposed to 

minimize risks to the human subjects; 

(iii) The expected benefits of such 

research, and to whom they would 

accrue; 

(iv) Alternative means of obtaining 

information comparable to what would 

be collected through the proposed 

research; and 

(v) The distribution and balance of 

risks and benefits of the proposed 

research. 

(2) The information for subjects and 

written informed consent agreements as 

provided to the IRB, and as approved by 

the IRB. 

(3) Information about how subjects 

will be recruited, including any 

advertisements proposed to be used. 

(4) All correspondence between the 

IRB and the investigators or sponsors. 

(5) Following initial evaluation of the 

protocol by Agency staff, EPA shall 

submit the protocol and all supporting 

materials, together with the staff 

evaluation, to the Human Studies 

Review Board. This Board shall consist 

of members who are not employed by 

the Agency, who meet the ethics 

requirements for special government 

employees, and who have expertise in 

fields appropriate for review of human 

research. The Board shall review and 

comment on the scientific and ethical 

aspects of research proposals and 

reports of completed intentional dosing 

research with human subjects which 

EPA intends to rely on in its decisionmaking under FIFRA or FFDCA, and, on 

request, advise EPA on ways to 

strengthen its programs for protection of 

human subjects of research. 

(c) Submission of information 

pertaining to ethical conduct of 

completed human research. Any person 

who submits to EPA data derived from 

human research covered by this subpart 

shall also provide to EPA information 

documenting compliance with the 

requirements of this subpart. Such 

information should include: 

(1) Copies of all of the records 

relevant to the research specified by 

§ 26.115(a) to be prepared and 

maintained by an IRB. 

(2) Copies of sample records used to 

document informed consent as specified 

by § 26.117, but not identifying any 

subjects of the research. 

(3) Copies of all correspondence, if 

any, between EPA and the researcher or 

sponsor pursuant to paragraph (b) of 

this section. 

6. By adding new subparts B through 

F to read as follows: 

Subpart B—Additional Protections for 

Pregnant Women, Fetuses, and Newborns 

Involved in Research 

Sec. 

§ 26.201 To what do these regulations 

apply? 

§ 26.202 Definitions. 

§ 26.203 Duties of IRBs in connection with 

research involving pregnant women, 

fetuses, and neonates. 

§ 26.204 Research involving pregnant 

women or fetuses. 

§ 26.205 Research involving neonates. 

§ 26.206 Research involving, after delivery, 

the placenta, the dead fetus, or fetal 

material. 

§ 26.207–26.219 [Reserved] 

§ 26.220 Prohibition of research involving 

intentional dosing of pregnant women, 

fetuses, or newborns. 

§ 26.221 Prohibition of EPA reliance on 

research involving intentional dosing of 

pregnant women, fetuses, or newborns. 

Subpart C—Additional Protections 

Pertaining to Research Involving Prisoners 

as Subjects [Reserved] 

Subpart D—Additional Protections for 

Children Involved as Subjects in Research 

§ 26.401 To what do these regulations 

apply? 

§ 26.402 Definitions. 

§ 26.403 IRB duties. 

§ 26.404 Research not involving greater 

than minimal risk. 

§ 26.405 Research involving greater than 

minimal risk but presenting the prospect 

of direct benefit to the individual 

subjects. 

§ 26.406 [Reserved] 

§ 26.407 [Reserved] 

53864 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

§ 26.408 Requirements for permission by 

parents or guardians and for assent by 

children. 

§ 26.409–26.419 [Reserved] 

§ 26.420 Prohibition of research involving 

intentional dosing of children. 

§ 26.421 Prohibition of EPA reliance on 

research involving intentional dosing of 

children. 

Subpart E—Administrative Actions for 

Noncompliance 

§ 26.501 Lesser administrative actions. 

§ 26.502 Disqualification of an IRB or an 

institution. 

§ 26.503 Public disclosure of information 

regarding revocation. 

§ 26.504 Reinstatement of an IRB or an 

institution. 

§ 26.505 Debarment. 

§ 26.506 Actions alternative or additional to 

disqualification. 

Subpart F—Ethical Standards for Assessing 

Whether to Rely on the Results of Human 

Research in EPA Regulatory Decisions 

§ 26.601 Human research conducted prior 

to [effective date of the final rule]. 

§ 26.602 Human research conducted after 

[effective date of the final rule]. 

§ 26.603 Exceptions for human research. 

Subpart B—Additional Protections for 

Pregnant Women, Fetuses, and 

Newborns Involved in Research 

§ 26.201 To what do these regulations 

apply? 

(a) Except as provided in paragraph 

(b) of this section, this subpart applies 

to all research involving pregnant 

women, human fetuses, neonates of 

uncertain viability, or nonviable 

neonates conducted or supported by the 

Environmental Protection Agency 

(EPA). This includes all research 

conducted in EPA facilities by any 

person and all research conducted in 

any facility by EPA employees. This 

subpart also applies to all research 

involving pregnant women, human 

fetuses, neonates of uncertain viability, 

or nonviable neonates covered by 

§ 26.101(j). 

(b) The exemptions at § 26.101(b)(1) 

through (b)(6) are applicable to this 

subpart. 

(c) The provisions of § 26.101(c) 

through (i) are applicable to this 

subpart. Reference to State or local laws 

in this subpart and in § 26.101(f) is 

intended to include the laws of federally 

recognized American Indian and Alaska 

Native Tribal Governments. 

(d) The requirements of this subpart 

are in addition to those imposed under 

the other subparts of this part. 

§ 26.202 Definitions. 

The definitions in § 26.102 shall be 

applicable to this subpart as well. In 

addition, the definitions at 45 CFR 

46.202(a) through (f) and at 45 CFR 

46.202(h) are applicable to this subpart. 

For purposes of this part, Administrator 

means the Administrator of the 

Environmental Protection Agency and 

any other officer or employee of the 

Environmental Protection Agency to 

whom authority has been delegated. 

§ 26.203 Duties of IRBs in connection with 

research involving pregnant women, 

fetuses, and neonates. 

The provisions of 45 CFR 46.203 are 

applicable to this section. 

§ 26.204 Research involving pregnant 

women or fetuses. 

The provisions of 45 CFR 46.204 are 

applicable to this section. 

§ 26.205 Research involving neonates. 

The provisions of 45 CFR 46.205 are 

applicable to this section. 

§ 26.206 Research involving, after delivery, 

the placenta, the dead fetus, or fetal 

material. 

The provisions of 45 CFR 46.206 are 

applicable to this section. 

§ 26.207–26.219 [Reserved] 

§ 26.220 Prohibition of research involving 

intentional dosing of pregnant women, 

fetuses, or newborns. 

Notwithstanding any other provision 

of this part, under no circumstances 

shall EPA or a person when covered by 

§ 26.101(j) conduct or support research 

involving intentional dosing of any 

pregnant woman, fetus, or newborn. 

§ 26.221 Prohibition of EPA reliance on 

research involving intentional dosing of 

pregnant women, fetuses, or newborns. 

In its regulatory decision-making 

under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 346a), EPA shall not rely on 

any research involving intentional 

dosing of any pregnant women, fetuses, 

or newborns, except when such research 

is deemed scientifically sound and 

crucial to the protection of public 

health, under the procedure defined in 

§ 26.603. 

Subpart C—Additional Protections 

Pertaining to Research Involving 

Prisoners as Subjects [Reserved] 

Subpart D—Additional Protections for 

Children Involved as Subjects in 

Research 

§ 26.401 To what do these regulations 

apply? 

(a) This subpart applies to all research 

involving children as subjects, 

conducted or supported by EPA. This 

subpart also applies to all research 

involving children covered by 

§ 26.101(j). 

(1) This includes research conducted 

by EPA employees, except that each 

head of an Office of the Agency may 

adopt such nonsubstantive, procedural 

modifications as may be appropriate 

from an administrative standpoint. 

(2) It also includes research 

conducted or supported by EPA outside 

the United States, but in appropriate 

circumstances, the Administrator may, 

under § 26.101(e), waive the 

applicability of some or all of the 

requirements of these regulations for 

research of this type. 

(b) Exemptions at § 26.101(b)(1) and 

(b)(3) through (b)(6) are applicable to 

this subpart. The exemption at 

§ 26.101(b)(2) regarding educational 

tests is also applicable to this subpart. 

However, the exemption at 

§ 26.101(b)(2) for research involving 

survey or interview procedures or 

observations of public behavior does not 

apply to research covered by this 

subpart, except for research involving 

observation of public behavior when the 

investigator(s) do not participate in the 

activities being observed. 

(c) The exceptions, additions, and 

provisions for waiver as they appear in 

§ 26.101(c) through (i) are applicable to 

this subpart. 

§ 26.402 Definitions. 

The definitions in § 26.102 shall be 

applicable to this subpart as well. In 

addition, as used in this subpart: 

(a) Children are persons who have not 

attained the age of 18. 

(b) Assent means a child’s affirmative 

agreement to participate in research. 

Mere failure to object should not, absent 

affirmative agreement, be construed as 

assent. 

(c) Permission means the agreement of 

parent(s) or guardian to the 

participation of their child or ward in 

research. 

(d) Parent means a child’s biological 

or adoptive parent. 

(e) Guardian means an individual 

who is authorized under applicable 

State, Tribal, or local law to consent on 

behalf of a child to general medical care. 

§ 26.403 IRB duties. 

The provisions of 45 CFR 46.403 are 

applicable to this section. 

§ 26.404 Research not involving greater 

than minimal risk. 

EPA will conduct or fund research in 

which the IRB finds that no greater than 

minimal risk to children is presented, 

only if the IRB finds that adequate 

provisions are made for soliciting the 

assent of the children and the 

Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 53865 

permission of their parents or guardians, 

as set forth in § 26.408. 

§ 26.405 Research involving greater than 

minimal risk but presenting the prospect of 

direct benefit to the individual subjects. 

EPA will conduct or fund research in 

which the IRB finds that more than 

minimal risk to children is presented by 

an intervention or procedure that holds 

out the prospect of direct benefit for the 

individual subject, or by a monitoring 

procedure that is likely to contribute to 

the subject’s well-being, only if the IRB 

finds and documents that: 

(a) The risk is justified by the 

anticipated benefit to the subjects. 

(b) The relation of the anticipated 

benefit to the risk is at least as favorable 

to the subjects as that presented by 

available alternative approaches. 

(c) Adequate provisions are made for 

soliciting the assent of the children and 

permission of their parents or guardians, 

as set forth in § 26.408. 

§ 26.406 [Reserved] 

§ 26.407 [Reserved] 

§ 26.408 Requirements for permission by 

parents or guardians and for assent by 

children. 

(a) In addition to the determinations 

required under other applicable sections 

of this subpart, the IRB shall determine 

that adequate provisions are made for 

soliciting the assent of the children, 

when in the judgment of the IRB the 

children are capable of providing assent. 

In determining whether children are 

capable of assenting, the IRB shall take 

into account the ages, maturity, and 

psychological state of the children 

involved. This judgment may be made 

for all children to be involved in 

research under a particular protocol, or 

for each child, as the IRB deems 

appropriate. If the IRB determines that 

the capability of some or all of the 

children is so limited that they cannot 

reasonably be consulted or that the 

intervention or procedure involved in 

the research holds out a prospect of 

direct benefit that is important to the 

health or well-being of the children and 

is available only in the context of the 

research, the assent of the children is 

not a necessary condition for proceeding 

with the research. Even where the IRB 

determines that the subjects are capable 

of assenting, the IRB may still waive the 

assent requirement under circumstances 

in which consent may be waived in 

accord with § 26.116(d). 

(b) In addition to the determinations 

required under other applicable sections 

of this subpart, the IRB shall determine, 

in accordance with and to the extent 

that consent is required by § 26.116, that 

adequate provisions are made for 

soliciting the permission of each child’s 

parents or guardian. Where parental 

permission is to be obtained, the IRB 

may find that the permission of one 

parent is sufficient for research to be 

conducted under §26.404 or §26.405. 

(c) In addition to the provisions for 

waiver contained in § 26.116, if the IRB 

determines that a research protocol is 

designed for conditions or for a subject 

population for which parental or 

guardian permission is not a reasonable 

requirement to protect the subjects (for 

example, neglected or abused children), 

it may waive the consent requirements 

in subpart A of this part and paragraph 

(b) of this section, provided an 

appropriate mechanism for protecting 

the children who will participate as 

subjects in the research is substituted, 

and provided further that the waiver is 

not inconsistent with Federal, State or 

local law. The choice of an appropriate 

mechanism would depend upon the 

nature and purpose of the activities 

described in the protocol, the risk and 

anticipated benefit to the research 

subjects, and their age, maturity, status, 

and condition. 

(d) Permission by parents or 

guardians shall be documented in 

accordance with and to the extent 

required by § 26.117. 

(e) When the IRB determines that 

assent is required, it shall also 

determine whether and how assent must 

be documented. 

§§ 26.409–26.419 [Reserved] 

§ 26.420 Prohibition of research involving 

intentional dosing of children. 

Notwithstanding any other provision 

of this part, under no circumstances 

shall EPA or a person when covered by 

§ 26.101(j) conduct or support research 

involving intentional dosing of any 

child. 

§ 26.421 Prohibition of EPA reliance on 

research involving intentional dosing of 

children. 

In its regulatory decision-making 

under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 346a), EPA shall not rely on 

any research involving intentional 

dosing of any child, except when such 

research is deemed scientifically sound 

and crucial to the protection of public 

health, under the procedure defined in 

§ 26.603. 

Subpart E—Administrative Actions for 

Noncompliance 

§ 26.501 Lesser administrative actions. 

(a) If apparent noncompliance with 

the applicable regulations in subparts A 

through D of this part concerning the 

operation of an IRB is observed by a 

duly authorized investigator during an 

inspection, the inspector will present an 

oral or written summary of observations 

to an appropriate representative of the 

IRB. EPA may subsequently send a letter 

describing the noncompliance to the 

IRB and to the parent institution. The 

agency will require that the IRB or the 

parent institution respond to this letter 

within a time period specified by EPA 

and describe the corrective actions that 

will be taken by the IRB, the institution, 

or both to achieve compliance with 

these regulations. 

(b) On the basis of the IRB’s or the 

institution’s response, EPA may 

schedule a reinspection to confirm the 

adequacy of corrective actions. In 

addition, until the IRB or the parent 

institution takes appropriate corrective 

action, the Agency may: 

(1) Withhold approval of new studies 

subject to the requirements of this part 

that are conducted at the institution or 

reviewed by the IRB; 

(2) Direct that no new subjects be 

added to ongoing studies subject to this 

part; 

(3) Terminate ongoing studies subject 

to this part when doing so would not 

endanger the subjects; or 

(4) When the apparent noncompliance 

creates a significant threat to the rights 

and welfare of human subjects, notify 

relevant State and Federal regulatory 

agencies and other parties with a direct 

interest in the agency’s action of the 

deficiencies in the operation of the IRB. 

(c) The parent institution is presumed 

to be responsible for the operation of an 

IRB, and EPA will ordinarily direct any 

administrative action under this subpart 

against the institution. However, 

depending on the evidence of 

responsibility for deficiencies, 

determined during the investigation, 

EPA may restrict its administrative 

actions to the IRB or to a component of 

the parent institution determined to be 

responsible for formal designation of the 

IRB. 

§ 26.502 Disqualification of an IRB or an 

institution. 

(a) Whenever the IRB or the 

institution has failed to take adequate 

steps to correct the noncompliance 

stated in the letter sent by the Agency 

under § 26.501(a) and the EPA 

Administrator determines that this 

noncompliance may justify the 

53866 Federal Register / Vol. 70, No. 175 / Monday, September 12, 2005 / Proposed Rules 

disqualification of the IRB or of the 

parent institution, the Administrator 

may institute appropriate proceedings. 

(b) The Administrator may disqualify 

an IRB or the parent institution if the 

Administrator determines that: 

(1) The IRB has refused or repeatedly 

failed to comply with any of the 

regulations set forth in this part, and 

(2) The noncompliance adversely 

affects the rights or welfare of the 

human subjects of research. 

(c) If the Administrator determines 

that disqualification is appropriate, the 

Administrator will issue an order that 

explains the basis for the determination 

and that prescribes any actions to be 

taken with regard to ongoing human 

research, covered by subparts A through 

D of this part, conducted under the 

review of the IRB. EPA will send notice 

of the disqualification to the IRB and the 

parent institution. Other parties with a 

direct interest, such as sponsors and 

investigators, may also be sent a notice 

of the disqualification. In addition, the 

agency may elect to publish a notice of 

its action in the Federal Register. 

(d) EPA may refuse to consider in 

support of a regulatory decision the data 

from human research, covered by 

subparts A through D of this part, that 

was reviewed by a disqualified IRB or 

conducted at a disqualified institution, 

unless the IRB or the parent institution 

is reinstated as provided in § 26.504, or 

unless such research is deemed 

scientifically sound and crucial to the 

protection of public health, under the 

procedure defined in § 26.603. 

§ 26.503 Public disclosure of information 

regarding revocation. 

A determination that EPA has 

disqualified an institution and the 

administrative record regarding that 

determination are disclosable to the 

public under 40 CFR part 2. 

§ 26.504 Reinstatement of an IRB or an 

institution. 

An IRB or an institution may be 

reinstated if the Administrator 

determines, upon an evaluation of a 

written submission from the IRB or 

institution that explains the corrective 

action that the institution or IRB plans 

to take, that the IRB or institution has 

provided adequate assurance that it will 

operate in compliance with the 

standards set forth in this part. 

Notification of reinstatement shall be 

provided to all persons notified under 

§ 26.501(c). 

§ 26.505 Debarment. 

If EPA determines that an institution 

or investigator repeatedly has not 

complied with or has committed an 

egregious violation of the applicable 

regulations in subparts A through D of 

this part, EPA may recommend that 

institution or investigator be declared 

ineligible to participate in EPAsupported research (debarment). 

Debarment will be initiated in 

accordance with procedures specified at 

40 CFR part 32. 

§ 26.506 Actions alternative or additional 

to disqualification. 

Disqualification of an IRB or of an 

institution is independent of, and 

neither in lieu of nor a precondition to, 

other statutorily authorized proceedings 

or actions. EPA may, at any time, on its 

own initiative or through the 

Department of Justice, institute any 

appropriate judicial proceedings (civil 

or criminal) and any other appropriate 

regulatory action, in addition to or in 

lieu of, and before, at the time of, or 

after, disqualification. The Agency may 

also refer pertinent matters to another 

Federal, State, or local government 

agency for any action that that agency 

determines to be appropriate. 

Subpart F—Ethical Standards for 

Assessing Whether to Rely on the 

Results of Human Research in EPA 

Regulatory Decisions 

§ 26.601 Human research conducted prior 

to [effective date of the final rule]. 

Unless there is clear evidence that the 

conduct of that research was 

fundamentally unethical (e.g., the 

research was intended to seriously harm 

participants or failed to obtain informed 

consent), or was significantly deficient 

relative to the ethical standards 

prevailing at the time the research was 

conducted, EPA will generally accept 

and rely on relevant, scientifically valid 

data from research that: 

(a) Was initiated prior to [effective 

date of the final rule], 

(b) Involved intentional exposure of a 

human subject, 

(c) Did not involve intentional 

exposure of a pregnant woman, fetus, 

newborn, or child, and 

(d) Is being considered under the 

Federal Insecticide, Fungicide, and 

Rodenticide Act or the Federal Food, 

Drug, and Cosmetic Act. 

§ 26.602 Human research conducted after 

[effective date of the final rule]. 

EPA will generally accept and rely on 

relevant, scientifically valid data from 

research that: 

(a) Was initiated after [effective date 

of the final rule], 

(b) Involved intentional exposure of a 

human subject, 

(c) Did not involve intentional 

exposure of a pregnant woman, fetus, 

newborn, or child, and 

(d) Is being considered under the 

Federal Insecticide, Fungicide, and 

Rodenticide Act or the Federal Food, 

Drug, and Cosmetic Act only if EPA has 

adequate information to determine that 

the research was conducted in a manner 

that substantially complies with 

subparts A through D of this part. 

§ 26.603 Exceptions for human research. 

(a) Before reaching a decision not to 

rely on scientifically useful and relevant 

data derived from research that does not 

meet the applicable standards of 

§§ 26.601 through 26.602, or that 

involves intentional exposure of a 

pregnant woman, fetus, newborn, or 

child, EPA will consider whether the 

data are crucial to a regulatory decision 

that would be more protective of public 

health than could be justified without 

relying on the data. 

(b) Before making a decision under 

this section, EPA will solicit the views 

of the Human Studies Review Board and 

provide an opportunity for public 

comment. 

(c) If EPA decides to rely on data 

derived from a study that does not meet 

the applicable standards of §§ 26.601 

through 26.602, EPA will include in the 

explanation of its decision a thorough 

discussion of the significant ethical 

deficiencies of the study, as well as the 

full rationale for concluding that relying 

on the study is crucial to protection of 

public health. 

[FR Doc. 05–18010 Filed 9–8–05; 9:19 am] 

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