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Protections for Subjects in Human Research

 [Federal Register: February 6, 2006 (Volume 71, Number 24)]

[Rules and Regulations]

[Page 6137-6176]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr06fe06-7]

[[Page 6138]]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Parts 9 and 26

[EPA-HQ-OPP-2003-0132; FRL-7759-8]

RIN 2070-AD57

Protections for Subjects in Human Research

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AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: With this final rule, EPA bans research for pesticides 

involving intentional exposure of human subjects, when the subjects are 

pregnant women or children. The rule further strengthens existing 

protections for subjects in research conducted or supported by EPA, by 

prohibiting such research if it would involve intentional exposure of 

human subjects who are pregnant women or children. The rule also 

extends new protections to adult subjects in research for pesticides 

conducted by others who intend to submit the research to EPA, when it 

involves intentional exposure of human subjects who are non-pregnant 

adults, and creates a new, independent Human Studies Review Board to 

advise the Agency on the ethical and scientific issues arising in such 

research. This final rule focuses on third-party intentional dosing 

human studies for pesticides and sets the stage for further Agency 

actions. In addition, in order to display the OMB control number for 

the information collection requirements contained in this final rule, 

EPA is amending the table of OMB approval numbers for EPA regulations 

that appears in 40 CFR part 9.

DATES: This rule is effective on April 7, 2006.

ADDRESSES: EPA has established a docket for this action under docket 

identification (ID) number EPA-HQ-OPP-2003-0132. All documents in the 

docket are listed in the index for the docket. Although listed in the 

docket index, some information is not publicly available, i.e., 

Confidential Business Information (CBI) or other information whose 

disclosure is restricted by statute. Certain other material, such as 

copyrighted material, is not available through the electronic docket 

and will be publicly available only in hard copy form. Publicly 

available docket materials are available either electronically at 

http://www.regulations.gov 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) 

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305-1049; fax number: (703) 308-4776; e-mail address: 

jordan.william@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. What Does this Final Rule Do?

 With this final rule EPA significantly strengthens and expands the 

protections for subjects of ``third-party'' human research (i.e., 

research that is not conducted or supported by EPA) by: (1) Prohibiting 

new research involving intentional exposure of pregnant women or 

children, intended for submission to EPA under the pesticide laws; (2) 

extending the provisions of the Federal Policy for the Protection of 

Human Subjects of Research (the ``Common Rule'') to other human 

research involving intentional exposure of non-pregnant adults, 

intended for submission to EPA under the pesticide laws; (3) requiring 

submission to EPA of protocols and related information about covered 

human research before it is initiated; and (4) establishing an 

independent Human Studies Review Board to review both proposals for new 

research and reports of covered human research on which EPA proposes to 

rely under the pesticide laws.

 The final rule also: (1) Categorically prohibits any EPA research 

involving intentional exposure of human subjects who are pregnant women 

or children to pesticides or any substances; and (2) adapts regulations 

of the Department of Health and Human Services providing additional 

protections beyond those of the Common Rule to pregnant women and 

children as subjects in EPA observational research--i.e., research 

which does not involve intentional exposure to any substance. (Research 

conducted by EPA is referred to as ``first-party'' research, and 

``second-party'' research refers to research supported by EPA but 

performed by others.)

 Finally, this rule forbids EPA to rely, in its actions under the 

pesticide laws, on intentional-exposure human research that either 

involves pregnant women or children or is otherwise considered 

unethical, except in narrowly defined circumstances. For example, if 

children were at risk from unsafe exposure to a substance, the Agency 

would be permitted to rely on otherwise unacceptable research to 

justify setting a more restrictive standard to protect them.

B. Legal Authority

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 EPA is promulgating this final rule to effectuate the express 

mandate of the United States Congress as set forth in section 201 of 

the Department of the Interior, Environment, and Related Agencies 

Appropriations Act, 2006, Public Law No. 109-54 (Appropriations Act), 

which provides appropriated funds for EPA and other federal departments 

and agencies. In addition, today's final rule is authorized under 

provisions of the following statutes that EPA administers: Section 3(a) 

of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), 

which authorizes the Administrator to regulate the distribution, sale, 

or use of any unregistered pesticide in any State ``[t]o the extent 

necessary to prevent unreasonable adverse effects on the environment'' 

(defined at FIFRA section 2(bb), in pertinent part, as ``any 

unreasonable risk to man or the environment, taking into account the 

economic, social, and environmental costs and benefits of the use of 

any pesticide''); section 25(a) of FIFRA, which authorizes the 

Administrator to ``prescribe regulations to carry out the purposes of 

[FIFRA],'' and section 408(e)(1)(C) of the Federal Food, Drug, and 

Cosmetic Act (FFDCA), which authorizes the Administrator to issue a 

regulation establishing ``general procedures and requirements to 

implement [Section 408].'' In addition, EPA's expansion of its human 

subject protection regulations to include additional subparts 

supplementing EPA's codification of the Common Rule regarding firstand second-party research are authorized pursuant to 5 U.S.C. 301 and 

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

C. Does this Action Apply to Me?

 You may be potentially affected by this action if you conduct human 

research on substances regulated by EPA. Potentially affected entities 

may include, but are not limited to, entities that conduct or sponsor 

research involving intentional exposure of human subjects that may be 

submitted to EPA under FIFRA or FFDCA. Although EPA has in the past 

received such third-party research from pesticide registrants, other 

entities could submit such information to EPA.

 ? Pesticide and other Agricultural Chemical Manufacturing 

(NAICS code 325320).

[[Page 6139]]

 This listing is not intended to be exhaustive, but rather provides 

a guide regarding entities likely to be affected by this action. Other 

types of entities not listed in this unit could also be affected. The 

North American Industrial Classification System (NAICS) code has been 

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provided to assist you and others in determining whether this action 

might apply to certain entities. To determine whether you or your 

business may be affected by this action, you should carefully examine 

the applicability provisions of 40 CFR part 26. If you have any 

questions regarding the applicability of this action to a particular 

entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.

D. How Can I Access Electronic Copies of this Document and Other 

Related Information?

 You may access an electronic copy of this Federal Register document 

and the associated electronic docket at http://www.regulations.gov, 

or 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/. 

II. Background

A. Summary of EPA Goals for this Final Rule

 EPA's most important statutory responsibility is to protect public 

health and the environment by regulating air and water pollutants, 

pesticides, hazardous wastes, industrial chemicals, and other 

environmental substances. To meet this responsibility the Agency 

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 about toxicity with estimates of exposure, EPA can estimate 

the risk a substance poses to exposed populations, and then decide 

whether and how best to regulate releases of the substance into the 

environment.

 EPA believes that in general it can best protect public health by 

considering all available, relevant, scientifically sound information, 

including information developed through research with human subjects. 

But at the same time, EPA wants to take action to ensure that research 

conducted by EPA or for EPA, submitted to EPA, and relied on by EPA--

especially research with human subjects--has been conducted ethically.

B. The Role of Human Research in EPA Risk Assessments

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 The Agency's understanding of potential risks to people is usually 

based on many tests performed with laboratory animals. These tests 

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, the results of all these 

studies provide a good general understanding of a pesticide's potential 

effects.

 Animal studies, however, are not the only source of relevant 

information for characterizing potential risks of a substance. 

Epidemiological studies, for example, provide valuable information 

about the relationship between chemical exposure and effects of 

concern. Monitoring studies that measure concentrations of a substance 

in air, water, food, or on surfaces also provide valuable insights into 

chemical exposures. 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, a farmer's actual exposure to a 

pesticide he or she is applying will depend on his or her equipment, 

the kind and quantity of pesticide he or she uses, what protective 

clothing or equipment he or she uses, and how many hours he or she 

works each day. To be able to take these factors into account, workers 

will often wear monitors in the field to measure exposure levels in 

their routine work. Research like this provides critical data for 

defining 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 to require for a pesticide, or how soon 

harvesters or other workers could safely enter pesticide-treated areas.

 Some human research, however, involves intentional exposure of 

human subjects--defined in this rule as exposure they would not have 

experienced had they not participated in the research. One kind of 

research involves exposing subjects to low doses of a substance to 

measure how it is absorbed, distributed, metabolized, and excreted. 

Humans process some substances differently from animals, and studies of 

this kind can provide essential support for safety monitoring programs, 

such as those which measure the known metabolites of a substance in the 

blood or urine of workers to estimate their exposure to the substance.

 Although EPA has not required or encouraged it, some third parties 

have occasionally conducted and submitted to EPA reports of research 

involving intentional exposure of human subjects to a substance to 

identify or measure its toxic effects. These studies occur in a 

controlled laboratory or clinical setting.

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 Animal data alone can sometimes provide an incomplete or misleading 

picture of a substance's safety or risks. Sometimes human research 

shows people to be more susceptible than animals to the effects of a 

chemical, and supports regulatory measures more protective than could 

be justified by animal data alone. This has been the case, for example, 

for arsenic, certain air pollutants, and the pesticide ingredients 

methyl isothiocyanate (MITC) and hexavalent chromium. Even when human 

research does not show people to be more sensitive than animals, 

scientifically sound human data developed under strict ethical 

standards can strengthen the basis for EPA regulatory actions.

C. Societal Concern over the Ethics of Human Research

 Scientific experimentation with human beings has always been 

controversial. 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. In the United States the 

``Common Rule,'' a regulation followed by EPA and 17 federal 

departments and agencies, contains a widely accepted set of standards 

for conducting ethical research with human subjects, together with a 

set of procedures designed to ensure that the standards are met. See 

Unit V.

 For several years EPA has been at the center of an intense debate 

about the acceptability of intentional dosing human toxicity studies 

for pesticides, and about what to do with human studies that are 

ethically deficient. In this debate some have argued that all research 

involving intentional exposure of human subjects to pesticides is 

fundamentally unethical and should never be conducted or accepted. 

Others, while acknowledging the possibility of

[[Page 6140]]

ethical human research with pesticides, have argued that EPA should 

simply refuse to consider data from ethically problematic research 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 unethical research. Some 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 

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shows humans to be less sensitive than animals, the result might be a 

less stringent regulatory measure, advantageous to the company that 

conducted the study. If the key study was unethical, the company could 

benefit from its own misconduct.

 On the other hand, human research has contributed enormously to 

scientific understanding of the risks posed by many substances in the 

environment, and to some of EPA's past regulatory actions. With this in 

mind, others argue that the Agency should consider all relevant and 

scientifically sound information--not excluding ethically deficient 

human data--because to do so will lead to better decisions, based on 

assessments that better reflect actual risks. Holders of this view 

argue that the ethical deficiencies of the research are the 

responsibility of the researchers, not of EPA. They further argue that 

EPA can do no additional harm to the subjects of the research by 

relying on scientifically valid and relevant data from an ethically 

deficient study, whereas 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. Holders of 

this view also stress the importance of strengthening protections for 

volunteers who participate in future studies, while taking advantage of 

all that past research can offer to benefit society.

D. EPA's Solicitation of Expert Advice

 In response to public concerns over human research with pesticides, 

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 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 public docket for this rulemaking, and on the web at: 

http://www.epa.gov/science1/pdf/ec0017.pdf.

 The DTHSS advisory 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 

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but their distribution must be considered in assessing research protocols.

 ? Bad science is always unethical.

 No clear consensus, however, emerged from the committee on many 

other points, including either the scientific merit or 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 accept, consider, or rely on third-party 

intentional dosing human studies for pesticides.

 In December 2001, EPA asked the advice of the National Academy of 

Sciences (NAS) on the many difficult scientific and ethical issues 

concerning intentional human dosing studies. 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. After 

long and thoughtful consideration of the full range of issues, the 

committee released 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/. 

 The NAS recommendations addressed what standards should guide the 

conduct of future human research and whether or not EPA should rely on 

the results of ethically deficient human studies. 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 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. 

EPA has relied heavily on the advice of this committee in developing 

this rule. 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.

E. Balancing Conflicting Societal Goals

 EPA's mission is to make the best possible regulatory decisions to 

protect public health and the environment. EPA does not want to ignore 

potentially important information that might benefit its assessments 

and decision-making. At the same time, the Agency's conduct should 

encourage high ethical standards in research with human subjects. If 

all research with human subjects always met the highest contemporary 

ethical standards, these goals could all be pursued together. But 

sometimes they conflict.

 Two salient issues illustrate the difficulty in striking an 

appropriate balance between societal goals in conflict. First, the 

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Agency must decide what standard to apply to assess the ethical 

acceptability of research performed before the new rule takes effect. 

The choices are: To apply today's standards of ethical conduct to 

research performed in the past, or to judge past research against the 

ethical norms prevailing when it was conducted.

 Codes of ethical research conduct regulate the behavior of 

investigators before and during the research. It is reasonable to 

expect investigators to follow ethical codes that prevail when they do 

their work; but EPA believes it is unreasonable to expect them to 

anticipate and follow standards that may be developed after their work 

is done. EPA believes that scientifically meritorious research that 

adhered to accepted high ethical standards when it was conducted should 

not be set aside because ethical standards have subsequently changed. 

EPA also believes that ethical standards are likely to continue to 

change in the future and that if and when they do, such a change should 

not invalidate or make unacceptable otherwise meritorious research 

conducted now, in conformity with high ethical standards of today. 

Other parts of the U.S. government, and other countries, have arrived 

at a similar position.

 In the final rule, EPA has implemented the applicable 

recommendation of the NAS, and will accept scientificatiated before the 

rule becomes effective unless there is clear and convincing evidence 

that it was fundamentally unethical or significantly deficient with 

respect to the ethical standards prevailing when the research was conducted.

 The second salient issue concerns whether it is ever justified to 

rely on a

[[Page 6141]]

report of scientifically sound research judged to be unethical. To 

illustrate this problem, assume that EPA received a report of 

scientifically valid research involving intentional exposure of 

children, which is defined by this rule as unacceptable. But assume 

this study shows that the level of exposure to the tested substance 

safe for children is 5 parts per billion (ppb), whereas all other 

information available from animal studies and ethical human studies 

suggests that children would be safe if exposed at levels up to 90 ppb. 

A regulatory standard of 5 ppb based on the unacceptable study would 

adequately protect exposed children; a standard which did not rely on 

the unacceptable study would be set at 90 ppb, and would not adequately 

protect exposed children.

 In such a situation, what should the Agency do? If EPA refused to 

rely on the unethical research in this example, it would set its 

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standard at 90 ppb and would not adequately protect exposed children. 

Moreover, if the final rule always prohibited reliance on data from 

research involving intentional exposure of children, even in this 

exceptional case, using the data to justify a level at 5 ppb would be a 

plain violation of a regulation that could be subject to legal challenge.

 The ethical and responsible course, EPA believes, would be to rely 

on the data to set a fully protective standard, while strongly 

condemning unethical research conduct and imposing appropriate 

administrative sanctions. Moreover, the number of people who would 

benefit from EPA's regulatory intervention could be far greater than 

the number of subjects involved in the research. Thus EPA has retained 

the proposed exception, to permit it to take legally defensible action 

to protect public health in this kind of exceptional situation.

 EPA expects a circumstance like this example to arise only rarely, 

if at all. But however rarely it might occur, any decision to rely on 

unacceptable data, should only be made with great care, with full 

opportunity for public discussion, and in reliance on expert advice. As 

discussed further later, the final rule both provides for the essential 

public health protection exception, narrowly defined, and meets all 

these additional criteria.

III. EPA's Proposed Human Studies Rulemaking and General Public Comments

 Summary: This unit reviews the general public comments on EPA's 

proposed rulemaking. The detailed comments are addressed in subsequent 

units of this preamble.

 An extensive review of the historical development of ethical 

standards for the conduct of human research and the events leading up 

to the promulgation of this final rule appeared in the preamble to the 

proposed rule, available in the public docket for this action.

 Today's final rule is the first to emerge from the process which 

began with publication of an Advance Notice of Proposed Rulemaking in 

the Federal Register on May 7, 2003 (68 FR 24410) (FRL-7302-8). On 

February 8, 2005 (70 FR 6661) (FRL-7695-4), EPA published and invited 

public comment on a Federal Register notice announcing its plan to 

establish a comprehensive framework for deciding whether to consider or 

rely on certain types of research with human subjects.

 On September 12, 2005 (70 FR 53838) (FRL-7728-2), EPA published in 

the Federal Register a notice of proposed rulemaking to strengthen the 

protections for people who participate as subjects in human research. 

The Agency proposed 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 

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human research conducted or supported by EPA, and to extend new 

protections to adult subjects in human research for pesticides, 

involving intentional exposure of human subjects and conducted by 

others who intend to submit the research to EPA. The proposal also 

contained provisions to establish an independent Human Studies Review 

Board responsible for reviewing proposals to conduct new, intentionalexposure human research under the pesticide laws and EPA decisions to 

rely on the results of certain types of completed human research in its 

actions under the pesticides laws.

 EPA received approximately 50,000 comments during the 90-day public 

comment period. The vast majority of the comments were submitted by 

private individuals as part of e-mail and letter-writing campaigns. The 

remaining unique comments came from individuals and organizations 

representing a range of stakeholders including pesticide companies, 

farm groups and other pesticide users, and environmental and public 

health advocacy groups. EPA has reviewed, summarized, and responded to 

these comments in the Response to Comments document available in the 

docket for this rule. In addition, this unit summarizes the major 

themes raised by the comments on the proposal, and explains how EPA has 

addressed them in the final rule.

 Comment: All human research with pesticides is fundamentally unethical.

 Response: EPA agrees with the advice it has received, as discussed 

in Unit II., from its advisory committees. The SAB/SAP Data from 

Testing of Human Subjects Subcommittee agreed that although ethical 

human research with pesticides was possible, the threshold of 

justification should be set very high. The NAS Committee likewise 

counseled care, recommending many specific conditions which should be 

satisfied, but nonetheless acknowledged the possibility of ethical 

research when those conditions were met. On that basis EPA has gone 

forward with this final rule.

 Comment: Comments objected to the Agency's rulemaking on the ground 

that it would promote unethical research on human subjects by pesticide 

companies.

 Response: EPA expects its tougher new rules will eliminate all 

unethical research and will decrease the overall number of future 

intentional dosing studies conducted for pesticides. The additional 

science and ethics reviews by EPA and the Human Studies Review Board 

should eliminate any proposed unethical research.

 Over the period 1996 to 2001, EPA received approximately 33 

intentional dosing studies of all types annually. These included 

studies measuring worker exposure; the efficacy of insect repellents; 

studies of absorption, distribution and excretion that help EPA assess 

exposure; and studies of systemic toxicity. Of these 33, only 4 a year, 

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on average, involved intentional exposure of human subjects to measure 

minor, reversible systemic toxic effects. (Systemic effects are those 

that occur within the body, such as trembling, nausea, or headaches 

resulting from chemical changes in the nervous system.) See the 

Economic Analysis, Appendix B.

 Since 1996 we have received about 26 intentional dosing, systemic 

toxicity studies on humans. After this rule is finalized, we expect 

that number to decrease from an average of 3 a year to as few as 0 or 1 

per year. We expect that number of non-toxicity intentional dosing 

studies to remain about the same.

 Comment: The proposal was unclear.

 Response: Many comments on the proposed rule reflected confusion 

about which provisions applied to EPA and which to regulated third 

parties, and about how the standards applying to the conduct of new 

research by EPA or third parties differed from the standards applying 

to EPA decisions to consider

[[Page 6142]]

completed research. These different elements were mingled in some 

subparts of the proposed rule, contributing to this confusion. A 

concerted effort has been made in the final rule to eliminate these 

potential causes of confusion, by sharpening the focus of each subpart 

and grouping subparts in three broad groups:

 ? Rules applying to EPA's conduct and support of new 

research with human subjects.

 ? Rules applying to certain types of new third-party 

research for pesticides with human subjects.

 ? Rules applying to EPA in its regulatory capacity.

 Comment: Ethical standards can be evaded simply by denying intent 

to submit the results of the research to EPA.

 Response: The final rule, like the proposal, extends the Common 

Rule requirements only to third-party research intended for submission 

to EPA under the pesticide laws, FIFRA and FFDCA. EPA believes this is 

appropriate because there has not been adequate consideration of the 

policy consequences of extending the provisions of the final rule to 

investigators who have no intent to provide their research results to 

EPA and would otherwise have no reason to be aware of these requirements.

 EPA also disagrees that the approach used in the final rule makes 

it easy to evade ethical standards for research by denying the intent 

to submit. Several elements in the final rule interact to ensure the 

application of appropriate standards. First is the explicit presumption 

in the rule that all research submitted by a pesticide registrant was 

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intended for submission to EPA. Specific, credible documentation would 

have to be provided to rebut this presumption; a denial of intent, 

standing alone, could not serve as a rebuttal.

 Second, if a submitter successfully rebutted the presumption of 

intent, it would make little practical difference, and would certainly 

not compel the Agency to accept unethically conducted research. Under 

the final rule, whether or not it was intended for submission to EPA 

when research was initiated, and whether or not it was otherwise 

subject to the requirements of subpart K: (1) After the effective date 

of the rule, all reports of human research submitted to EPA under the 

pesticide laws are required by subpart M to be accompanied by 

documentation of ethical conduct of the research, (2) all completed 

post-rule intentional-exposure research, on which the Agency intends to 

rely in actions under the pesticide laws, is required by subpart P to 

be reviewed by the Human Studies Review Board, and (3) all post-rule 

intentional-exposure research considered under the pesticide laws is 

subject under subpart Q to the Common Rule as the ethical standard of 

acceptability.

 Consequently, the likelihood that unethical research will be used 

by EPA in actions under its pesticide laws is very small--only when it 

is determined that the data are crucial to support more protective 

public health actions would the Agency consider such data.

 Comment: Limitation to research involving intentional exposure of 

human subjects excludes many kinds of studies.

 Response: Most third-party human research for pesticides conducted 

by or for EPA, or intended for submission to EPA, meets the rule's 

definition of research involving intentional exposure, and thus will be 

subject to the requirements of subpart K. But whether or not research 

is subject to subpart K, all reports of all post-rule human research 

submitted to EPA are required by subpart M to be accompanied by 

documentation of ethical conduct.

 Comment: Prohibitions of new research involving intentional exposure 

of pregnant women, fetuses, and children are subject to exceptions.

 Response: The rule provides for no exceptions under any 

circumstances to the bans on the conduct of new research involving 

intentional exposure of pregnant women, fetuses, and children as 

subjects. The final rule has been revised for clarity; the prohibitions 

have been moved to subparts B (applying to EPA) and L (applying to 

third parties,) where they stand alone, and they have been reworded to 

emphasize that they apply notwithstanding any other provisions anywhere 

in 40 CFR part 26.

 Comment: The prohibition on considering human subjects research 

involving intentional exposure of pregnant women, fetuses, and children 

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applies only to regulatory decisions, and not to such non-regulatory 

agency actions as risk assessments.

 Response: The final rule has been changed from the proposal to make 

this prohibition applicable to all Agency actions taken under the 

pesticide laws.

 Comment: The proposed exception permitting EPA to consider 

unethically obtained data when to do so would be ``crucial to 

protection of public health'' undermines all other provisions of the 

rule. Anything from a more accurate risk assessment to increased 

agricultural production could be interpreted as ``crucial to protection 

of public health,'' and used to justify reliance on unethical data.

 Response: Such a broad interpretation was never intended by the 

Agency, but EPA acknowledges that its intentions were not perfectly 

clear from the language of the proposal. The final rule retains a 

``public health exception,'' but it is reworded to make it very clear 

that it could never be invoked to support a less stringent regulatory 

outcome than could be justified without consideration of the unethical 

research.

 Comment: Many provisions of the Common Rule allow for exceptions to 

its requirements at the discretion of the Administrator or 

Institutional Review Boards (IRBs); these exceptions should not be 

allowed for third-party research.

 Response: EPA agrees that some exceptions in the Common Rule are 

not appropriate for the kinds of third-party human research covered by 

this rule. In mirroring the core protections of the Common Rule as they 

apply to third parties in subpart K of the final rule, EPA has 

eliminated or narrowed many of these exceptions, as discussed in detail 

in Unit VII.

IV. Reorganization of the Rule Structure

 Summary: To clarify the various requirements in the proposal and 

how they apply to first, second, and third parties, the Agency has 

extensively reorganized the final rule. The new organization regroups 

the provisions of the proposal into several new subparts.

 In this final rule, EPA's codification of the Common Rule remains 

in force with no changes except to designate it as subpart A of part 

26. Following today's action, the text of 40 CFR 26.101 through 26.124 

remains identical to the codifications of the Common Rule by the other 

federal departments and agencies that have promulgated it.

 The remaining subparts in the final rule, each discussed in a later 

unit of this preamble, are grouped as follows:

 ? Subparts A through D apply to EPA as an investigator or 

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sponsor of new research with human subjects, and to second-party 

investigators whose research EPA supports. Subpart A contains the basic 

policy for human research (the unchanged Common Rule). Subpart B 

prohibits EPA human subjects research on any substance involving 

intentional exposure of pregnant women, fetuses, or children. Subparts 

C and D provide additional protections for pregnant women, fetuses, and 

children when they are subjects of observational studies conducted or 

supported by EPA.

 ? Subparts K and L apply to third parties as investigators 

or sponsors of

[[Page 6143]]

new research involving intentional exposure of human subjects and 

intended for submission to EPA under the pesticide laws. Subpart K 

establishes the basic protections for non-pregnant adult subjects in 

covered third-party research, corresponding in substance to subpart A. 

Subpart L prohibits covered third-party human subjects research for 

pesticides involving intentional exposure of pregnant women or children.

 ? Subpart M applies to all third parties who submit reports 

of any research with human subjects to EPA under the pesticide laws, 

whether or not the research is covered by subpart K, and requires 

concurrent submission of information documenting the ethical conduct of 

such research.

 ? Subparts O--Q apply to EPA in its regulatory capacity. 

Subpart O identifies potential actions for noncompliance with subparts 

A through L. Subpart P addresses the establishment and operation of the 

Human Studies Review Board, and subpart Q defines the ethical standards 

EPA will use to decide whether to rely on data from human research in 

EPA actions.

 Because this reorganization causes extensive changes in the 

numbering of the provisions of the final rule, EPA provides the 

following table to make it easier to follow how the reorganization 

affects the location of specific provisions.

 Table 1.--Location in Proposed and Final Rule Text of Rules Applying to EPA as an Investigator or Sponsor of

 Research with Human Subjects

----------------------------------------------------------------------------------------------------------------

 Location in Final Rule Location in Proposed Rule

---------------------------------------------------- Title/Description ---------------------------------------

 Subpart Section Subpart Section

----------------------------------------------------------------------------------------------------------------

A Sec. Sec. Basic Policy for A Sec. Sec.

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 26.201 thru Protection of 26.101 thru

 26.124 Subjects in Human 26.124

 Research Conducted

 or Supported by

 EPA

--------------------------------------------------------------------------

B Sec. Sec. Prohibition of B and D Sec. Sec.

 26.201 thru Human Subjects 26.220 and 26.420

 26.203 Research Conducted

 or Supported by

 EPA Involving

 Intentional

 Exposure of

 Pregnant Women,

 Fetuses, or

 Children

--------------------------------------------------------------------------

B Sec. 26.201 To what does this n/a n/a

 subpart apply?

--------------------------------------------------------------------------

B Sec. 26.202(a) Definition of A Sec. 26.102(k)

 research involving

 intentional

 exposure of a

 human subject

--------------------------------------------------------------------------

B Sec. 26.202(b) Definition of child D Sec. 26.402(a)

--------------------------------------------------------------------------

B Sec. 26.203 Prohibition of EPA B and D Sec. Sec.

 human subjects 26.220 and 26.420

 research involving

 intentional

 exposure of

 pregnant women,

 fetuses, or

 children

--------------------------------------------------------------------------

C Sec. Sec. Additional B Sec. Sec.

 26.301 thru Protections for 26.201 thru

 26.305 Pregnant Women or 26.206

 Fetuses Involved

 as Subjects in

 Observational

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 Research Conducted

 or Supported by

 EPA

--------------------------------------------------------------------------

D Sec. Sec. Additional D Sec. 26.401 thru

 26.401 thru Protections for 26.408

 26.406 Children Involved

 as Subjects in

 Observational

 Research Conducted

 or Supported by

 EPA

----------------------------------------------------------------------------------------------------------------

 Table 2.--Location in Proposed and Final Rule Text of Rules Applying to Third Parties as Investigators or

 Sponsors of Research with Human Subjects

----------------------------------------------------------------------------------------------------------------

 Location in Final Rule Location in Proposed Rule

---------------------------------------------------- Title/Description ---------------------------------------

 Subpart Section Subpart Section

----------------------------------------------------------------------------------------------------------------

K Sec. Sec. Basic Ethical A Sec. Sec.

 26.1101 thru Requirements for 26.101 thru

 26.1125 Third-Party Human 26.124

 Subjects Research

 for Pesticides

 Involving

 Intentional

 Exposure of Non-

 Pregnant Adults

--------------------------------------------------------------------------

K Sec. 26.1101(a) To what does this A Sec. 26.101(j)

 subpart apply?

--------------------------------------------------------------------------

K Sec. 26.1101(b) Exemption of A Sec.

 research involving 26.101(b)(4)

 only the

 collection or

 study of existing

 data . . .

--------------------------------------------------------------------------

K Sec. 26.1101(c) Administrator A Sec. 26.101(c)

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 retains final

 judgment as to

 whether a

 particular

 activity is

 covered by this

 subpart

--------------------------------------------------------------------------

K Sec. 26.1101(d), Relation to other A Sec. 26.101(e),

 (e), and (f) Federal, State, (f), and (g)

 Tribal, Local, or

 foreign laws or

 regulations

--------------------------------------------------------------------------

K Sec. 26.1101(g) For purposes of A Sec. 26.101(k)

 determining a

 person's intent

 under paragraph

 (a) of this

 section . . .

--------------------------------------------------------------------------

[[Page 6144]]

K Sec. Sec. Definitions A Sec. Sec.

 26.1102(a) thru 26.102(a) thru

 26.1102(h) 26.102(i)

--------------------------------------------------------------------------

K Sec. 26.1102(i) Definition of A Sec. 26.102(k)

 research involving

 intentional

 exposure . . .

--------------------------------------------------------------------------

K Sec. 26.1102(j) Definition of n/a n/a

 person

--------------------------------------------------------------------------

K Sec. Sec. IRB and informed A Sec. Sec.

 26.1107 thru consent 26.107 thru

 26.1117 requirements 26.117

--------------------------------------------------------------------------

K Sec. 26.1123 Early termination A Sec. 26.123(a)

 of research

--------------------------------------------------------------------------

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K Sec. 26.1125 Prior submission to A Sec. 26.124(b)

 EPA of proposed

 human research

--------------------------------------------------------------------------

L Sec. Sec. 1201 Prohibition of B and D Sec. Sec.

 thru 26.1203 Third-Party Human 26.220 and 26.420

 Subjects Research

 for Pesticides

 Involving

 Intentional

 Exposure of

 Pregnant Women,

 Fetuses, or

 Children

--------------------------------------------------------------------------

M Sec. Sec. 1301 Requirements for A Sec. 26.124(c)

 thru 26.1303 Submission of

 Information on the

 Ethical Conduct of

 Completed Human

 Research

----------------------------------------------------------------------------------------------------------------

 Table 3.--Location in Proposed and Final Rule Text of Rules Applying to EPA in its Regulatory Capacity

----------------------------------------------------------------------------------------------------------------

 Location in Final Rule Location in Proposed Rule

---------------------------------------------------- Title/Description ---------------------------------------

 Subpart Section Subpart Section

----------------------------------------------------------------------------------------------------------------

O Sec. Sec. Administrative E Sec. Sec.

 26.1501 thru Actions for 26.501 thru

 26.1503 Noncompliance 26.506

--------------------------------------------------------------------------

P Sec. Sec. 26.160 Review of Proposed A Sec. 26.124(b)

 1 thru 26.1603 and Completed

 Human Research

--------------------------------------------------------------------------

P Sec. 26.1601(c) Determination of A Sec. 26.101(h)

 Equivalence of

 Foreign Ethical

 Standards

--------------------------------------------------------------------------

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P Sec. 26.1603 Operation of the A Sec.

 Human Studies 26.124(b)(5)

 Review Board

--------------------------------------------------------------------------

Q Sec. Sec. Ethical Standards B, D, and F Sec. Sec.

 26.1701 thru for Assessing 26.221, 26.421,

 26.1703 Whether to Rely on 26.601, 26.602,

 the Results of and 26.603

 Human Subjects

 Research in EPA

 Actions

--------------------------------------------------------------------------

Q Sec. Sec. Applicability and n/a n/a

 26.1701 and Definitions

 26.1702

--------------------------------------------------------------------------

Q Sec. 26.1703 Prohibition of B and D Sec. Sec.

 reliance on 26.221 and 26.421

 research involving

 intentional

 exposure of

 pregnant women,

 fetuses, or

 children

--------------------------------------------------------------------------

Q Sec. 26.1704 Prohibition of F Sec. 26.601

 reliance on

 unethical human

 research conducted

 before the

 effective date of

 the final rule

--------------------------------------------------------------------------

Q Sec. 26.1705 Prohibition of F Sec. 26.602

 reliance on

 unethical human

 research conducted

 after the

 effective date of

 the final rule

--------------------------------------------------------------------------

Q Sec. 26.1706 Criteria and F Sec. 26.603

 procedures for

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 decisions to

 protect public

 health by relying

 on otherwise

 unacceptable

 research

----------------------------------------------------------------------------------------------------------------

V. Subpart A--Basic Ethical Protections for Subjects of Human Research 

Conducted or Supported by EPA

 Summary: This unit describes the basic ethical protections that 

apply to human research conducted or supported by EPA. Unit V.A. 

discusses the comprehensive system of ethical protections created by 

the ``Basic Federal Policy for Protection of Human Research Subjects,'' 

generally referred to as the Common Rule. The Common Rule applies to 

all human research conducted or supported by EPA and 17 other federal 

departments and agencies. Unit V.B. discusses the proposed rule, Unit 

V.C. discusses public comments, and Unit V.D. discusses the final rule.

A. The Common Rule

 The Common Rule defines the core protections for human subjects of 

research, and it is important to understand just what those protections are.

 First, the Common Rule requires that research with human subjects 

be overseen by a qualified, independent

[[Page 6145]]

IRB meeting specific requirements laid out in the rule governing 

membership, procedures, decision-making, recordkeeping, and avoidance 

of conflicts of interest. The IRB is vested with responsibility to 

review proposed research, and with authority to approve or disapprove 

it. The IRB is also responsible for overseeing the conduct of approved 

research, and investigators are required to report any unanticipated 

events to the responsible IRB. IRB members must be trained, and must 

remain current with extensive guidance promulgated by the Office for 

Human Research Protections in HHS.

 Under the Common Rule an IRB may approve proposed human subjects 

research only when it concludes that all of the following conditions 

are satisfied:

 ? Risks to subjects have been minimized.

 ? Risks to subjects are reasonable in relation to 

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anticipated benefits, if any, to subjects, and the importance of the 

knowledge that may reasonably be expected to result.

 ? Selection of subjects is equitable.

 ? Informed consent will be sought from each prospective 

subject or the subject's legally authorized representative.

 ? Informed consent will be appropriately documented.

 ? The research plan makes adequate provision for monitoring 

the data collected to ensure the safety of subjects.

 ? There are adequate provisions to protect the privacy of 

subjects and to maintain the confidentiality of data.

 ? Additional safeguards have been included in the study to 

protect the rights and welfare of subjects who are likely to be 

vulnerable to coercion or undue influence, such as children, prisoners, 

pregnant women, mentally disabled persons, or economically or 

educationally disadvantaged persons.

 The Common Rule also requires each IRB to maintain records of 

everything it reviews, of its discussion of controversial issues, and 

of its decisions and their rationale.

 The second major element in the Common Rule is its requirement that 

no investigator involve a human being as a subject in research without 

the informed consent of the subject or the subject's legally authorized 

representative. The Common Rule further specifically requires that:

 ? An investigator shall seek such consent only under 

circumstances that provide the prospective subject sufficient 

opportunity to consider whether or not to participate and that minimize 

the possibility of coercion or undue influence.

 ? The information given to the subject must be in language 

understandable to the subject.

 ? No informed consent, oral or written, may include any 

exculpatory language through which the subject is made to waive or 

appear to waive any of the subject's legal rights, or releases or 

appears to release the investigator, the sponsor, the institution or 

its agents from liability for negligence.

 The Common Rule defines the following mandatory elements in 

informed consent:

 ? A statement that the study involves research, an 

explanation of the purposes of the research and the expected duration 

of the subject's participation, a description of the procedures to be 

followed, and identification of any procedures which are experimental.

 ? A description of any reasonably foreseeable risks or 

discomforts to the subject.

 ? A description of any benefits to the subject or to others 

which may reasonably be expected from the research.

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 A disclosure of appropriate alternative procedures or courses of 

treatment, if any, that might be advantageous to the subject.

 ? A statement describing the extent, if any, to which 

confidentiality of records identifying the subject will be maintained.

 ? For research involving more than minimal risk, an 

explanation as to whether any compensation and any medical treatments 

are available if injury occurs and, if so, what they consist of, or 

where further information may be obtained.

 ? An explanation of whom to contact for answers to pertinent 

questions about the research and research subjects' rights, and whom to 

contact in the event of a research-related injury to the subject.

 ? A statement that participation is voluntary, refusal to 

participate will involve no penalty or loss of benefits to which the 

subject is otherwise entitled, and that the subject may discontinue 

participation at any time without penalty or loss of benefits to which 

the subject is otherwise entitled.

 The Common Rule specifies additional elements of informed consent 

that are sometimes required, and defines standards for documenting 

informed consent by use of a written consent form approved by the IRB 

and signed by the subject. The Common Rule requires that a copy be 

given to the person signing the form.

 The Common Rule extends these core protections to all human 

subjects of covered research, including those in vulnerable 

populations. It is to this base of core protections for all subjects 

that ``additional protections'' for pregnant women, fetuses, and 

children as subjects of observational research conducted or supported 

by EPA, as contained in subparts C and D of this final rule, are added. 

Vulnerable populations for which no ``additional protections'' are 

provided by rule are not left defenseless or exploited; they are 

covered by these core protections of the Common Rule, including its 

requirement that IRBs ensure, on a case-by-case basis, that additional 

safeguards are employed in any study involving vulnerable populations 

to protect their rights and welfare.

 In addition to these substantive protections for research subjects, 

the Common Rule as it applies to research conducted or supported by EPA 

or any other signatory department or agency also contains many 

administrative provisions intended to accommodate the wide range of 

circumstances in all the departments and agencies to which it applies. 

Among others, these administrative provisions include:

 ? Authority for the agency head to extend coverage of the 

rule to research ``otherwise subject to regulation'' (Sec. 26.101(a)) 

and to determine what is within its scope (Sec. 26.101(c) and (d)).

 ? Provision that only certain sections apply to third-party 

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research subject to regulation (Sec. 26.101(a)(2)).

 ? A list of six kinds of human research exempted from 

coverage by the rule (Sec. 26.101(b)).

 ? Provision for approving research conducted under foreign 

standards that ``afford protections that are at least equivalent to 

those provided in'' the Common Rule (Sec. 26.101(h)).

 ? A grant of discretion to the agency head to waive 

provisions of the rule, with public notice in the Federal Register and 

to the DHHS Office for Human Research Protections (Sec. 26.101(i)).

 ? A grant of discretion to IRBs to waive or alter 

requirements for informed consent (Sec. 26.116(c) and (d)) or 

documentation of informed consent (Sec. 26.117(c)).

B. The Proposed Rule

 The September 12 proposal to extend EPA's Common Rule to thirdparty research involved extending all the provisions of subpart A, 

Sec. Sec. 26.101 through 26.124, to covered third-party research. It 

also would have altered the shared text of the Common Rule by adding:

 ? A new paragraph defining the scope of third-party research 

to which it applied (proposed Sec. 26.101(j)).

[[Page 6146]]

 ? A new paragraph defining how a party's intent to submit 

research to EPA would be determined (proposed Sec. 26.101(k)).

 ? A new definition of research involving intentional 

exposure of a human subject (proposed Sec. 26.102(k)).

 ? A new requirement for prior submission to EPA of proposals 

for covered third-party research (proposed Sec. 26.124(b)).

 ? A new requirement for submission to EPA of documentation 

of the ethical conduct of completed research (proposed Sec. 26.124(c)).

 As noted in the preamble to the proposal, HHS requested EPA not to 

make any alterations in the text of the shared Common Rule, and to 

codify the extension of the Common Rule standards to third-party 

research in the final rule in a way that left subpart A--the Common 

Rule--intact and unchanged. EPA agreed that the Common Rule should not 

be altered, and committed to making this change in the final rule.

C. Public Comment

 Comment: The proposed extension of the entire Common Rule, 

including its provisions for administrative waivers of many 

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requirements, alarmed many commenters. These administrative provisions 

were perceived as loopholes which could be exploited to undermine the 

whole purpose of extending the Common Rule.

 Response: Such exploitation of these provisions was never the 

Agency's intent, and EPA agrees with the commenters who argued that 

many of these administrative provisions were not appropriate in a rule 

applying to third-party research. Thus, while subpart K in the final 

rule does extend all the substantive core protections of the Common 

Rule to non-pregnant adult subjects of covered research, it also 

eliminates or narrows the exceptions in the Common Rule. Unit VII. 

discusses each change from the Common Rule to subpart K in detail.

D. The Final Rule

 In the final rule subpart A is the unaltered Common Rule, exactly 

as promulgated in 1991 except for its designation as ``Subpart A.'' It 

applies to all research with human subjects conducted or supported by EPA.

VI. Subpart K--General Provisions Applying to Third Party, Intentional 

Exposure Human Research under the Pesticide Laws

 Summary: Subpart K extends the basic protections of the Common Rule 

to subjects in certain research conducted or supported by third 

parties. It applies to third-party human research involving intentional 

exposure of non-pregnant adult subjects and that is intended to be 

submitted to EPA under the pesticide laws. In addition to the basic 

procedures and protections contained in the Common Rule, it also 

requires researchers who propose to conduct new research covered by the 

rule to submit protocols and other materials for science and ethics 

review by both EPA and a newly created Human Studies Review Board 

(HSRB). Unit VI.A. summarizes EPA's proposal, Unit VI.B. discusses 

public comment, and Unit VI.C. discusses the provisions of the final rule.

A. EPA's Proposed Rule

 EPA's proposal added to the ``Scope'' section of the Common Rule 

additional paragraphs, proposed Sec. 26.101(j) and (k), to make the 

provisions of the Common Rule applicable to certain third-party human 

research. Thus, the Agency's proposal would have extended the Common 

Rule requirements to third parties, without substantive or editorial 

modification.

 The scope of the third-party human research covered by the proposal 

was defined as:

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 [A]ll 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).

 In effect, this provision would have included all intentionalexposure human research conducted with the intent to submit the results 

to the Agency under the pesticide laws. The proposal also established a 

rebuttable presumption that any information submitted by a person 

regulated under the pesticide laws was generated with the intent to 

submit it to EPA.

 In Sec. 26.102(k), the proposal defined ``research involving 

intentional exposure of a human subject'' to mean ``a study of a 

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.'' The preamble to the 

proposed rule explained that this term did not include a study that 

``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'' (70 FR 53846). The preamble also 

explained that intentional exposure studies did not include ``most 

occupational exposure studies, and studies involving use of registered 

pesticides for approved uses according to label directions'' (70 FR 53845).

 In addition, the proposed rule included a new section, proposed 

Sec. 26.124, that would have required any person proposing to conduct 

a new human study covered by the rule to submit the protocol and other 

materials for a science and ethics review by EPA. The same proposed 

section also created a new independent panel of experts, called the 

Human Studies Review Board, to review all proposed new research covered 

by the rule. The HSRB would also review all completed human research 

that EPA intended to rely on under the pesticide laws.

B. Public Comments

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 The major public comments applicable to subpart K of the final rule 

are discussed in Unit III.

C. The Final Rule

 The final rule establishes new requirements for third-party 

research in a separate subpart K, and the rule text defining the scope 

of the types of third-party research covered by the proposed rule 

remains unchanged in the final rule. The Agency, however, has decided 

that the types of research captured by the definition of ``research 

involving intentional exposure of a human subject'' is broader than 

suggested by the preamble to the proposal. Although the text of the 

definition remains the same, EPA thinks it is important to clarify that 

the term covers any research on a substance, unless the subjects of the 

research retain complete control over whether, when, and how they are 

exposed to the substance. Thus, if the researcher decides a particular 

compound will be studied in the research and determines the manner in 

which subjects will be exposed, the research falls within the scope of 

``research involving intentional exposure.''

 The substantive requirements applicable to covered third-party 

research are similar to the requirements contained in the Common Rule. 

In most cases the text is identical, and the sections employ a parallel 

numbering

[[Page 6147]]

system. The sections in subpart K are designated as Sec. Sec. 26.1101 

through 26.1125 and correspond to the sections of the Common Rule 

designated Sec. Sec. 26.1xx. For example, Sec. 26.1107 in subpart K 

corresponds to Sec. 26.107 of the Common Rule.

 EPA also made a number of minor modifications to the text of the 

Common Rule in order to reflect the applicability of subpart K to a 

particular subset of human subjects research studies involving 

intentional exposure of non-pregnant adults intended for submission 

under the pesticide laws. These modifications are discussed in 

paragraph 1 below.

 1. Modifications to the text of the Common Rule in subpart K. In a 

number of its provisions the Common Rule refers to itself as a 

``policy.'' Throughout subpart K, EPA has replaced the word ``policy'' 

with ``subpart,'' to remove any doubt about whether the provisions of 

subpart K create binding requirements.

 Throughout subpart K, EPA replaced references to ``department or 

agency head'' with ``the Administrator.'' Section 26.1102 includes a 

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definition stating that Administrator refers to the Administrator of 

EPA or any officer or employee to whom authority has been delegated.

 Section 26.101(b) of the Common Rule exempts research in six 

categories from the requirements of the Common Rule. These exemptions 

generally cover:

 (i) Research on educational practices conducted in an educational 

setting.

 (ii) Research involving surveys, educational tests, observation, 

or interviews that involve no collection of sensitive personal 

information on identifiable individuals.

 (iii) Research involving surveys, educational tests, observation, 

or interviews that involve public officials or candidates for public office.

 (iv) Research involving the collection or study of existing data, 

documents, specimens, etc. from publicly available sources or sources 

that do not disclose the identity of individual subjects.

 (v) Research examining the delivery of public benefit programs.

 (vi) Research involving taste and food quality evaluation and 

consumer acceptance.

 Subpart K, however, covers only third-party research for pesticides 

involving intentional exposure of non-pregnant adults. Because five of 

these exemptions describe types of research that either could not 

possibly or should not involve ``intentional exposure'' to a pesticide, 

EPA deleted them from subpart K. Because the fourth category, above, 

could encompass the examination of results from research involving 

intentional exposure, the Agency did retain exception number 4 in 

subpart K. See Sec. 26.1101(b) of the regulatory text.

 Section 26.101(d) of the Common Rule states that, without prior 

notice, an agency head may extend the requirements of the Common Rule 

to specific research activities or classes of research. As a legal and 

policy matter, EPA believes that the public should receive notice of 

and an opportunity for public comment on any extension of these 

requirements to additional categories of third-party research. Accordingly, 

subpart K does not contain a provision comparable to Sec. 26.101(d).

 Section 26.101(f) of the Common Rule indicates that State and local 

laws may contain additional requirements governing the conduct of human 

research and that the Common Rule does not supersede those 

requirements. Recognizing that Native American governmental entities 

also have legal authority to regulate the conduct of human research, 

EPA has added Tribal authority to the list of legal sources that may 

establish additional requirements beyond those in the final rule. See 

Sec. 26.1101(e) of the regulatory text.

 Section 26.101(h) of the Common Rule authorizes the head of an 

agency to allow human research conducted in a foreign country to 

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proceed in accordance with the requirements of that country, even if 

foreign authorities require behavior that does not fully comply with 

the Common Rule, so long as the agency head determines that the 

requirements of the foreign country provide protections ``at least 

equivalent to those [of the Common Rule.]'' This section further 

provides that when an agency head makes such a decision, he must 

publish a notice of the action in the Federal Register. In promulgating 

subpart K, EPA retained a comparable provision, but with several 

changes. First, EPA moved this provision to subpart P of the final 

rule, which addresses EPA's decisions on the acceptability of proposed 

research, where it appears as Sec. 26.1601(c). Second, EPA did not 

adopt the Common Rule's requirement to publish a Federal Register 

Notice announcing such a decision on proposed third-party research. The 

Agency concluded that such a procedure was redundant with the HSRB 

process, which will involve both a transparent presentation of EPA's 

positions regarding proposed research and public meetings about such 

positions and an opportunity for the public to comment on them.

 Section 26.101(i) contains language allowing the Administrator to 

waive any of the requirements of the Common Rule. While every other 

federal Common Rule agency and department has such discretion, and 

while such discretion seems appropriate for first- and second-party 

research, EPA has never exercised this authority under the Common Rule 

and sees no need for such discretion under subpart K. Accordingly, 

subpart K does not contain a provision comparable to Sec. 26.101(i).

 The definitions in the Common Rule include the term research 

subject to regulation; see Sec. 26.102(e). Subpart K omits this 

definition because the types of third-party research covered by the 

rule are specified by the paragraphs in Sec. 26.1101 delineating the 

scope of subpart K.

 Section 26.102(j) contains a definition of the term certification. 

Because this definition actually establishes a substantive obligation 

to submit documentation of IRB approval, the substantive requirement 

appears in Sec. 26.1125 as one of the items that must be submitted to 

EPA in connection with review of proposed research. See Sec. 

26.1125(f) of the regulatory text.

 EPA added a new definition of person in Sec. 26.1102(j) of the 

final rule to clarify that the requirements of subpart K (as well as 

subparts L and M) do not apply to first-party and second-party human 

research by other federal departments and agencies that are subject to 

the Common Rule. Having operated under the Common Rule for many years, 

these agencies and departments are very familiar with its meaning and 

application and have well developed procedures for assuring compliance. 

Therefore, EPA sees no reason either to promulgate requirements that 

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duplicate regulations already in force, or to impose on these agencies 

the new requirements of subpart K concerning submission of proposals 

for future research for EPA and HSRB review. Of course, the Agency 

will, on request, work with other agencies intending to submit the 

results of human research to EPA to ensure that the results may be 

considered under subpart Q.

 Several sections of the Common Rule--Sec. Sec. 26.107(a), 

26.111(a)(3), 26.111(b), and 26.116(b)(1)--refer to additional measures 

required when research involves pregnant women, children, or other 

special populations as subjects. Subpart L, however, prohibits thirdparty research involving intentional exposure of human subjects who are 

pregnant women (and therefore their fetuses) or children. Thus subpart 

K covers only third-party research involving intentional exposure of 

non-pregnant adults. To be consistent with this scope, EPA removed from 

subpart

[[Page 6148]]

K all references to pregnant women, fetuses, newborns, or children.

 The first sentence of Sec. 26.107 of the Common Rule states:

 Each IRB shall have at least five members, with varying 

backgrounds to promote complete and adequate review of research 

activities commonly conducted by the institution.

 This provision reflects the assumption that IRBs are always 

associated with an ``institution.'' It also arguably would excuse an 

IRB from having adequate expertise to assess studies beyond those 

``commonly conducted'' at the institution. EPA believes that IRBs 

should acquire whatever expertise they need to evaluate the types of 

studies they agree to review. Accordingly, EPA has revised that 

sentence to read:

 Each IRB shall have at least five members, with varying 

backgrounds to promote complete and adequate review of research 

activities which are presented for its approval.

 Section 26.108(a) of the Common Rule contains a cross-reference to 

certain earlier sections of the Common Rule. For greater clarity, and 

consistent with FDA's approach in its similar rules. EPA simply 

repeated the substantive requirements of the referenced sections in 

Sec. 26.1108(a) of subpart K. This led to redesignation of some paragraphs.

 Section 26.109(c) of the Common Rule includes a reference to Sec. 

26.117(c), which gives IRBs the authority, under certain circumstances, 

to waive the requirement for written documentation of informed consent. 

Since EPA has not included in subpart K a paragraph comparable to Sec. 

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26.117(c) of the Common Rule, the Agency has deleted the crossreference in Sec. 26.1109(c) of subpart K.

 Section 26.114 of the Common Rule contains a provision designed to 

facilitate cooperative research among multiple investigators in 

different institutions. This section authorizes the head of an agency 

to accept a joint review or review by a single IRB to avoid duplication 

of effort. Rather than use the text of the Common Rule provision, EPA 

has adopted in Sec. 26.1114 a similar but clearer provision from FDA 

regulation; see 21 CFR 56.114.

 Section 26.115(a)(5) of the Common Rule cites another provision of 

the Common Rule that specifies the information about the members of an 

IRB which the IRB is required to provide in its records. In the 

parallel section of subpart K, Sec. 26.1115(a)(5), EPA followed the 

approach FDA used in its regulations and repeated the substantive 

provisions of the referenced sections.

 Sections 26.116(c) and (d) of the Common Rule authorize an IRB to 

waive or alter the requirement for informed consent in certain 

circumstances for research conducted or supported by EPA. EPA deleted 

these paragraphs from subpart K because of the central importance of 

informed consent to ensuring ethical treatment of subjects in human 

research. In addition, EPA concluded that the types of human research 

covered by subpart K--research involving intentional exposure of nonpregnant adults intended for submission under the pesticide laws--would 

not meet any of the Common Rule criteria for waiving or altering the 

informed consent procedures.

 EPA added a new paragraph to Sec. 26.1116 to clarify that the 

informed consent materials for research covered by subpart K must 

include ``the identity of the pesticide and the nature of its 

pesticidal function.'' While implicit in the requirements of Sec. 

26.1116(a)(1), which is derived from Sec. 26.116(a)(1) of the Common 

Rule, the Agency thought that the final rule should make this 

obligation explicit.

 In a provision that parallels the waiver authority discussed above, 

Sec. 26.117(c) of the Common Rule authorizes an IRB to waive the 

requirement for an investigator to obtain a signed consent form from 

each subject for research conducted or supported by EPA. Because of the 

importance of being able to demonstrate that each subject was fully 

informed and freely volunteered to participate in the types of research 

covered by subpart K, EPA decided not to adopt this Common Rule 

provision in subpart K. The Agency also made minor editorial changes to 

Sec. 26.1117(a) and (b) to reflect the deletion of paragraph (c).

 Section 26.101(a)(2) identifies the sections of the Common Rule 

which apply to ``research that is neither conducted nor supported by a 

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Federal department of agency but is subject to regulation as defined in 

Sec. 26.102(e).'' These sections include Sec. Sec. 26.107 through 

26.117, but not Sec. 26.103 or Sec. Sec. 26.118 through 26.124. 

Sections 26.118 through 26.124 generally apply to procedures associated 

only with first-party and second-party research, but which would not be 

relevant to third-party research. Consistent with the thrust of Sec. 

26.101(a)(2) and in order to reduce confusion, EPA has not created 

parallel sections for Sec. 26.103 or, with two exceptions, any of the 

sections after Sec. 26.117.

 The first of these exceptions is to include in subparts K and P of 

the final rule two passages parallel to Sec. 26.123 of the Common 

Rule. Section 26.1123, which corresponds to Sec. 26.123(a) in subpart 

A, authorizes the Administrator to suspend or terminate research if EPA 

determines that a sponsor, IRB, or investigator has materially failed 

to comply with the terms of subpart K. (FDA's regulations contain a 

similar provision at 21 CFR 56.113.) In addition, EPA has included the 

substance of Sec. 26.123(b)--authorizing EPA to consider an 

investigator's record in past ethical (or unethical) human research 

when reviewing proposals for new research--in Sec. 26.1601(b) of 

subpart P, which governs EPA's review of proposed new research.

 The second exception is to include in subpart P of the final rule a 

Sec. 26.1601, parallel to Sec. 26.124 of subpart A. This provides 

that, in its review of proposed new research, EPA may, on a case-bycase basis, impose additional conditions applicable to the conduct of a 

study that are necessary for the protection of human subjects.

 2. Revisions to the requirements for information concerning 

proposed research. In reorganizing the final rule, EPA has moved the 

substantive content of proposed Sec. 26.125, which would have required 

third parties to submit proposals for new human research for EPA 

review, to Sec. 26.1125 of subpart K. In addition, EPA has revised 

this section in the final rule in two ways. A new Sec. 26.1125(d) adds 

``a description of the circumstances and methods for presenting 

information to potential human subjects for the purpose of obtaining 

their informed consent'' to the list of what information must be 

included with a submitted proposal for new research, and Sec. 

26.1125(f) adds an explicit requirement for documentation of IRB approvals.

VII. Intentional Exposure Research: Subparts B and L--Prohibitions of 

Human Research Involving Intentional Exposure of Pregnant Women, 

Fetuses, and Children

 Summary: Subpart B of the final rule categorically prohibits EPA 

from conducting or supporting human subjects research on a substance 

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that involves intentional exposure of pregnant women, fetuses, and 

children to the substance. See 40 CFR 26.203 of the regulatory text.

 Subpart L of the final rule prohibits human subjects research for 

pesticides conducted or supported by third parties that involves 

intentional exposure of pregnant women, fetuses, or children. See 40 

CFR 26.1203 of the regulatory text.

 Unit VII.A. summarizes EPA's proposal, Unit VII.B. discusses public 

comments, and Unit VII.C. discusses the provisions of the final rule.

[[Page 6149]]

A. The Proposed Rule

 The September 12 proposal contained, in Sec. 26.220 of proposed 

subpart B, a clear prohibition of any future EPA research involving 

intentional dosing of pregnant women, fetuses or certain newborns. 

Section 26.420 of proposed subpart D contained an equally clear prohibition 

of any future EPA research involving intentional dosing of children.

 The same sections of the proposal--Sec. 26.220 in subpart B and 

Sec. 26.420 in subpart D--also prohibited any new third-party research 

intended for submission to EPA under the pesticide laws, and involving 

intentional dosing of pregnant women, fetuses, or children. The 

proposed prohibition would, as a practical matter, have applied to any 

research conducted by pesticide companies or by investigators working 

on their behalf.

B. Public Comments

 Almost without exception, comments on the prohibitions contained in 

the proposed rule drew no distinction between third-party research and 

first- and second-party research. Therefore, unless otherwise 

indicated, the following discussion applies both to the proposed 

prohibitions against human subjects research conducted or supported by 

EPA that involves intentional exposure of pregnant women, fetuses, or 

children and to the prohibitions against such research by third parties 

who intend to submit the results to EPA under the pesticide laws. In 

addition, comments generally made the same recommendations regarding 

the prohibition on research involving intentional exposure of children 

as for the prohibition on research involving intentional exposure of 

pregnant women and fetuses. Again, unless otherwise indicated, the 

discussion below refers to both sets of prohibitions.

 Comment: Some commenters argued that the proposed prohibitions were 

too narrow and should be expanded in order that all potentially 

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affected test subjects received protection. Specifically, these 

comments recommended that: (1) The prohibition on research with 

children should not be limited to research involving intentional 

exposure, but should cover all types of human research (including 

scientific observation of public behavior of children); (2) the 

prohibition on research with pregnant women should be similarly broad; 

and (3) additional groups should be protected under the ban on 

intentional exposure research, including prisoners, all women of 

childbearing age, the elderly, and people with chronic diseases or 

developmental disabilities.

 Response: EPA believes that ``observational research,'' i.e., 

research that does not involve intentional exposure of human subjects, 

often provides a great deal of valuable scientific information that can 

be critical for effective environmental and public health regulation. 

To adopt the commenters' approach would mean, for example, that EPA 

could not collect, through research involving little or no risk to the 

subjects, information on the amount of time that children spend 

outdoors, the types of food consumed by pregnant women, or the possible 

correlation between air pollution and asthma in newborns. Therefore, 

EPA has decided not to accept the comments recommending expansion of 

the prohibitions to cover all types of human research.

 EPA agrees with the commenters who point out that other groups 

deserve special consideration if they are to be included in research as 

test subjects. The Common Rule and EPA's extension of it to certain 

types of third-party research already direct IRBs to pay particular 

attention to the issues involved with research on several of these 

groups. See Sec. 26.111(b) and Sec. 26.1111(b) of the regulatory 

text. EPA believes that the approach created by the final rule--which 

requires both EPA and HSRB review of all future third-party research 

covered by the rule--will successfully identify those studies that may 

proceed ethically and those for which it would not be ethical to 

involve individuals from the identified groups.

 Comment: Some commenters argued that the proposed prohibitions were 

too broad and that certain kinds of research should be excluded from 

the bans on conduct of future research involving intentional exposure 

of human subjects. Specifically, these comments recommended exclusion 

of: (1) Pharmaceutical studies, particularly products for control of 

head and body lice; (2) nutrition studies with micronutrients that may 

also be pesticides; (3) research on the efficacy of insect repellents; 

(4) research involving only use of registered pesticides for approved 

uses, or ``product-in-use'' studies; and (5) research on the efficacy 

of swimming pool and spa sanitizers and disinfectants;

 Response: For a variety of reasons, EPA is not persuaded by these 

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comments to modify the scope of its proposed prohibitions.

 EPA notes that it does not conduct or support pharmaceutical 

studies and nutritional studies with any human subjects, and therefore 

there is no need to modify the proposed prohibitions for first- and 

second-party research. Further, EPA did not intend its proposed 

prohibitions to apply to third parties when conducting pharmaceutical 

or micronutrient research, and believes that such third-party research 

generally would fall outside the scope of the prohibitions because they 

would not meet the ``intent to submit'' criterion in Sec. 26.1201. In 

fact, EPA thinks it would be contrary to the public interest to ban 

research of the effects on pregnant women and children of drugs, like 

streptomycin, or micronutrients, like copper or iodine, simply because 

these compounds also have approved uses as pesticides. Given that it is 

unlikely an investigator would undertake such research for submission 

to EPA in support of a pesticide action, these types of studies would 

not be prohibited.

 EPA believes that there is no need to perform research on the 

efficacy of insect repellents with pregnant women or children. The 

efficacy of a repellent depends primarily on the properties of the 

pesticide formulation and does not vary with the age of the person to 

whom it is applied. Therefore, studies using non-pregnant adults should 

provide adequate information to assess how well insect repellents work, 

and there is no reason to exclude this type of research from the 

prohibition.

 Similarly, EPA does not believe that comments have presented a 

compelling argument for recommending the Agency exclude from the 

prohibitions ``product-in-use'' research on pesticides. The Agency 

agrees with comments that such product-in-use research will generally 

pose relatively little risk to test subjects, because the exposures 

occurring during the research would correspond to exposures authorized 

by the Agency under its pesticide regulatory program--exposures that 

EPA has found cause no unreasonable adverse effects on human health or 

the environment. But these comments contain no satisfactory explanation 

of why it is necessary to conduct such product-in-use research with 

pregnant women, fetuses, or children. Like research on insect 

repellents, the Agency believes that general product-in-use research 

with non-pregnant adults should provide sufficient information to meet 

legitimate scientific needs.

 Finally, research on the efficacy of antimicrobial agents used in 

swimming pools, spas, and hot tubs raises unusual and difficult issues. 

The Agency issues experimental use permits for these studies to 

determine whether, under typical use conditions, the antimicrobial can 

successfully control the additional

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[[Page 6150]]

microbial load introduced by bathers. The Agency, however, does not 

approve such field research until the Agency can conclude that both the 

experimental use is likely to be effective and the levels of the 

antimicrobial in water will pose no risk to the bathers.

 EPA, however, does not regard such studies as ``research with human 

subjects'' under the definitions in the Common Rule at Sec. Sec. 

26.102 and 26.1102, and therefore does not believe they are subject to 

the prohibitions or any other provisions in part 26. The definitions of 

``research'' and ``human subject'' make clear that the phrase 

``research with a human subject'' applies to a systematic investigation 

in which an investigator collects information through an intervention 

or interaction with an individual for the purpose of developing 

generalizable knowledge about humans. In the case of these 

antimicrobial efficacy studies, the research does not involve 

interactions with, or collection of information on, identifiable 

individuals for the purpose of producing generalizable knowledge.

 Comment: A number of comments objected to what they perceived to be 

``loopholes'' in the proposed rule's prohibition on research involving 

intentional exposure of children. Specifically, they argued that: (1) 

Proposed Sec. 26.401(a)(1) permitted EPA to waive the prohibition when 

research was conducted outside the United States; (2) proposed Sec. 

26.401(a)(2) permitted EPA to waive any provision of proposed subpart 

D, including the prohibition; and (3) proposed Sec. 26.408, which 

authorized an IRB to waive the requirement for assent from children 

lacking the capacity to give it, and to waive the requirement for 

permission from abusive or neglectful parents, meant that EPA intended 

to allow research on mentally retarded, abused, or neglected orphans.

 Response: Many commenters misinterpreted EPA's proposed language. 

Contrary to public comments, none of the alleged ``loopholes'' ever 

existed, because the prohibition in proposed Sec. 26.420 stated 

``Notwithstanding any other provision of this part, under no 

circumstances shall EPA or a person when covered by Sec. 26.101(j) 

conduct or support research involving intentional dosing of any 

child.'' The words, ``Notwithstanding any other provision of this 

part,'' mean that the provisions in proposed Sec. 26.420 override all 

other provisions of the entire regulation, including Sec. Sec. 26.401 

and 26.408. Even though those two sections would have given EPA 

authority to waive certain requirements, they would not have authorized 

any departure from the ban in proposed Sec. 26.420.

 Nonetheless, in order to remove any doubt about the scope of the 

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prohibitions, EPA has made several changes in the final rule. The 

prohibitions appear in separate subparts so that there is less chance 

someone will misread the provisions intended to confer flexibility in 

the approach to observational research as applying to research 

involving intentional exposure. In subpart D, which addresses 

observational research with children conducted or supported by EPA, EPA 

has removed or revised the text of Sec. Sec. 26.401 and 26.408 to make 

clear that they do not create an opportunity to relax the protections 

for children.

C. The Final Rule

 After careful consideration of public comments--particularly the 

thousands of comments expressing strong opposition to EPA's ever 

conducting human subjects research that involves intentional exposure 

of pregnant women, fetuses, or children, the Agency has retained in the 

final rule the proposed prohibitions, essentially without change. 

Subpart B contains the proposed prohibitions against EPA conducting or 

supporting new research involving intentional exposure of pregnant 

women, fetuses, and children. This prohibition applies to EPA's firstand second-party research with any substance, and is not restricted to 

pesticides.

 Subpart L of the final rule contains a parallel prohibition of new 

third-party human subjects research for pesticides involving 

intentional exposure of pregnant women, fetuses, or children. Subpart L 

applies to research conducted or supported by any person who intends to 

provide the results of the research to EPA under FIFRA or the FFDCA. 

The final rule retains the text from the proposal establishing how EPA 

will determine a person's intent for purposes of applying the prohibition.

 The Agency recognized that the wording of the proposed prohibitions 

and other requirements could be interpreted to apply to studies, which 

do not constitute ``research'' with ``human subjects,'' as these terms 

are defined in the Common Rule, but in which humans who are not 

subjects of the research may be incidentally exposed. The Agency did 

not intend, for example, that the proposal would affect animal research 

on a pesticide simply because a person might be intentionally exposed 

to a test material as a consequence of working as a lab technician. 

Accordingly, EPA has revised the rule text in subparts B, C, L, and Q 

to clarify that the prohibitions and other provisions apply only to 

research with human subjects and not to other types of research.

 The Agency hopes that the reorganization of the final rule gives 

greater prominence to these prohibitions, and clarifies EPA's intent 

that there be no exceptions to or loopholes in these prohibitions. Both 

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subparts B and L begin by expressly stating the universe of research 

activities to which they apply. To further reinforce the point that the 

bans on these types of testing are not subject to any exceptions, the 

prohibitory provisions use the introductory phrase ``Notwithstanding 

any other provision of this part, under no circumstances . . . .'' This 

language means that this provision is to be enforced over all other 

provisions of every other subpart of part 26.

VIII. Observational Research: Subparts C and D--Additional Protections 

for Pregnant Women, Fetuses, and Children Involved as Subjects in 

Observational Research Conducted or Supported by EPA

 Summary: This unit discusses protections additional to the core 

protections provided by the Common Rule (subpart A), which are 

established by the final rule for pregnant women and fetuses (subpart 

C) and children (subpart D) when they are subjects in observational 

research conducted or supported by EPA. The final rule defines 

observational research as research not involving intentional exposure. 

The provisions of the final rule are similar to regulations promulgated 

by HHS to govern studies with these populations when conducted or 

supported by HHS. Unit VIII.A. summarizes the proposal, Unit VIII.B. 

discusses public comment, and Unit VIII.C. describes the position taken 

in the final rule.

A. The Proposed Rule

 Most of the provisions of proposed subparts B and D would have 

defined additional protections for individuals from vulnerable 

populations when they were subjects in observational research conducted 

or supported by EPA--i.e., studies that do not involve intentional 

exposure. Proposed subpart B contained protections for pregnant women, 

fetuses, and certain newborns, and proposed subpart D contained 

protections for children. The protections in both proposed subparts 

were in addition to the basic protections created by the Common Rule, 

40 CFR part, 26 subpart A. Because the HHS regulations affording 

additional protections for

[[Page 6151]]

pregnant women and fetuses and for children had been in existence for 

over 20 years and enjoyed widespread acceptance by the research ethics 

community, EPA proposed to adopt the HHS rules without substantive 

change, except as noted below.

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 1. Proposed subpart B. EPA proposed to adopt by reference much of 

the content of subpart B of the HHS rule, 45 CFR part 46, with only a few 

changes. Thus, EPA proposed to adopt several sections from the HHS rule:

 ? In proposed Sec. 26.201, EPA adapted the text of 45 CFR 

46.201, thereby defining the scope of the subpart--research conducted 

or supported by EPA that involved research with pregnant women, 

fetuses, or certain newborns.

 ? Proposed Sec. 26.202 cross referenced several paragraphs 

of 45 CFR 46.202 defining such terms as delivery, fetus, neonate, and 

pregnancy.

 ? Proposed Sec. 26.203 cross referenced the requirement of 

45 CFR 46.203 that assigns to IRBs the primary responsibility for 

ensuring that investigators follow the requirements of the subpart.

 ? Proposed Sec. 26.204 cross referenced the requirements of 

45 CFR 46.204 defining the findings an IRB must make (in additional to 

those required by the Common Rule at Sec. 26.111) before approving 

proposed research with pregnant women or fetuses. (Because of the 

prohibition in proposed Sec. 26.220, the provisions in proposed 

Sec. Sec. 26.204 and 26.205 would have applied only to EPA's 

observational research.) In summary, these include findings that: 

Adequate preliminary research exists to characterize potential risk, 

the risks to pregnant women and fetuses have been minimized, either the 

risks are minimal or the research holds out the prospect of direct 

benefit, and appropriate informed consent is obtained, in some cases 

from both the father and the pregnant woman.

 ? Proposed Sec. 26.205 cross referenced the requirements of 

45 CFR 46.205 defining the findings an IRB must make before approving 

observational research with certain newborns, including, where 

applicable, that the observational research has the prospect of 

improving the chances of survival of neonates of uncertain viability or 

that the observational research will develop important biomedical 

knowledge which could not otherwise be obtained.

 ? Proposed Sec. 26.206 cross referenced the requirements of 

45 CFR 46.206 concerning observational research involving, after 

delivery, the placenta, the dead fetus, or fetal material.

 The major substantive change EPA made to the HHS rule in proposed 

subpart B was the choice not to propose adopting the provisions in 45 

CFR 46.207, which provide a special procedure for approving in 

exceptional cases observational research which does not meet the 

standards of 45 CFR 46.204 or 46.205. EPA considered such a provision 

both inappropriate and unnecessary for observational research with 

environmental substances.

 2. Proposed subpart D. EPA proposed to adopt much of the content of 

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subpart D of the HHS rule, 45 CFR part 46, specifically:

 ? In proposed Sec. 26.401, EPA adopted the text of 45 CFR 

46.401, thereby defining the scope of the subpart--research conducted 

or supported by EPA involving children as subjects. The proposed rule 

text contained the same exceptions that appear in the HHS rule.

 ? Proposed Sec. 26.402 contained the same definitions that 

appear in the HHS rule in 45 CFR 46.402, except that EPA proposed to 

define a child as a person younger than 18 years old, in contrast to 

the HHS definition, which relies on local law to determine when a 

person becomes an adult.

 ? Proposed Sec. 26.403 cross referenced the requirement of 

45 CFR 46.403 that assigns to IRBs the primary responsibility for 

ensuring that investigators follow the requirements of the subpart.

 ? Proposed Sec. 26.404 adapted, essentially verbatim, the 

text of the HHS regulation in 46 CFR 46.404 that authorizes IRBs to 

approve observational research with children (which also meets the 

criteria in Sec. 26.111), which involves ``no more than minimal risk'' 

only if there are adequate procedures, as specified in Sec. 26.408, 

for soliciting the assent of the children and the permission of their 

parents or guardians. (Because of the prohibition in proposed Sec. 

26.420, the provisions in proposed Sec. Sec. 26.404, 26.405, and 

26.408 would have applied only to EPA's observational research.)

 ? Proposed Sec. 26.405 adopted, essentially verbatim, the 

text of the HHS regulation in 46 CFR 46.405 that authorizes IRBs to 

approve observational research with children (which also meets the 

criteria in Sec. 26.111), which involves ``greater than minimal risk'' 

only if the IRB finds the observational research offered the prospect 

of direct benefit to the individual subjects or would otherwise 

contribute to their well-being, and there are adequate procedures, as 

specified in Sec. 26.408, for soliciting the assent of the children 

and the permission of their parents or guardians.

 ? Proposed Sec. 26.408 adopted, essentially verbatim, the 

text of the HHS regulation in 45 CFR 46.408 establishing special 

requirements for obtaining permission by parents or guardians and for 

assent by children. Among other provisions this section provided that 

in some cases an IRB could determine that a child was not capable of 

assent, in light of their age, maturity, or psychological state. If so, 

the inability of the investigator to obtain assent could not be a basis 

for excluding a child from research that held out the prospect of 

benefit to the child. The proposal also allowed an IRB to waive assent 

on the same grounds that it could waive informed consent by adults (see 

Sec. 26.116(d)). This proposed section also granted to IRBs discretion 

to determine that, in some cases, it would not be reasonable to require 

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the permission of a child's parent or guardian because, for example, 

the adult abused or neglected the child. In such instances, this 

section authorizes the IRB to approve an alternative mechanism of 

obtaining permission from an adult who would better represent the 

child's interests.

 As noted above, most of the proposed rule text came directly from 

the existing HHS regulations establishing additional protections. The 

Agency did propose a few revisions. In addition to minor editorial 

changes necessary to reflect that the proposed rule would be 

implemented by EPA, the most notable substantive changes were: (1) 

Defining a child as a person under the age of 18 years, (2) choosing 

not to propose adopting the provisions in 45 CFR 46.406 and 46.407, and 

(3) choosing not to propose adopting the provisions in 45 CFR 46.409.

 In 45 CFR 46.406 and 46.407, HHS establishes special standards and 

procedures for approving in exceptional cases research which does not 

meet the standards of 45 CFR 46.404 or 46.405--i.e., research which 

poses more than minimal risk to the children in the study but which 

offers no prospect of direct benefit to them. EPA considers such 

provisions both inappropriate and unnecessary for research with 

environmental substances, particularly observational studies. 

Consistent with the choice not to adopt those two sections, EPA chose 

to omit 45 CFR 46.409 of the HHS rule as well, since it specifies 

measures which are required only when the children in a study approved 

under the authority of 45 CFR 46.406 or 46.407 were wards of the state.

B. Public Comment

 Most comments on proposed subparts B and D addressed the proposed

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prohibitions on research involving intentional exposure of pregnant 

women, fetuses, or children. These comments are addressed in Unit VIII. 

This unit covers the public comments which addressed the adoption of 

additional protections for pregnant women and children as subjects in 

observational research conducted or supported by EPA.

 Comment: Some commenters supported EPA's proposal to adopt only 

some of the provisions of the HHS regulations in 45 CFR part 46, 

subparts B and D that create additional protections for pregnant women, 

fetuses, and children in observational research. Other comments 

recommended the Agency adopt these HHS regulations in their entirety. 

By doing so, EPA and HHS would follow consistent approaches. These 

comments also noted HHS has operated under these regulations for over 

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20 years without significant debate over their ethical adequacy.

 Response: The Agency agrees there is considerable value in 

employing consistent approaches in similar areas of research. 

Consistency makes it easier for affected researchers to comply and 

helps to build a broader consensus on what constitutes ethical 

behavior. Accordingly, EPA is adopting large parts of the HHS 

regulations from 45 CFR part 46, subparts B and D essentially verbatim. 

The Agency, however, is not promulgating all of these HHS rules 

because, in EPA's judgment, the omitted provisions would never apply to 

observational research. Specifically, EPA has not adopted the following 

sections from the HHS rules: 45 CFR 46.205, 46.207, 46.406, 46.407, and 

46.409. These sections would apply only when proposed research would 

present more than a minimal risk to the subjects and would have no 

prospect for direct benefit to the subjects. EPA simply cannot conceive 

of observational research that could not meet such criteria, and in the 

unlikely event that an investigator proposed such research, EPA would 

not expect to approve it.

 Comment: Some comments objected to the inclusion in the proposed 

rule of provisions that allowed observational research if an IRB judged 

the potential risks to subjects as ``minimal.'' These comments claimed 

that the concept of ``minimal risk'' was not adequately defined and 

potentially subject to abuse. These comments recommended that no 

observational research be allowed unless there was ``no risk'' to 

subjects. (Many of these comments further argued that no human research 

was totally risk free and therefore no human research should be allowed.)

 Response: The Common Rule and subpart D of the final rule define 

minimal risk as ``the probability and magnitude of harm or discomfort 

anticipated in the research are not greater in and of themselves than 

those ordinarily encountered in daily life or during the performance of 

routine physical or psychological examinations or tests.'' 40 CFR 

26.402. The Agency agrees that this definition leaves room for the 

exercise of expert judgment by a person reviewing a proposed protocol, 

and that different people may disagree on whether a particular research 

technique poses minimal risk. Nonetheless, this definition has been 

part of the Common Rule since 1991, and this provision has been in the 

HHS regulations since 1983. Based on its long history of application 

and the benefits of consistency with HHS, EPA has decided to retain 

proposed Sec. 26.404 without change. In addition, EPA thinks the 

prospects for abuse are extremely small since all research allowed 

using these criteria would need approval both from a local IRB and from 

EPA's Human Subjects Research Review Official (HSRRO).

 Comment: Some comments objected to EPA's proposal to adopt 45 CFR 

46.405, which would allow an IRB to approve observational research with 

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children if the IRB found the risks to children were ``greater than 

minimal,'' but presented ``the prospect of direct benefits to the 

individual subjects.'' These comments argued that observational 

research would never meet such criteria.

 Response: EPA rarely expects observational research to pose 

``greater than minimal risk.'' By its very nature, observational 

research leaves all decisions regarding exposure to the subjects. Thus, 

an investigator ordinarily just measures and records information about 

exposure and effects that the subjects, in their own discretion, choose 

to experience. EPA, nonetheless, believes its final rule should include 

a provision comparable to 45 CFR 46.405. Although unlikely, EPA thinks 

some measurement techniques used in observational research could 

theoretically involve more than minimal risk to subjects and therefore 

would fail to meet the criteria for approval under Sec. 26.304 of the 

final rule. Consistent with the HHS approach in 45 CFR 46.205, EPA 

believes that, if such risks exist, the research should not be allowed 

unless an IRB finds that the ``greater than minimal risks'' were 

justified by the prospect of direct benefits to the subjects. Because 

EPA does not want to prevent potentially valuable research that requires 

non-standard measurement techniques, EPA has adopted in Sec. 26.305 of 

its final rule the content of the provision of the HHS regulations.

 Comment: Although most comments agreed with EPA's proposal to 

define child as a person younger than 18 years old, some comments 

recommended using the text in the HHS rule, which defers to the legal 

standards defining children and adults in the local jurisdictions where 

the research is conducted. These comments pointed out that EPA's 

proposed definition could lead to the exclusion of an emancipated 

minor, typically an older teenager who has married. Excluding these 

potential subjects could deny them the benefits of participating in the 

research simply because of their age. Other comments favored raising 

the age to 21 years old because the human body, particularly the brain, 

continues to mature after the age of 17 years and research might 

adversely affect 18-21 year olds during this developmental period of 

potentially increased sensitivity.

 Response: EPA is not persuaded that the potential increased 

sensitivity of people between the ages of 18 and 20 years to some 

effects warrants defining a child as a person under 21 years old. The 

Agency notes that such sensitivity is not likely to exist for all 

chemicals. If, however, a proposal to perform observational research 

did raise concerns about an increased sensitivity of subjects, those 

concerns can be addressed on a case-by-case basis by the IRB and EPA's 

HSRRO. It is not necessary, in EPA's view, to deal with these 

theoretical concerns by redefining who is a child.

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 While EPA sees benefit to using a definition consistent with HHS, 

the Agency is concerned about the added complexity for investigators 

who are conducting research in multiple jurisdictions. In addition, EPA 

questions whether youngsters no older than 15 years, as an adult is 

defined in some states, are sufficiently mature to make decisions about 

whether to volunteer to participate in human research. In light of 

these concerns and the broad support for EPA's proposal, EPA has 

decided to retain the proposed definition of child as a person younger 

than 18 years old.

 Comment: Some comments found unclear the provisions in proposed 

subpart D allowing the waiver, under narrow conditions, of the 

requirements for permission of parents and assent of children to 

participate in observational research conducted or supported by EPA. 

Other comments objected to these proposed provisions asserting that 

children should never become subjects

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in research without their parent's permission and without their own 

assent. Still other commenters asserted that the rule should not allow 

parents to permit their children's participation in human research 

unless the children will benefit directly from doing so.

 Response: EPA's final rule has retained the proposed rule text, 

with only minor changes. EPA believes that these provisions give the 

Agency needed flexibility to protect the interests of the child when 

either the child or the parent(s) cannot. For example, the proposal 

would allow waiver of assent when the child is too young or otherwise 

unable to make responsible choices, and where the child's refusal to 

assent would cause his or her exclusion from research that provides a 

direct benefit. The proposal also allows waiver of parental permission 

from a parent who abuses or neglects their children; clearly such 

parents do not have adequate concern for the child's welfare to make 

decisions about whether the child should participate in research. (This 

provision strengthening the protections for children was widely 

misinterpreted as indicating EPA's intention to authorize or conduct 

research involving intentional exposure of mentally retarded, abused, 

and neglected children.)

 To clarify the operation of the provision allowing waiver of 

parental permission, EPA has modified the text to make clear that any 

alternative procedure must be ``equivalent'' to the process of parental 

permission. By ``equivalent'' EPA means that the child's participation 

must be approved by an adult who by position or relationship puts the 

child's well being foremost and who will exercise sufficient diligence 

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to make a considered and informed decision. Otherwise, EPA has decided 

not to accept the changes recommended by the commenters. EPA relies on 

the facts that the concepts in this provision comport with the 

generally accepted legal principles defining the scope of parental 

authority and that HHS has operated successfully under these provisions 

for over 20 years. Finally, as noted above, EPA sees considerable 

benefit from using an approach consistent with that of HHS.

C. The Final Rule

 Subpart C of the Agency's final rule retains most of the rule text 

appearing in proposed subpart B. The most significant changes from the 

proposal are the isolation in subparts B and L of the prohibition of 

new research proposed at Sec. 26.220, and removal to subpart Q of the 

restriction on EPA reliance on completed research proposed at Sec. 

26.221. To make the applicability of the remaining provisions of 

subpart C as clear as possible, EPA has revised the titles of the 

subpart and of Sec. 26.301, and reworded the text to emphasize 

repeatedly that these provisions apply only to observational research, 

and only to research conducted or supported by EPA. In the final rule 

observational research is defined in Sec. 26.302 as research that does 

not involve intentional exposure of research subjects. In addition, EPA 

has deleted from the final rule proposed Sec. 26.205 (which referenced 

45 CFR 46.205) because its provisions would never apply to the kinds of 

observational research that this subpart permits.

 Subpart D of the Agency's final rule retains most of the rule text 

appearing in proposed subpart D. The most significant change from the 

proposal is the isolation in subparts B and L of the prohibition of new 

research proposed at Sec. 26.420, and the removal to subpart Q of the 

restriction on EPA reliance on completed research proposed at Sec. 

26.421. To make the applicability of the remaining provisions of 

subpart D as clear as possible, EPA has revised the titles of the 

subpart and some of its sections, and reworded the text to emphasize 

repeatedly that these provisions apply only to observational research, 

not involving any intentional exposure to any substance, and only to 

research conducted or supported by EPA.

 In addition, EPA has made the following revisions in subpart D to 

the proposed rule text:

 ? In Sec. 26.401(a)(2), EPA clarified that the authority to 

waive requirements related only to the sections of subpart D and did 

not confer broad authority on the Agency to waive any requirement in 

any other subpart.

 ? In Sec. 26.402(a) and (f), EPA added definitions of 

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Administrator and observational research.

 ? In Sec. 26.403, the text from 45 CFR 46.403 of the HHS 

regulation is incorporated explicitly, rather than by reference as was 

done in the proposal.

 ? In Sec. 26.405, EPA reordered the text to make its 

applicability clearer. The revision was not intended to make a 

substantive change.

 ? In Sec. 26.406(c), EPA has revised the text to clarify 

that if an IRB determines that it is not appropriate to require the 

permission of the parent or guardian for a child to participate in a 

study, the IRB must approve an equivalent, alternative procedure for 

obtaining permission from another adult who will appropriately 

represent the interests of the child.

IX. Additional Protections Pertaining to Research Involving Prisoners 

Involved as Subjects

 Summary: Research with prisoners conducted or supported by EPA is 

subject to basic ethical requirements in the Common Rule; the parallel 

requirements in subpart K of the final rule apply to the conduct of 

research by third parties involving intentional dosing of prisoners, if 

the research is intended to be submitted under the pesticide laws. The 

Agency has not reached a final position on either the need or the most 

appropriate form for any additional protections for prisoners beyond 

these basic requirements. The Agency may, in a future action, issue a 

final rule to address the aspects of its September 12, 2005, proposal 

that relate to establishing standards for the ethical protections of 

imprisoned subjects of research. Unit IX.A. summarizes EPA's proposal 

and Unit IX.B. explains EPA's decision not to adopt additional 

protections for prisoners in this final rule.

A. The Proposed Rule

 In its September 12, 2005, proposal, EPA noted that HHS has 

promulgated regulations that provide additional protections for 

prisoners in research conducted or supported by HHS, codified at 45 CFR 

part 46, subpart C. The proposal explained that EPA had decided not to 

propose adoption of the HHS subpart C rules for a number of reasons, 

among them that HHS and its advisory committee, the Secretary's 

Advisory Committee on Human Research Protections (SACHRP), were 

actively considering revisions to the HHS subpart C, unchanged since 

its adoption in 1978.

 In addition, the proposal noted that EPA has never conducted or 

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supported any human studies with prisoner subjects, and has no 

intention to do so in the future. It also noted that 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. Finally, the proposal noted if either EPA or third parties 

should consider performing studies with prisoner subjects, such 

research would be subject to the requirements of the Common Rule and 

EPA's final rule.

B. The Final Rule

 All provisions of the Common Rule would apply to any EPA research 

with imprisoned subjects. In particular, any such research would be 

subject to the

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Common Rule requirements for IRB review and approval and written 

informed consent. Sections 26.111(a)(3) and 26.111(b) require an IRB to 

determine that selection of research subjects is equitable and free 

from coercion or undue influence, and note that particular attention to 

these aspects of subject selection is needed when prisoners are 

involved. Implicit in other sections, e.g., Sec. Sec. 26.102(i), 

26.116, and 26.117, is the concept that research must treat each subject 

involved ethically, taking into account their particular circumstances.

 In addition, the prohibitions in subpart B and the additional 

protections in subparts C and D would also apply to imprisoned pregnant 

women or children under the age of 18 years if EPA were to conduct 

observational research with subjects from those populations.

 EPA does not expect third parties to submit to EPA any new studies 

on prisoners. In the unlikely event that a third party wished to 

conduct or sponsor research involving intentional exposure of prisoners 

for submission under the pesticide laws, it would be covered under 

subparts K and L. Unless prohibited by subpart L, such research would 

have to meet the requirements of subpart K, which parallel the 

provisions of the Common Rule. In addition, an investigator would also 

be required to submit for EPA and HSRB review a proposal describing in 

detail how the study would be carried out in an ethical manner. Should 

such a study proposal involve prisoners, it would receive extremely 

close review, and EPA almost certainly would not approve it, absent a 

compelling justification.

 The Agency has concluded that the requirements of this final rule 

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should provide adequate protections for prisoners, especially since 

there are not likely to be any such studies. Nonetheless, the Agency is 

still considering the recommendation from public comments to prohibit 

both EPA and third-parties to conduct certain types of research with 

prisoners. EPA may, at a later date, adopt such a provision, if it 

determines that such a measure is needed and cannot be effectuated 

under existing regulations. In addition, EPA will continue to monitor 

the work of the SACHRP committee on prisoner protections, and will 

reconsider adopting additional protections for prisoners as subjects of 

research when its recommendations are known.

X. Subpart M--Requirements for Submission of Information on the Ethical 

Conduct of Completed Human Research

 Summary: Subpart M of the final rule requires third parties who 

submit the results of completed human research to EPA for consideration 

under the pesticide laws to document the ethical conduct of that 

research. Subpart M specifies the range of information required, 

including documentation of any IRB reviews, documentation of informed 

consent by subjects, and other information required to support thirdparty proposals to conduct new human research for pesticides involving 

intentional exposure of non-pregnant adults. The final rule directs 

submitters to provide this information about completed research to the 

extent it is available, and if any of it is not available, to describe 

the efforts made to obtain it. Unit X.A. describes the proposed rule, 

Unit X.B. addresses the major public comments, and Unit X.C. discusses 

the final rule.

A. The Proposed Rule

 In the September 12 proposal, Sec. 26.124(c) required ``any person 

who submits to EPA data derived from human research covered by this 

subpart'' to provide information documenting compliance with the 

requirements of the subpart. The required information included records 

required of the IRBs that approved the research; copies of sample 

informed consent documents; and copies of correspondence between EPA 

and the investigator or sponsor about the proposed protocol.

 In addition, although the proposal contained no provision directed 

at data submitters requiring documentation of ethical conduct of 

completed research, the proposal indicated that EPA would not rely on 

the results of research conducted after the effective date of the final 

rule unless the Agency had ``adequate information to determine the 

research was conducted in a manner that substantially complied'' with 

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the requirements of the rule.

B. Public Comments

 EPA received no major public comments on the proposed provisions 

addressing the content of reports of completed human research.

C. The Final Rule

 EPA has created a new subpart M that requires people who submit 

data from completed human research to EPA to accompany that submission 

with information documenting the ethical conduct of the research. The 

final rule requires that reports on completed human research contain 

essentially the same range of information concerning the ethical 

conduct of the research as would have been required by the proposal.

 The final rule, however, differs from the proposal in several 

respects. First, the final rule clarifies that it applies only to 

reports of completed human research submitted after the effective date 

of the final rule.

 Second, EPA has broadened the scope of the proposed requirement to 

apply to reports on all types of human research submitted to the Agency 

for consideration under the pesticide laws, FIFRA and FFDCA. This 

provision of the final rule is broader than the proposal in two ways: 

It applies to all persons who submit data, whether or not they 

developed the data with the intent to provide it to EPA; and it applies 

to all types of human research, not only to research involving 

intentional exposure of human subjects. The Agency decided to extend 

the scope of this reporting requirement because it expects to make 

ethical assessments of all human research it receives under the 

pesticide laws, irrespective of who did it, who submitted it, or what 

type of human research was involved. Obtaining the information 

specified by subpart M as part of the initial submission will improve 

the efficiency and quality of such ethical assessments. Under FIFRA 

sections 3(c)(2)(A) and 3(c)(2)(B), EPA has the authority to require 

information necessary to support both applications for new registration 

and for continued registration of a pesticide. Since the Agency regards 

information about the ethical conduct of human research as relevant to 

the assessment of the acceptability of such research, the Agency 

concludes that the reporting provision is consistent with these 

sections of FIFRA.

 Finally, the Agency made two changes to minimize the burden of 

reporting information on the ethical conduct of completed research. 

First, the final rule provides that information need not be resubmitted 

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if it has previously been provided to the Agency, for example as part 

of the submission required for protocol review under Sec. 26.1125. 

Second, recognizing that not all of the information specified by 

subpart M may be available to the data submitter in some cases--for 

example, if the research were conducted in the past, or if the 

submitter did not conduct the study, Sec. 26.1303 states that the 

specified information should be provided ``to the extent available'' 

and asks the submitter to describe the efforts made to obtain

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information which he or she was unable to provide.

XI. Subpart O--Administrative Actions for Noncompliance

 Summary: Subpart O contains provisions, adapted from similar 

regulations issued by FDA, that describe the range of administrative 

actions EPA could take to address noncompliance by third parties with 

the requirements of part 26. These actions include: Withdrawal or 

suspension of a research institution's Federal wide assurance; 

disqualification of an institution or an IRB; debarment; and public 

censure. This subpart describes procedures EPA would follow in reaching 

a decision to take any of these administrative actions. Other than the 

addition of a new section explaining the scope of research to which 

these actions could be applied, the final rule is unchanged from the 

proposal.

A. The Proposed Rule

 In proposed subpart E the Agency identified a number of specific 

administrative actions that could be taken, as circumstances warrant, 

against any person or organization that failed to comply with 

requirements of the rule. These actions included: (1) Withdrawal or 

suspension of a research institution's FWA; (2) disqualification of a 

research institution or its IRB; (3) debarment of an entity from 

receiving federal funds for research; or (4) public censure--presenting 

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. The provisions in proposed Sec. Sec. 

26.501 through 26.504 and Sec. 26.506 closely follow FDA's existing 

regulations in 21 CFR 56.120 through 56.124.

B. Public Comment

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 EPA received only a few public comments on this subpart, most 

supporting the appropriate use of the actions identified in proposed 

subpart E to promote compliance. EPA also agreed with several 

commenters that refusal to rely on completed research provided the 

strongest incentives for investigators to follow the new requirements. 

Other major comments, discussed below, addressed the operation of EPA's 

compliance oversight program.

 Comment: One comment complained that the proposal gives EPA 

discretion not to impose any of these sanctions at all, even for the 

most egregiously unethical research, and argued that only mandatory 

sanctions could effectively deter unethical human research. Another 

commenter recommended that EPA explain what types of actions it would 

apply to different types of violations.

 Response: EPA generally believes that enforcement programs work 

best when they employ a system of graduated penalties that increase as 

the gravity of the violation increases. Such an approach requires the 

exercise of discretion, but that discretion should not operate entirely 

free from constraints. Accordingly, the Agency intends to establish 

policies to guide its exercise of discretion about the imposition of 

the sanctions. Although EPA does not regard such policies or penalty 

structure as appropriate for inclusion in this rulemaking, the Agency 

does intend to explain in guidance how it will encourage compliance 

with the new requirements in the final rule.

 Comment: Several comments urged EPA to adopt procedures similar to 

those of FDA by which it would decide whether to disqualify an 

institution for violating the requirement of the final rule.

 Response: EPA agrees it should have a procedure for deciding 

whether to disqualify an IRB or institution, and that it may be 

appropriate to establish such procedures through rulemaking. EPA will 

further consider adopting procedures similar to those used by FDA and 

promulgated in 21 CFR part 16, but has decided not to adopt them at 

this time.

C. The Final Rule

 Subpart O of the final rule is substantively unchanged from subpart 

E of the proposal. EPA has added a new Sec. 26.1501 entitled ``To what 

does this subpart apply?'' which clarifies that EPA will consider using 

the administrative actions identified in the subpart only to address 

instances of non-compliance with the requirements of the new rule 

occurring after the new rule takes effect. Thus, actions debarring an 

institution from receiving federal funds for research or disqualifying 

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an institution from performing research covered by subpart K could not 

be taken on the basis of events that happened before the final rule 

becomes effective. The Agency notes, however, that actions which 

violate the requirements of FIFRA section 12(a)(2)(P) would be subject 

to civil or criminal penalties if they happened at any time after that 

provision became law in 1972. The Agency also made minor wording 

changes in Sec. 26.1502 of the final rule to reflect FIFRA terminology 

and enforcement practices.

 EPA recognizes the importance of an effective program to ensure 

compliance with the requirements of the final rule. The office of the 

Agency's Human Subjects Research Review Official (HSRRO) will have 

responsibility for ensuring compliance with the new rule. The HSRRO 

will also have responsibility for managing the development of any new 

guidelines needed to explain or implement the provisions of the final rule.

 The Agency thinks that one of the most important ways to encourage 

and monitor compliance is through the review of proposals for new 

research before it is conducted, as required by the final rule at Sec. 

26.1125. Once such studies are initiated, EPA's Office of Enforcement 

and Compliance Assurance, through its laboratory audit program, can 

monitor facilities that conduct human research covered by the rule.

 EPA inspectors conduct inspections and audit studies under EPA's 

good laboratory practice (GLP) regulations. As stated in the GLP 

regulations (40 CFR 160.15), EPA will not consider reliable for 

purposes of supporting an application for a research or marketing 

permit any data developed by a testing facility or sponsor that refuses 

to permit such inspection. In addition, the recordkeeping provisions of 

FIFRA which cover records of any tests conducted on human beings and 

records containing research data relating to registered pesticides 

including all test reports submitted to the Agency in support of 

registration or in support of a tolerance petition also apply to 

studies conducted under this rule.

 Finally, the close examination of reports on completed research 

represents another important part of the compliance program. EPA will 

train scientists who conduct, approve, or review human research about 

the provisions of the final rule so they can identify possible 

violations. Throughout all of these efforts, the Agency hopes to work 

with the HHS Office for Human Research Protections and FDA, to ensure 

that sponsors, investigators, and IRBs understand and fulfill their 

responsibilities under the final rule.

XII. Subpart P--Review of Proposed and Completed Human Studies

 Summary: This subpart of the final rule provides that EPA will 

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review all proposals by third parties to conduct research covered by 

subpart K, i.e., all research involving the intentional exposure of 

human subjects, if the research is intended for submission to EPA under 

the pesticide laws. The subpart also requires EPA to establish

[[Page 6156]]

an independent group of experts, referred to as the Human Studies 

Review Board (HSRB), to assist EPA in evaluating such proposals. In 

addition, the subpart requires that EPA review reports submitted by 

third parties on completed human research and, if EPA decides to rely 

on information from such research in an action under the pesticide 

laws, to submit the results of its assessment of the research to the 

HSRB. The HSRB would perform science and ethics reviews of proposals 

from third parties to conduct specified types of human research and of 

the results of specified types of human research if EPA intended to 

rely on the information in its decision-making under the pesticide 

laws. Further, when HSRB review is not required by the final rule, EPA 

would nonetheless retain discretion to ask the HSRB to review studies 

or to offer advice on other issues.

 Finally, although not required by the final rule, EPA has decided 

to establish the HSRB under the authority of the Federal Advisory 

Committee Act. By operating as a federal advisory committee, the HSRB 

will be required to use procedures that ensure transparency in its 

operation and that afford opportunities for the public to express their 

views on issues being considered by the HSRB.

A. The Proposed Rule

 Proposed Sec. 26.124 would have required third parties to submit 

to EPA detailed information concerning any proposed new research 

covered by the new rule at least 90 days before initiating of the 

research. The proposal would also have established a HSRB to address in 

an integrated fashion the scientific and ethical issues raised by human 

research covered by the proposal. Specifically, the Agency proposed to 

convene a small group of appropriately qualified experts and to enlist 

their support in reviewing covered research proposals, i.e., thirdparty research involving intentional exposure of human subjects, when 

the results of such research are intended to be submitted to EPA under 

the pesticide laws.

 The same section also provided that EPA would review the results of 

completed research covered by the rule. This section of the proposal 

also stated that, after completing its initial staff assessment of a 

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research proposal or a completed study if EPA intended to rely on the 

results in its decision-making under the pesticide laws, the Agency 

would send its review and supporting materials concerning the study to 

the HSRB for further review and comment.

 EPA's proposal did not specify any details of how the HSRB would 

function, other than to state that the members would not be EPA 

employees, would meet the conflict of interest standards applying to 

special government employees, and would have expertise appropriate for 

the review of human research. The Agency invited public comment on 

whether the final rule should specify the functions of the HSRB. The 

preamble also indicated that, as recommended by the NAS, EPA intended 

to reexamine the functions of the HSRB after 5 years.

B. Public Comment

 EPA received a great many public comments on its proposal to 

require submission of proposed protocols and other information relating 

to proposed new human research and to submit its assessments of the 

proposed new human research to a new HSRB for further review. The 

Agency's Response to Comments document, in the docket for this action, 

provides a full response to these comments. EPA agrees with comments 

that stressed the importance of having the HSRB use the substantive 

standards contained in EPA's final rule when reviewing the ethics of 

proposed and completed human research. As an entity intended to help 

the Agency make ethical and scientific judgments, the HSRB will use the 

provisions of this final rule in the formulation of their advice. The 

major issues raised by the comments are discussed below under three 

headings: HSRB procedures; HSRB membership and qualifications; and the 

scope of research subject to HSRB review.

 1. HSRB procedures. The Agency notes that most, if not all, 

comments on the HSRB implicitly accepted EPA's proposal that HSRB 

review of proposed new research would occur following its review and 

approval by a local IRB and after EPA developed its review.

 Comment: Many comments addressed whether EPA should charter the 

HSRB under the Federal Advisory Committee Act (FACA). Environmental and 

public health advocacy groups favored this approach because it would 

assure the use of procedures that provided opportunities for public 

comment and transparency. Others, primarily commenters affiliated with 

the pesticide industry, objected on the grounds that a FACA-chartered 

HSRB would be inefficient, and the ensuing delays would affect Agency 

decision-making, particularly about new products. These comments 

recommended either staffing the HSRB only with EPA employees or relying 

on the HHS Office for Human Research Protections (OHRP) for the kinds 

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of reviews described in the proposed rule. Industry commenters also 

expressed concern that a FACA process might lead to public disclosure 

of CBI.

 Response: EPA has decided to charter the HSRB under FACA. While 

operating under the requirements for advisory committees adds some 

procedural steps to the review process, it is not apparent, given the 

intensity of public concern about the use of data from human research, 

that a FACA process would necessarily take longer than a process 

involving internal EPA review. More important, in EPA's view, the 

benefits of the transparency and opportunities for public participation 

outweigh any potential delays. Given the difficult nature of the 

issues, EPA sees significant advantages in ensuring that all the 

considerations influencing the Agency's final position have been publicly 

identified, carefully weighed, and commented on by independent experts.

 The Agency recognizes the need to manage aggressively to ensure 

both the HSRB's and its own review processes operate efficiently. As 

part of its commitment to effective management, the Agency intends to 

acknowledge receipt of new research proposals and to respond promptly 

with a projected timeline for completing EPA and HSRB review. In 

addition, upon completion of its internal reviews, EPA will send copies 

to the submitter of the protocol and the schedule for HSRB review. EPA 

expects that it will continue to meet the statutory deadlines for 

reaching decisions on new applications for pesticide registrations, 

even if HSRB review is required.

 Finally, the Agency notes that under FIFRA and FACA, EPA follows 

procedures designed to protect CBI from disclosure. Whenever EPA 

provides CBI to a federal advisory committee, that information is not 

placed in a public docket or discussed in a public meeting, and special 

steps are taken to maintain its confidentiality.

 Comment: Many comments asked EPA to clarify in the final rule the 

procedures that the HSRB would use. In particular, many suggested that 

the rule require that the HSRB meetings afford an opportunity for 

public comment.

 Response: The Agency believes that, at this early stage, the HSRB 

should have the flexibility to adopt procedures which best allow it to 

meet its responsibilities. Since the HSRB will function as a federal 

advisory committee, FACA will dictate many of its procedures, including 

key procedures relating to transparency and public participation. Since 

these were

[[Page 6157]]

the areas of greatest concern for most commenters, EPA believes that 

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its decision to establish the HSRB under FACA adequately addresses 

these comments.

 Comment: Some comments complained that the proposed rule did not 

vest the HSRB with authority to disapprove proposed new research or EPA 

decisions to rely on the results of completed human studies. Other 

comments supported giving the HSRB only an advisory role.

 Response: EPA believes the HSRB should have an advisory role. The 

decision to disapprove proposed new research or to decide whether or 

not to rely on the results of completed studies is inherently 

governmental. The Agency cannot legally confer authority to make such 

decisions on an advisory committee. The Agency notes, however, that it 

expects to give considerable weight to the advice of the HSRB.

 2. HSRB membership and qualifications.

 Comment: Many comments emphasized that the HSRB must be 

independent, that its members must have no conflicts of interest, 

including any financial relationships with the pesticide industry.

 Response: EPA agrees. Chartering the HSRB as a federal advisory 

committee to provide expert advice means that all candidates for 

membership on the HSRB must meet the federal requirements governing 

conflicts of interest. Although other requirements relating to the 

operation of the HSRB as an advisory committee are not specified in the 

final rule, EPA did retain in the final rule a requirement that members 

have no conflicts of interest. Specifically, the final rule provides 

that HSRB members must ``meet the ethics and other requirements for 

special government employees.'' See Sec. 26.1603(a) of the regulatory text.

 Comment: Several comments stressed the importance of having HSRB 

members with sufficient expertise in the substantive disciplines raised 

by the types of human research covered under the rule. They 

specifically identified the disciplines of clinical toxicology, 

research ethics and the Common Rule, and public health. Comments also 

noted that the Agency might need to supplement the HSRB to obtain 

expertise to address particular types of research covered by the rule.

 Response: EPA generally agrees with the comment and on January 3, 

2006, issued a Federal Register Notice inviting nominations of experts 

to serve on the HSRB (71 FR 116). The Notice described the following 

areas of expertise: Bioethics, human toxicology, biostatistics, and 

human risk assessment. Under FACA, EPA has the authority to appoint 

consultants to the HSRB who can provide additional expertise when needed.

 Comment: Several comments recommended that the members of the HSRB 

include non-scientists who are members of the community and who could 

represent the views of special populations that could be the focus of 

proposed human research.

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expert community members on the HSRB. However, under FACA, the public, 

including non-expert community representatives have opportunities to 

provide both written and oral public comment to the HSRB. In addition, 

the HSRB has the flexibility under FACA to ask representatives of 

community groups to make presentations to the committee on specific 

topics. EPA also notes that, before a proposal reaches the HSRB, an IRB 

will have reviewed and approved it. Such IRBs are required by the new 

rules (Sec. 26.1107), to include people familiar with the concerns 

arising in research with special populations. Thus, EPA expects in most 

cases that the concerns of community-based representatives will be a 

part of the information before the HSRB.

 3. Scope of research subject to HSRB review.

 Comment: Some comments favored expanding the scope of studies 

reviewed by the HSRB to include all first-party and second-party 

research, as well as third-party research; all types of human research, 

not only research involving intentional exposure of human subjects; 

studies performed with any substance regulated by EPA, not only studies 

with pesticides; and all human research considered by EPA, not only the 

completed studies on which EPA intends to rely.

 Response: EPA agrees that it may sometimes be appropriate to obtain 

HSRB review of some of these types of studies. The final rule gives EPA 

discretion to seek the advice of the HSRB on additional types of 

studies beyond those for which HSRB review is required. For the reasons 

explained earlier, however, the Agency has decided not to expand the 

scope of subpart K now, and therefore sees no reason to expand the 

scope of required EPA or HSRB review of proposed new research. 

Similarly, the Agency has decided not to extend without further 

analysis and public discussion the ethical framework in subpart Q to 

decisions made under statutory authorities other than FIFRA or FFDCA. 

It would make no sense to require the HSRB to review human research 

that fell outside the scope of the other substantive provisions of the 

rule. Finally, EPA has decided that it would not be an efficient use of 

resources to require HSRB review of human research that the Agency had 

decided not to rely on, typically because it falls short of 

contemporary standards of scientific validity. The Agency does not 

anticipate that the HSRB would often disagree with such conclusions, 

and therefore EPA will use its discretion to determine whether such 

scientific judgments warrant HSRB review.

 Comment: Many comments generally supported the proposed review of 

new research and completed research reports by both EPA staff and the 

HSRB, at least in some cases. A number of commenters, however, 

suggested ways to narrow the scope of the reviews performed by the 

HSRB, including: (1) By having the HSRB review only studies intended to 

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identify or measure toxic effects, (2) by exempting from HSRB review 

consumer acceptance studies, insect repellent efficacy tests, or other 

``product-in-use'' studies; (3) by exempting from HSRB review proposals 

to employ protocols for ``routine'' exposures or other studies that 

follow established EPA guidelines; and (4) by exempting from HSRB 

review the results of research which the HSRB had previously reviewed 

and approved as a proposal, unless the investigator failed to follow 

the approved protocol. Finally, some comments recommended that the HSRB 

be restricted to considering ethical issues, but not scientific issues.

 Response: EPA disagrees with the comments suggesting a narrowed 

scope for HSRB review. EPA agrees that each of the categories described 

above may contain at least some studies that present no difficult 

scientific or ethical issues. To the extent EPA's review indicates that 

a study presents no difficult science or ethics issues, the Agency 

would expect the HSRB to agree and quickly conclude its review. But any 

research involving intentional exposure may present risks to individual 

human subjects greater than those they would receive in their normal 

activities, and therefore warrants careful examination, even if the 

purpose of the study is not to identify or measure toxic effects. 

Similarly, while EPA anticipates that many consumer acceptance tests, 

insect repellent efficacy tests, and other ``product-in-use'' studies 

will raise no difficult scientific or ethical issues, the Agency has 

relatively little experience with assessing explicitly the ethical 

attributes of such research. Therefore the Agency thinks it would be 

imprudent to exclude

[[Page 6158]]

HSRB review of these studies. EPA likewise recognizes that following 

established guidelines may reduce the chances of scientific 

deficiencies in a study, but EPA's guidelines do not address the full 

range of potential ethical issues that should be considered on a caseby-case basis. Finally, EPA believes that even if a study follows an 

established protocol, unanticipated scientific and ethical issues may 

arise that will warrant expert advice.

C. The Final Rule

 As a result of the reorganization of the final rule, all provisions 

relating to EPA and HSRB review of proposals for new, third-party 

research or reports of completed studies, or to the establishment of 

the HSRB, now appear in subpart P.

 The final rule reflects one significant change from the proposal. 

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Under the final rule, the HSRB will review all research involving 

intentional exposure conducted after the effective date of the final 

rule, as well as all research involving intentional exposure performed 

before the rule takes effect, if the purpose of the research was to 

identify or measure a toxic effect. But the final rule grants to the 

Agency discretion to decide whether studies performed before the 

effective date of the final rule that do not measure toxicity should 

undergo HSRB review.

 After publishing the proposal, EPA examined how the proposal would 

affect its plans to complete tolerance reassessment by August 2006, as 

required by the 1996 FQPA amendments to FFDCA. The Agency reviewed the 

existing toxicity and exposure databases for upcoming tolerance 

reassessment decisions and determined that as many as several hundred 

studies relevant to the risk assessments for these actions appeared to 

meet the definition of ``research involving intentional exposure of 

human subjects.'' Only a relative few of these intentional exposure 

studies measure the toxicity of a pesticide; the great majority of them 

measure the levels of potential human exposure resulting from pesticide 

use, the efficacy of insect repellents, or the absorption, 

distribution, metabolism, and excretion of pesticides.

 Since the enactment of the Food Quality Protection Act in 1996 EPA 

has relied on many of these non-toxicity, intentional-exposure human 

studies in its registration and reregistration decisions. Moreover, the 

Agency has afforded multiple opportunities for public comment on 

several hundred draft and final Reregistration Eligibility Decision 

(RED) documents and Interim RED (IRED) documents, but has never 

received any public comment on a RED or IRED concerning the ethics of 

intentional-exposure human studies other than a toxicity study. Taking 

all of these non-toxicity, intentional-exposure studies to the HSRB 

would significantly increase its workload and expand the number of 

pending regulatory decisions affected. Accordingly, EPA has decided 

that while the final rule should require the Agency to send to the HSRB 

all completed toxicity studies on which it intends to rely, it need not 

require all non-toxicity studies in its existing databases to undergo 

HSRB review. Thus, under the final rule, the Agency will retain the 

discretion to submit additional types of old studies to the HSRB, and 

will consider public comments on its upcoming pesticide actions for 

tolerance reassessment in deciding which of the non-toxicity studies 

raise significant ethical or scientific issues warranting HSRB review.

 In addition, subpart P in the final rule reflects a few other minor 

revisions to the proposal. The provisions governing Agency review of 

proposals for new third-party research were placed in subpart P in 

preference to subpart K, so that subpart P would apply only to EPA, and 

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subpart K would apply only to regulated third parties.

 To help ensure effective implementation of the final rule, EPA has 

made several administrative decisions affecting the HSRB. Most 

important, the Agency has decided to establish the HSRB as a separately 

chartered advisory committee under the Federal Advisory Committees Act 

(FACA). FACA requires the HSRB, as a federal advisory committee, to 

follow certain basic procedures designed to promote transparency and to 

ensure public participation. These include timely public notice of 

meetings, public access to meetings, and opportunity for the public to 

comment; public availability of documents considered by the HSRB and 

meeting minutes; and a Federal officer or employee attending each 

meeting. Of course, the HSRB will be required to protect materials 

designated as confidential from public disclosure. Finally, EPA is also 

committing to aggressive management of the process to promote efficient 

use of resources and timely decisions, and to ensure affected 

stakeholders have complete information about the status of ongoing reviews.

XIII. Subpart Q--Ethical Standards for Assessing Whether to Rely on the 

Results of Human Research in EPA Regulatory Decisions

 This unit discusses the ethical standards EPA will use to guide its 

decisions whether to rely in its actions under the pesticide laws on 

the results from completed human research. Unit XIII.A. summarizes 

EPA's proposal, Unit XIII.B. discusses public comment, and Unit XIII.C. 

describes the positions taken in the final rule.

 Summary: The final rule is substantively unchanged from the 

proposal, although the provisions have been revised to make them 

clearer. One new section (Sec. 26.1701) clarifies the applicability of 

this subpart to EPA decisions to rely on relevant, scientifically valid 

``data from research involving intentional exposure of human subjects 

to a pesticide'' in its actions under the pesticide laws, FIFRA and 

FFDCA. A second new section (Sec. 26.1702) provides needed definitions 

of terms. The remaining four sections in the final rule together 

delineate the framework within which EPA will decide whether to rely on 

the results of certain types of human research.

 This framework rests on the basic principle that EPA will not rely 

in its actions on data derived from unethical research. Section 26.1703 

forbids EPA to rely on data from any study involving intentional 

exposure of pregnant women, fetuses, or children. Section 26.1704 

forbids EPA to rely on data from ``old'' research--i.e., covered 

studies initiated before the effective date of the final rule--

concluded to be fundamentally unethical or significantly deficient with 

respect to the ethical standards prevailing when it was conducted. 

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Section 26.1705 forbids EPA to rely on data from any ``new'' research--

i.e., research initiated after the effective date of the final rule--

unless EPA finds that the research complied with the new requirements. 

Finally, Sec. 26.1706 creates a very narrow exception to the Agency's 

general refusal to rely on unethical data, one that allows reliance on 

unethical data when it is crucial to supporting more stringent 

regulatory measures to protect public health.

A. The Proposed Rule

 In proposed subpart F of 40 CFR part 26, EPA set out ethical 

standards for its decisions to rely on or not to rely in its regulatory 

decisions under FIFRA or FFDCA on reports of completed intentionaldosing research with human subjects. For covered research initiated 

after the effective date of the rule, EPA

[[Page 6159]]

proposed to refuse to rely on data from scientifically sound and 

relevant human research unless EPA had adequate information 

demonstrating that the research complied with the Common Rule. For 

covered research initiated before the effective date of the rule, EPA 

proposed to rely on data from scientifically sound and relevant human 

research unless there was clear evidence to show the conduct of the 

research was fundamentally unethical or was significantly deficient 

relative to the ethical standards prevailing when it was conducted. EPA 

also proposed a formal 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.

B. Public Comments

 EPA received many public comments on proposed subpart F. The major 

issues raised by the comments are grouped and summarized below under 

these four headings:

 ? Comments advocating a broader or narrower scope for this 

subpart--a change to the kinds of research and the range of EPA 

decisions the framework should cover.

 ? Comments questioning the proposed framework itself, 

including arguments to include standards for scientific validity of 

human research, and arguments that EPA should never reject 

scientifically sound data for ethical reasons.

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 ? Comments on the substantive ethical standard to be applied 

to ``old'' research initiated before this final rule takes effect.

 ? Comments on the proposed ``public health exception'' to 

the general refusal to rely on unethical research.

 The Agency notes that, although some comments favored more 

specificity in EPA's final rule, many comments expressed support for 

EPA's proposal to rely on the Common Rule as the ethical benchmark for 

judging the acceptability of research conducted after the effective 

date of the final rule.

 1. The scope of application of EPA's ethical framework.

 Comment: Some comments advocated expanding the application of the 

ethical framework beyond research involving intentional exposure of 

human subjects to cover all types of human subjects research considered 

by the Agency, or to embrace consideration of human subjects research 

conducted with pesticides under EPA statutes other than the pesticide 

laws, or to cover research involving intentional exposure of human 

subjects to any environmental substance, not only to pesticides.

 Response: The Agency has decided not to expand the application of 

the ethical standards in this subpart to encompass all types of human 

subjects research relied on by EPA, to research involving substances 

other than pesticides, or to actions taken under authorities other than 

the pesticide laws. In the future, the Agency will consider further 

actions to address these and other issues beyond the scope of this 

final rule.

 The Agency believes an initial focus on research involving 

intentional exposure is warranted in that potential risks to research 

subjects are generally greater when exposure is intentional than in 

other types of studies. It is reasonable to scrutinize such research 

closely to ensure that research subjects are fully protected and the 

research is ethical. EPA has not fully considered, and public comments 

have not thoughtfully addressed, what protective measures would be 

appropriate for research that does not involve intentional exposure. 

Thus, the Agency thinks it premature to conclude that all of the 

provisions applying to research involving intentional exposure should 

apply more widely.

 EPA thinks there has also been inadequate consideration of the 

consequences of expanding the scope of the ethical framework to embrace 

research with substances other than pesticides. Most of the comments 

favoring expansion of the rule beyond pesticides came primarily from 

stakeholders affiliated with the pesticide industry, and EPA received 

essentially no meaningful response to its requests for comment from 

other stakeholder interests, including those likely to be affected by 

such an expansion. Given the mandate of the 2006 Appropriations Act to 

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address research ``for pesticides,'' the final rule retains the 

proposed focus on human research for pesticides.

 Finally, the Agency has decided to retain the proposed 

applicability of the framework to actions taken under the pesticide 

laws. Although EPA recognizes the theoretical possibility that human 

research with a pesticide may be considered under other statutes, the 

Agency notes that the 2006 Appropriation Act does not require the 

adoption of a broader scope than decisions under FIFRA and FFDCA. Also, 

the Agency has not received meaningful public comment on whether its 

authorities under other statutes permit it to refuse to rely on 

relevant, scientifically sound data which were derived from an 

unethical study. Because of the questions about the Agency's legal 

authorities and the absence of a clear mandate, EPA has decided not to 

require the application of the ethical framework to actions taken under 

its other laws.

 Comment: Other comments argued for restricting the application of 

the ethical framework to only certain kinds of human research--to 

research intended to identify or measure toxic effects, to research 

conducted in a laboratory or clinical setting, or to exclude research 

involving only exposures that EPA had already approved (e.g., studies 

of registered pesticides used in accordance with their approved 

labeling). Two general reasons were offered for these recommendations: 

(i) Public controversy has focused exclusively on a narrower set of 

studies than those falling within the scope of proposed subpart F, and 

(ii) there is so little risk from the types of studies suggested for 

exclusion that no additional measures would be needed to protect subjects.

 Response: Because EPA finds these reasons unpersuasive, the Agency 

has decided to retain, at this time, the scope of the proposal for its 

final rule. Thus, EPA is not narrowing the scope of its framework in 

any of the ways recommended above.

 Although recent controversy has focused on ``intentional dosing, 

human toxicity testing for pesticides'' (see the Appropriations Act 

discussed in Unit XIV.A.), there has also been public debate about 

other kinds of human research, including product-in-use studies using 

registered pesticides, studies performed outside the laboratory 

setting, and studies which do not measure toxicity. To promote public 

confidence in its operations and judgments EPA must address this larger 

universe of research. Second, EPA thinks that it is important to 

examine the risks of studies involving intentional exposure of research 

subjects--even when comparable exposures have already been approved for 

the general public under a pesticide registration. While the risks 

experienced by the research subjects and the general public may not 

differ, the risks experienced by the particular subjects may exceed 

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what they would otherwise receive, and therefore researchers must 

provide each potential subject a full explanation of the potential for 

any additional risk they might assume by volunteering for a study. For 

its part, EPA should ensure that, in their interactions with subjects, 

the sponsors and investigators have acted ethically.

 2. The adequacy of the ethical standards.

[[Page 6160]]

 Comment: Although nearly all comments supported EPA's application 

of an explicit ethical standard in deciding whether or not to rely on 

data from completed human research, one significant line of comment 

argued that EPA should never refuse to rely on relevant, scientifically 

sound research even if it were conducted unethically. This conclusion 

rested on three arguments: (i) Rejecting scientifically sound data 

would deprive decision-makers of information that would serve the 

mission of protecting public health; (ii) applying a new standard of 

ethical acceptability retroactively to completed research would be 

unfair; and (iii) refusing to rely on data from unethical research 

could do nothing to remedy any harm done to the subjects in the research.

 Response: While EPA sees some merit in each of these arguments, the 

Agency disagrees with the conclusion. EPA believes that rejecting 

unethical data is an appropriate and powerful means of promoting 

compliance with ethical standards, and that rejecting unethical data 

generally meets public expectations about conduct of the government.

 First, EPA agrees that it is important to consider all available 

information in carrying out its mission to protect public health. This 

is especially important when reliable data show humans to be more 

sensitive than animals. Sometimes, however, data from human research 

will show that humans are less sensitive--or no more sensitive--than 

animals, and that a less restrictive regulatory measure may provide 

adequate protection for public health. This is important to know 

because the Agency is interested in cost-efficient regulations. 

Finally, human research often confirms a risk assessment based on 

animal toxicity data. Such confirmation increases confidence in the 

Agency's decisions. Therefore, the Agency agrees that it is always 

important to assess data from available human research.

 The Agency also agrees that it is generally inappropriate to apply 

current ethical standards to judge the acceptability of research 

completed before such standards were articulated. Not only could that 

lead to declaring unethical much completed research which was 

considered ethical when it was conducted, it would also set a standard 

for ethical conduct--adherence to standards not yet articulated--that 

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even the most ethically concerned investigators and sponsors could 

never meet. To avoid such an outcome EPA will generally judge the 

ethical acceptability of research initiated before the effective data 

of this rule in terms of the ethical standards prevailing when it was 

performed.

 The Agency also agrees that no actions taken after research is 

completed can undo any harm experienced by the human subjects in the 

research. But this point ignores the deterrent value of government 

actions that ``punish'' unacceptable conduct. EPA believes that by 

refusing to rely on unethical data it creates a strong incentive for 

the scientific community to conduct future research ethically. If 

investigators and sponsors understand that EPA will not rely on the 

results of their research unless it is performed ethically, they will 

not wish to risk losing either their direct investment in the research 

or any benefit its use might bring to them.

 Finally, EPA believes that the public expects its government to 

apply a clear standard of ethical acceptability in deciding whether to 

rely on the results of completed research. Such an expectation, evident 

in thousands of public comments on the proposed rule, provides 

additional reason for establishing an explicit ethical framework for 

making these decisions, and for refusing to rely on unethically 

obtained data. (As discussed below, EPA believes that in certain very 

limited circumstances the ethical course of conduct may require 

reliance on ethically deficient research when to do so is crucial to 

supporting more stringent regulatory measures to protect public health.)

 Comment: Some comments, noting that scientifically unsound research 

is always unethical, argued that the proposed framework should 

articulate explicit standards of scientific validity.

 Response: EPA agrees that its ethical framework should exclude data 

which are not scientifically sound, and thus the final rule clarifies 

that subpart Q applies only to ``scientifically valid and relevant 

data.'' The Agency has not, however, attempted to define a standard for 

scientific validity and relevance, because this is necessarily a caseby-case judgment. EPA has long had in place policies and procedures to 

ensure rigorous scientific review of research it is considering, 

including procedures for formal peer review of research and assessments 

critical to Agency actions. In addition, Sec. 26.1603(b) of the final 

rule provides that the HSRB ``shall review and comment on the 

scientific and ethical aspects of research proposals and reports of 

completed intentional exposure research. . . .'' Over time the results 

of HSRB review of the scientific aspects of both proposed and completed 

human research will support articulation of general principles for the 

scientifically sound and ethical conduct of different types of human 

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research.

 3. The ethical standard for accepting ``old'' research. Opinions 

about research conducted before the final rule varied widely, and are 

summarized below under these headings:

 ? The proposed standard is too weak; the Common Rule should 

be applied to all research, regardless of when it was conducted;

 ? The rule should define such terms as ``standards 

prevailing when research was conducted''; ``fundamentally unethical''; 

and ``significantly deficient.''

 ? Rejection of any research involving intentional exposure 

of pregnant women, fetuses, or children is inconsistent with 

``standards prevailing when research was conducted.''

 ? The standard of ``clear evidence'' should be different;

 Comment: Many comments favored application of the Common Rule to 

all research, regardless of when it was performed. These comments 

argued that the standard in proposed Sec. 26.601 was unacceptably weak 

because it failed to reflect contemporary ethical standards.

 Response: EPA believes it would be unreasonable to apply to 

completed research ethical standards articulated after the research was 

conducted. Thus, the final rule retains the proposed standard for 

judging the acceptability of completed ``old'' research--i.e., research 

initiated before the final rule becomes effective.

 First, for many years the prevailing ethical standard in the U.S. 

has been the Common Rule, and with respect to biomedical research, the 

earlier DHHS rules that form the basis for the Common Rule. 

Consequently, as a practical matter, the same standard of ethical 

acceptability--the Common Rule or its foreign equivalent--would apply 

to research conducted since its promulgation in 1991.

 Thus, reference to ethical standards prevailing at the time of the 

research makes a practical difference only when considering the 

acceptability of research which meets today's standards of scientific 

validity but which was conducted before today's ethical standards were 

articulated. Codes of ethical research conduct require investigators to 

do certain things in certain ways before and during the research. It is 

reasonable to expect investigators to follow ethical codes that prevail 

when they do their work; it is unreasonable to expect them to 

anticipate and follow standards developed after their work is done. EPA 

believes that scientifically meritorious research which adhered to accepted

[[Page 6161]]

ethical norms when it was conducted should not be set aside because 

ethical standards have subsequently changed. EPA also believes that 

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ethical standards are likely to continue to change in the future and 

that if and when they do, such a change should not invalidate or make 

unacceptable otherwise meritorious research conducted now, in 

conformity with the ethical standards of today.

 It is sometimes argued that to accept ``old'' research falling 

short of today's standards would encourage others to conduct unethical 

research in the future. EPA disagrees. With respect to new research, 

the principal incentive to conduct research ethically is the prospect 

that the Agency might refuse to rely on research that doesn't comply 

with contemporary ethical standards. A refusal by EPA to rely on new 

human research would carry serious economic consequences for the 

investigator and sponsor. Much third-party research is conducted by 

private, for-profit organizations in the hope that the results will 

lead to financial benefits, often through changes in government 

regulation. For example, the current controversy over pesticide studies 

centers on research conducted by pesticide companies who hoped to 

demonstrate through human studies that their products were safer than 

was indicated by available animal studies, and thus that their market 

could expand--or at least need not shrink--because of concerns about 

risk. An Agency refusal to rely on data would deprive the investigator 

and sponsor of such potential financial benefits. Importantly, under 

Sec. 26.1705 of the final rule, the Common Rule's provisions will 

guide EPA's decisions about reliance on the results of new research, 

i.e., studies conducted after the rule takes effect. The fact that EPA 

may apply a different standard to ``old'' studies is irrelevant. An 

investigator conducting a new, covered study after these final rules 

take effect would be very foolish to think that the Agency will judge 

its ethical acceptability by any standard other than the Common Rule.

 Comment: A number of comments called for the rule to specify that 

certain documents--the Nuremberg Code, various editions of the 

Declaration of Helsinki, the Belmont Report, and the Common Rule, among 

others--would serve as the point of reference in identifying the 

``standards prevailing at the time the research was conducted.'' Other 

comments asked that the Agency explain and give examples of the types 

of ethical deficiencies that it would deem ``fundamentally unethical'' 

or ``significantly deficient'' in the provision codified as Sec. 

26.1704 of the final rule.

 Response: In recent years, EPA has reviewed numerous reports of 

completed research on pesticides involving intentional exposure of 

human subjects. These studies have been conducted over many years, in 

many places, under a variety of ethical policies and regulatory 

schemes; they have addressed a wide range of research questions, and 

they have presented a wide spectrum of ethical shortcomings, from minor 

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flaws to more serious deficiencies. Given these variations, the Agency 

believes that its ethical framework must retain sufficient flexibility 

to judge each situation on its merits, in the context of the time and 

place the research was conducted. While the historical documents cited 

in the comments reflected widely shared views about what constitutes 

ethical conduct, they were not necessarily universal or comprehensive 

in their coverage. Certainly they are among the standards which may 

have prevailed when specific research was conducted, and EPA will rely 

on them when they are appropriate to the evaluation of a particular 

study. But it adds nothing to list them in the final rule.

 EPA also thinks it unnecessary to elaborate on the meaning of the 

narrative standards ``fundamentally unethical,'' ``significantly 

deficient'' or ``substantial compliance.'' The gravity of a particular 

ethical lapse depends not only on the details of the deficiency, but 

also on the circumstances in which it occurred. EPA agrees with the NAS 

that each study requires case-by-case evaluation. EPA expects these 

terms to acquire greater clarity over time, through HSRB and public 

review of Agency decisions concerning reliance on completed human research.

 Comment: Some comments objected to the proposed prohibition of 

EPA's reliance in its pesticide decisions on data from human subjects 

research involving intentional exposure of pregnant women, fetuses, or 

children. These comments argued that if such research was not 

considered unethical under the standards prevailing when it was 

conducted EPA should accept and consider it, and that exclusion of such 

research could deprive EPA of potentially valuable information.

 Response: EPA agrees that existing research involving intentional 

exposure of pregnant women, fetuses, or children may have been 

considered ethical according to the standards prevailing when the 

studies were conducted. Nonetheless, in light of the provisions of the 

2006 Appropriations Act and the thousands of public comments on the 

proposal condemning research of this kind, the Agency believes it must 

generally refuse to rely on such research. The Agency knows of only a 

very few existing studies involving intentional exposure of pregnant 

women or children. If it were determined that reliance on any of them 

were crucial to a decision that would impose a more stringent 

regulatory restriction to protect public health than could otherwise be 

justified, the exception procedure defined in Sec. 26.1706 in the 

final rule could be invoked.

 Comment: Several comments recommended revising the evidentiary 

standard for accepting ``old'' studies. Some suggested a change from 

``clear evidence'' to a less demanding test, such as ``any evidence.'' 

Others recommended adoption of the exact wording of the NAS 

recommendation on which EPA based the proposal, changing ``clear 

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evidence'' to ``clear and convincing evidence.''

 Response: It is conceivable that the standard requiring ``clear 

evidence'' could lead the Agency to accept data from research which it 

suspected but could not prove had serious ethical flaws. The Agency 

agrees this would be unfortunate, but believes a change to a standard 

of ``any evidence'' would likely lead to even more unfortunate 

outcomes. Because reliable information about its conduct is often very 

limited, in many cases it is difficult or impossible to prove that 

older research was ethical. An unsupported accusation of unethical 

conduct should thus not in itself be sufficient to force rejection of 

completed research. Rejection of research on the basis of weak or 

suggestive evidence of unethical conduct could deprive the Agency of 

information important to sound decisions. Because EPA can see no 

benefit that would flow from changing the standard to ``any evidence,'' 

EPA is not accepting this recommendation.

 On the other hand EPA agrees with the comments urging a return to 

the exact wording of the evidentiary test in NAS Recommendation 5-7. 

Since the Agency did not intend to alter the standard, and since 

``clear and convincing evidence'' has an accepted meaning under 

administrative law, EPA has changed the final rule to read, in 

pertinent part:

 . . . EPA shall not rely on data from any research initiated 

before April 7, 2006 if there is clear and convincing evidence that 

the conduct of that the research was fundamentally unethical . . .

 4. The exception allowing use of unethical data to justify more 

stringent regulatory restrictions to protect public health.

[[Page 6162]]

 Comment: One group of comments argued that the Agency should, 

without exception, never rely on data derived from unethical research 

because to do otherwise would condone unethical research. Many of these 

commenters also misunderstood the proposed exception as authorizing the 

conduct of unethical future research.

 Response: Although EPA thinks there will rarely, if ever, be 

situations requiring the use of this exception, EPA can easily imagine 

a circumstance in which ethical behavior could require Agency decisionmakers to rely on unethical data. (See Unit II.) The exception would be 

used when scientifically sound but ethically flawed data show that the 

Agency needs to take a more protective action than could be justified 

without considering the human research. Invoking the exception would 

allow EPA to protect the health of many people--perhaps millions; a 

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greater public good than any benefits that would flow from refusing to 

rely on the data. In EPA's moral calculus, the greater good should and 

will guide the choice whether to use unacceptable data.

 The Agency disagrees with the argument that the final rule should 

contain no exceptions to the basic principle of refusing to rely on 

unethical research, because an exception would encourage the conduct of 

unethical research. A public refusal by EPA to rely on unethical data 

brings shame to the investigator who acted unethically, and in most 

cases also directly affects the financial interests of the 

investigator, sponsor, or both. Such a refusal serves as an important 

deterrent to other investigators, discouraging unethical research in 

the future.

 To further ensure that EPA's exceptional use of ethically flawed 

data does not encourage unethical research conduct, Sec. 26.1706 

expressly requires the Agency to publish ``a full explanation of its 

decision to rely on otherwise unacceptable data, including a thorough 

discussion of the ethical deficiencies of the study . . . .'' In 

addition, the Agency will have recourse to any of the other measures 

identified in subpart O to promote compliance with standards of ethical 

research. EPA believes the exception as defined in the final rule, 

allowing for EPA consideration of unethical research under well defined 

and narrow conditions and requiring a full public discussion of its 

ethical deficiencies, will not in any way encourage other investigators 

to conduct unethical research.

 Comment: Some comments argued for a broad interpretation of the 

concept of ``protection of public health,'' such that it would not be 

limited to cases involving imposition of more stringent regulatory 

restrictions. Some comments suggested, for example, that a more 

accurate assessment of risks to humans should be interpreted as 

``protection of public health.'' Other comments called upon EPA to 

clarify in the final rule that ``protection of public health'' does not 

encompass the ability of American agriculture to produce more crops at 

a lower cost.

 Response: EPA does not agree that the public health exception 

should be interpreted to permit reliance on unethical research to 

support more accurate risk assessments or more efficient or lower cost 

agricultural production. EPA's ethical framework is built on the 

principle that unethical research should not be relied on in Agency 

actions except in the most extraordinary circumstances; such 

interpretations would amount to abandoning this principle altogether, 

and could severely undermine incentives for compliance with the new 

requirements.

 The Agency does agree, however, that the proposal was unclear with 

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respect to what would constitute a ``public health'' benefit justifying 

invocation of the exception. EPA has thus revised the final rule to 

clarify that invoking the public health exception would only permit the 

Agency to ``impose a more stringent regulatory restriction that would 

improve protection of public health . . . .'' See Sec. 26.1706 of the 

regulatory text.

C. The Final Rule

 Subpart Q of the final rule corresponds in substance to subpart F 

of the proposal. In this final rule EPA has moved the rule text to a 

new subpart, and has rewritten the proposed provisions to express the 

standards more clearly.

 Section 26.1701 of the final rule describes the scope of subpart Q; 

it applies to:

 . . . EPA's decisions whether to rely in its actions 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) on scientifically valid and relevant data from research 

involving intentional exposure of human subjects.

 The Agency has chosen to retain the scope of the proposed rule 

because it believes that the 2006 Appropriations Act does not require 

this rule to address a broader scope of issues, and because there has 

not been adequate consideration of the consequences of adopting a more 

expansive scope.

 Section 26.1703 prohibits EPA's reliance on data from research 

involving intentional exposures of pregnant women, fetuses, or 

children. Derived from proposed Sec. Sec. 26.221 and 26.421, this 

section states:

 Except as provided in Sec. 26.1706, in actions within the scope 

of Sec. 26.1701, EPA shall not rely on data from any research 

involving intentional exposure of any human subjects who is a 

pregnant woman (and therefore her fetus) or child.

 This provision makes clear that the Agency will not rely in its 

actions on the results of research that EPA and third parties are 

prohibited from conducting under subparts B and L, except under the 

narrow exception provided by Sec. 26.1706. To clarify that this 

prohibition applies to EPA's non-regulatory actions (such as issuance 

of a risk assessment or a health advisory level) as well as to its 

regulatory decisions, EPA has changed the phrase ``regulatory decisionmaking'' in the proposal to ``actions'' in the final rule.

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 Section 26.1704 defines the ethical standard EPA will use to decide 

whether to rely on the results of research conducted with non-pregnant 

adults before the effective date of the rule. It provides:

 Except as provided in Sec. 26.1706, in actions within the scope 

of Sec. 26.1701, EPA shall not rely on data from any research 

initiated before April 7, 2006, if there is clear and convincing 

evidence that the conduct of the 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. This prohibition is in 

addition to the prohibition in Sec. 26.1703.

 The above rule text is derived from proposed Sec. 26.601, and 

follows the language of the NAS recommendation 5-7. In response to 

public comment, the evidentiary standard for concluding research was 

unethical has been changed from ``clear evidence'' to ``clear and 

convincing evidence.'' The Agency made this change to minimize 

confusion, to conform to the wording of the NAS recommendation, and to 

use a formulation of the evidentiary standard that has an accepted 

legal meaning in administrative law. For purposes of clarity, the 

section also reaffirms that the prohibition in Sec. 26.1703 against 

relying on research involving pregnant women and children is unaffected 

by this provision.

 Section 26.1705 describes the ethical standard EPA will use to 

decide whether to rely on the results of human subjects research 

conducted with non-pregnant adults after the effective date

[[Page 6163]]

of the rule. It provides that the Agency will not rely on data from 

such research:

 Except as provided in Sec. 26.1706, in actions within the scope 

of Sec. 26.1701, EPA shall not rely on data from any research 

initiated after April 7, 2006, unless EPA has adequate information 

to determine that the research was conducted in substantial 

compliance with subparts A through M of this part, or if conducted 

in a foreign country, under procedures at least as protective as 

those in subparts A through L. This prohibition is in addition to 

the prohibition in Sec. 26.1703.

 This rule text is based on proposed Sec. 26.602. It has been 

revised to make clear that EPA may accept and rely on data from human 

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research conducted in a foreign country if EPA has adequate information 

to determine the research was ``conducted . . . under procedures at 

least as protective as those in subparts A through L.'' Allowing the 

use of foreign research provided the research meets ethical norms 

equivalent to those of the Common Rule is consistent with the Common 

Rule at Sec. 26.101(h). Like Sec. 26.1704, Sec. 26.1705 reaffirms, 

for the sake of clarity, that the prohibition in Sec. 26.1703 against 

relying on research involving pregnant women and children is unaffected 

by this provision.

 Finally Sec. 26.1706 provides for an exception to the general 

refusal to rely on the results of unethical research. This section 

defines the specific circumstance in which the Agency will use data 

from research judged unacceptable under Sec. 26.1703, Sec. 26.1704, 

or Sec. 26.1705, and the procedures EPA must follow in reaching that 

decision, as follows:

 EPA may rely on such data only if all the conditions in 

paragraphs (a) through (d) of this section are satisfied:

 (a) EPA has obtained the views of the Human Studies Review Board 

concerning the proposal to rely on the otherwise unacceptable data,

 (b) EPA has provided an opportunity for public comment on the 

proposal to rely on the otherwise unacceptable data,

 (c) EPA has determined that relying on the data is crucial to a 

decision that would impose a more stringent regulatory restriction 

that would improve protection of public health than could be 

justified without relying on the data, and

 (d) EPA publishes a full explanation of its decision to rely on 

the otherwise unacceptable data, including a thorough discussion of 

the ethical deficiencies of the study and the full rationale for 

finding that the standard in paragraph (c) of this section was met.

 The text of this section of the final rule contains a number of 

minor revisions to clarify the substantive and procedural requirements. 

Most notably, EPA changed the wording for the substantive standard for 

using the exception from ``crucial to the protection of public health'' 

in the proposal to ``crucial to a decision that would impose a more 

stringent regulatory restriction that would improve protection of 

public health'' in the final rule. This change reflects the Agency's 

intent to limit the exception to a very narrow circumstance and to 

prevent use of the exception in a way that could benefit a person 

responsible for the unethical conduct.

XIV. EPA's 2006 Appropriations Act and the Final Rule

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 This unit discusses how today's final rule meets the requirements 

of the Department of the Interior, Environment, and Related Agencies 

Appropriations Act, 2006, Public Law No. 109-54 (Appropriations Act), 

which required EPA to promulgate a final rule relating to intentional 

dosing human toxicity studies for pesticides within 180 days of 

enactment of the Act, and included various mandates concerning the 

promulgated final rule.

A. Section 201 of EPA's FY 2006 Appropriations Act

 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 EPA 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.

B. Compliance of the Final Rule with the Appropriations Act

 The first requirement of the Appropriations Act is that EPA not 

``accept, consider or rely on third-party intentional dosing human 

toxicity studies for pesticides, or . . . conduct intentional dosing 

human toxicity studies for pesticides until the Administrator issues a 

final rulemaking on this subject.'' EPA has not accepted, considered, 

or relied on any third-party intentional dosing human toxicity studies 

in its actions under FIFRA and FFDCA since September 2005. EPA has 

further neither conducted nor supported any intentional dosing human 

toxicity study for pesticides during this rulemaking period.

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 The second requirement of the Appropriations Act is to ``allow for 

a period of not less than 90 days for public comment on the Agency's 

proposed rule before issuing a final rule.'' A notice of proposed 

rulemaking addressing both third-party intentional dosing human 

toxicity studies for pesticides and EPA's conduct of intentional dosing 

human studies was published in the Federal Register on September 12, 

2005 (70 FR 53838); the public comment period ended on December 12, 2005.

 EPA's proposed rule addressed first-, second-, and third-party 

human subjects testing for pesticides. In particular, the proposal 

defined the scope of third-party human research covered by the proposal as:

 [A]ll 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).

 EPA used the act of submitting, or the intent to submit, to the 

Agency under FIFRA or FFDCA as a surrogate for the Appropriations Act's 

requirement that EPA promulgate a rule addressing ``third-party 

intentional dosing human toxicity studies for pesticides.'' The use, 

sale, and distribution of pesticides are exclusively regulated by EPA 

under FIFRA and FFDCA. Moreover, as discussed above, the ongoing 

controversy over EPA's use of human research data in its risk 

assessments has focused almost exclusively on the use of such data in 

risk assessments under FIFRA and FFDCA. Indeed, the Congressional 

debate that resulted in the passage of section 201 of the 

Appropriations Act focused entirely on

[[Page 6164]]

human subjects research related to Agency actions under FIFRA and 

FFDCA. Therefore, EPA believes that interpreting the phrase ``thirdparty intentional dosing human toxicity studies for pesticides'' to 

require either submission or intent to submit under FIFRA or FFDCA 

reflects the intent of the Congress as expressed in section 201 of the 

Appropriations Act.

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 The third requirement of the Appropriations Act is that the final 

rule ``not permit the use of pregnant women, infants or children as 

subjects.'' Today's final rule effectuates this mandate by: (1) 

Categorically prohibiting EPA from conducting or supporting research 

involving intentional exposure to any substance of human subjects who 

are pregnant women or children (subpart B of the final rule, Sec. 

26.203); and (2) prohibiting third-party research for pesticides 

involving intentional exposure of human subjects who are pregnant women 

or children (subpart L of the final rule, Sec. 26.1203).

 The fourth requirement of the Appropriations Act is that the final 

rule ``shall be 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 concludes 

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:

 [T]he 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 

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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. 

Today's final rule extending the substantive requirements of EPA's 

Common Rule to additional categories of regulated third-party research 

is thus consistent with those principles, as required by the 

Appropriations Act.

 The fifth requirement of the Appropriations Act is that the final 

rule ``shall be 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 1940's, 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 known as the Nuremberg 

Code. [Footnotes and references omitted]

 Before publishing the NPRM, EPA carefully assessed whether the 

proposed provisions were consistent with the 10 principles of the 

Nuremberg Code as a guide, and concluded that it was consistent with 

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such principles. EPA believes this final rule remains consistent with 

the principles of the Nuremberg Code. An analysis explaining this 

conclusion is in the docket for this action, and comments on this issue 

have been addressed in our Response to Comments document.

 The sixth requirement of the Appropriations Act is that the final 

rule ``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 Chapter 6 of the NAS Report. Consistent with 

both the requirement of the Appropriations Act and the recommendations 

of the NAS, this final rule establishes an independent HSRB. The HSRB 

will review proposed human subjects research after review by a local 

IRB and EPA staff. This sequence is consistent both with EPA's current 

practice for reviewing first- and second-party human research proposals 

and with the practice of FDA for reviewing human research proposals. 

Although the NAS Report recommended that the EPA and HSRB reviews come 

before the IRB review, EPA believes that HSRB review after local IRB 

and EPA review will better serve the purposes for which HSRB review of 

proposed research is intended.

 The final requirement of the Appropriations Act is that the final 

rule ``shall be issued no later than 180 days after enactment of this 

Act.'' This requirement was met when EPA Administrator Stephen L. 

Johnson signed the final rule before January 29, 2006, and it was made 

publicly available.

XV. Effective Date of the Final Rule

 EPA noted in the preamble to the proposed rule that it considered 

the expeditious application of the new protections in the final rule to 

be in the public interest. Accordingly the Agency explained that it 

would provide no longer period than is essential between publication of 

the final rule and its effective date. Since the final rule is being 

promulgated under the authority of FIFRA, EPA is subject to FIFRA 

section 25(a)(4), 7 U.S.C. 136w(a)(4), which 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

[[Page 6165]]

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.

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 Therefore, EPA proposed that the final rule would be effective 60 

days after its promulgation and transmittal to Congress.

 EPA received only one comment on the effective date, arguing that 

the requirements of the rule should not apply retroactively. EPA agrees 

that the provisions of the final rule should not apply retroactively, 

and the final rule contains no retroactive requirements. Specifically, 

the final rule establishes standards for the conduct by EPA and by 

third parties, in the future, of certain types of research. The Agency 

notes that the actions to promote compliance identified in subpart O of 

the final rule would only be applied to those whose actions, following 

the effective date of the final rule, did not comply with applicable 

requirements. Actions occurring before the final rule takes effect 

would not be subject to direct sanctions under subpart O, such as civil 

penalties or debarment. In addition, the final rule establishes 

standards to guide future Agency decisions about the ethical 

acceptability of completed research. While some of the research that 

EPA will evaluate under the new standards for ethical acceptability was 

conducted prior to the effective date of the final rule, such studies 

will be judged by the ethical standards prevailing when the research 

was performed. Thus, even the standard of acceptability is not 

``retroactive'' in the sense that conduct would be judged using a 

standard created after the conduct occurred.

 The Agency has decided to make the final rule effective 60 days 

after the date of publication of its Notice of Final Rulemaking in the 

Federal Register. As required by FIFRA section 25(a)(4), the Agency has 

previously transmitted copies of the signed final rule to the Secretary 

of the Senate and the Clerk of the House of Representatives. Although 

technically the rule could take effect a few days earlier, EPA 

concluded that allowing 60 days from the date of publication of this 

Federal Register document was appropriate. Accordingly, this rule takes 

effect on April 7, 2006.

 The Agency notes that a number of the provisions of the rule apply 

to research ``initiated'' after the effective date of this rule. For 

purposes of research conducted or supported by EPA, the Agency will 

consider that an investigator has initiated a study once the Agency's 

HSRRO has approved the protocol for the study. For purposes of research 

that is covered by subparts K or L or by Sec. 26.1705, a study was 

``initiated'' when the first subject was enrolled. If that date cannot 

be determined, EPA will consider the earliest date on which 

experimental activity involved a subject to be the date of initiation 

of the research.

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XVI. FIFRA Review Procedures for the Final Rule

 FIFRA section 25(a)(2)(B) provides: ``[a]t least 30 days prior to 

signing any regulation in final form for publication in the Federal 

Register, the Administrator shall provide the Secretary of Agriculture 

a copy of such regulation.'' This section also authorizes the Secretary 

to waive the opportunity to review and comment on final regulations. 

FIFRA section 25(d)(1) states that ``[t]he Administrator shall submit 

to an advisory panel for comment [the]

final form of regulations issued 

under section 25(a) within the same time periods as provided for the 

comments of the Secretary of Agriculture . . . .'' This section also 

authorizes the FIFRA Scientific Advisory Panel to waive the opportunity 

for review. Both, the FIFRA Scientific Advisory Panel (SAP) and the 

U.S. Department of Agriculture (USDA) have waived the opportunity under 

FIFRA to review the final rule.

 In addition, FIFRA section 25(a)(3) states that ``[a]t such time as 

the Administrator is required under paragraph (2) to provide the 

Secretary of Agriculture with . . . a copy of the final form of 

regulations, the Administrator shall also furnish a copy of such 

regulations to the Committee on Agriculture in the House of 

Representatives, and the Committee on Agriculture, Nutrition, and 

Forestry in the United States Senate.'' Because USDA waived review 

under FIRFA section 25(a)(2)(B), EPA is not required to furnish a copy 

of the final regulations to the specified committees 30 days prior to 

signature of the final rule. The Agency, nonetheless, provided copies 

of the final rule to the Congressional committees prior to its publication.

XVII. 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) has determined that this final 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, this 

action was submitted to OMB for review under Executive Order 12866 and 

any changes made based on OMB recommendations have been documented in 

the docket for this rulemaking as required by section 6(a)(3)(E) of the 

Executive Order.

 In addition, EPA prepared an economic analysis of the potential 

costs and benefits associated with this action. This analysis is 

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contained in a document entitled ``Economic Analysis of the Human 

Studies Final Rule'' (Economic Analysis). A copy of the Economic 

Analysis is available in the docket for this rulemaking and is briefly 

summarized here.

 The Economic Analysis describes the benefits of the rulemaking in 

qualitative terms. These benefits include greater protections for test 

subjects, and a corresponding reduction in their risks, to the extent 

that affected third-party researchers are not already following the 

Common Rule. The benefits to sponsors of third-party human research 

include a better understanding of the standards that EPA will apply in 

determining whether to rely on the results of their studies, and thus, 

the opportunity to design and perform studies that are more likely to 

meet EPA standards, leading to more efficient Agency reviews. The 

Agency believes the general public will also benefit from this action 

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 Economic Analysis also estimates the costs of the final 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, recent 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.

 After reviewing the history of EPA's consideration of research 

involving human subjects in its various program offices, EPA estimates 

that this action will 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.

[[Page 6166]]

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.

 As detailed in the Economic Analysis prepared for this final rule, 

this action is estimated to result in a total annual incremental cost 

to third parties of approximately $39,000, and an estimated annual cost 

to EPA of approximately $808,000.

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B. Paperwork Reduction Act

 The information collection requirements contained in this final 

rule have been approved by the Office of Management and Budget (OMB) 

under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq., under 

OMB control number 2070-0169. In accordance with the procedures at 5 

CFR 1320.11, EPA sought comment on the Information Collection Request 

(ICR) document that was submitted to OMB in conjunction with the 

proposed rule (identified under EPA ICR No. 2195.01). Revised to 

reflect the provisions in this final rule, the ICR document (identified 

under EPA ICR No. 2195.02) was prepared and submitted to OMB and serves 

as the basis for OMB's approval. A copy of this ICR document has been 

placed in the docket for this rulemaking.

 Under the PRA, 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 the EPA regulations codified in Chapter 40 of the CFR, 

after appearing in the preamble of the final rule, are listed in 40 CFR 

part 9, displayed either by publication in the Federal Register or by 

other appropriate means, such as on the related collection instrument 

or form, if applicable. The display of OMB control numbers in certain 

EPA regulations is consolidated in 40 CFR part 9. For this ICR 

activity, in addition to displaying the applicable OMB control number 

in this unit, the Agency is amending the table in 40 CFR 9.1 to list 

the OMB control number assigned to this ICR activity. Due to the 

technical nature of the table, EPA finds that further notice and 

comment about amending the table is unnecessary. As a result, EPA finds 

that there is ``good cause'' under section 553(b)(B) of the 

Administrative Procedures Act (APA), 5 U.S.C. 553(b)(B), to amend this 

table without further notice and comment.

 EPA estimates that respondents may submit to the Agency each year 

under FIFRA or FFDCA, approximately 33 reports of research involving 

intentional exposure of human subjects. The Agency expects extremely 

limited submission of toxicity studies per year (i.e., 0-4 studies), 

with the bulk of the 33 studies being composed of efficacy and skin 

sensitization studies. (See also the response to comment on this topic 

that appears in Unit III.) EPA estimates that it may receive 

approximately 29 reports each year of other types of pesticide research 

involving human subjects. EPA estimates that preparation of the 

required information will require about 32 hours per study, for a total 

estimated annual burden for affected entities of 1,984 hours, at an 

estimated cost of $1,927 per study, or a total estimated annual 

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paperwork cost to respondents of $84,647. 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 (in total 4,960 

hours), representing a paperwork related labor cost of about $14,672 

per response and a total annual cost of $909,664.

 In the context of 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.

 The information collection activity imposed by this final rule is 

planned to ensure that sound and appropriate scientific data are 

available to EPA when making regulatory decisions, and to protect the 

interests, rights and safety of those individuals who are participants 

in the type of research activity that is the subject of this rule. 

Specifically, this new information collection activity consists of 

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.

 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 

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consequences which are reasonably foreseeable therefrom, and (ii) 

freely volunteer to participate in the test.''

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 rule on small entities, the Agency hereby certifies that 

this final rule 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, 

summarized in Unit XVI.A., and a copy of which is available in the 

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 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-forprofit enterprise which is independently owned and operated and is not 

dominant in its field.

 Although we cannot predict whether or how many small entities might 

engage in the subject matter research in the future, as estimated in 

the Economic Analysis, the cost to researchers covered by this rule is 

estimated to be $5,200 per study. This is a trivially small portion of 

the overall cost of performing such

[[Page 6167]]

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 this 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 

estimated current costs of compliance with the Common Rule are low, the 

potential overall costs from this rule to third parties are also 

estimated to be small.

D. Unfunded Mandates Reform Act

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 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 

XVI.A. the estimated total costs associated with this action are 

approximately $38,837 per year. This cost represents the incremental 

cost to researchers attributed to the additional procedural 

requirements contained in this final rule. 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 final 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 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 

rare. Therefore, this final rule may seldom affect a state government. 

Thus, Executive Order 13132 does not apply to this rule.

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 final 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 rule.

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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 rule because this action is not designated 

as an ``economically significant'' regulatory action as defined by 

Executive Order 12866. Furthermore, this final rule 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 with regard to the research 

covered by the rule.

H. Executive Order 13211

 This final 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 this rule does 

not 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 require specific methods or standards to generate data. 

Therefore, this final rule does not impose any technical standards that 

would require Agency consideration of voluntary consensus standards.

J. Executive Order 12898

 This final 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 is 

not required to consider environmental justice-related issues. Although 

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not directly impacting environmental justice-related concerns, the 

provisions of this rule will require researchers to use procedures to 

ensure equitable selection of test subjects in covered human research.

XVIII. Congressional Review Act

 The Congressional Review Act, 5 U.S.C. 801 et seq., generally 

provides that before a rule may take effect, the Agency promulgating 

the rule must submit a rule report that includes a copy of the rule to 

each House of the Congress and the Comptroller General of the United 

States. EPA will submit a report containing this rule and other 

required information to the U.S. Senate, the U.S. House of 

Representatives, and the Comptroller General of the United States prior 

to publication of the rule in the Federal Register. This rule is not a 

``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 9

 Environmental protection, Reporting and recordkeeping requirements.

List of Subjects in 40 CFR Part 26

 Environmental protection, Human research subjects, Reporting and 

recordkeeping requirements.

 Dated: January 26, 2006.

Stephen L. Johnson,

Administrator.

? Therefore, 40 CFR chapter I is amended as follows:

? 1. Part 9 is amended as follows:

PART 9--[AMENDED]

? a. The authority citation for part 9 continues to read as follows:

 Authority: 7 U.S.C. 135 et seq., 136-136y; 15 U.S.C. 2001, 

2003, 2005, 2006, 2601-2671, 21 U.S.C. 331j, 346a, 348; 31 U.S.C. 

9701; 33 U.S.C. 1251 et seq., 1311, 1313d, 1314, 1318, 1321, 1326, 

1330, 1342, 1344, 1345 (d) and (e), 1361; E.O. 11735, 38 FR 21243, 3 

CFR, 1971-1975 Comp. p. 973; 42 U.S.C. 241, 242b, 243, 246, 300f, 

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2, 300j-3, 300j-4, 300j-9, 1857 et seq.,

[[Page 6168]]

6901-6992k, 7401-7671q, 7542, 9601-9657, 11023, 11048.

? b. In Sec. 9.1 the table is amended by adding the following new 

entries under the new heading ``Protection of Human Subjects'' to read 

as follows:

Sec. 9.1 OMB approvals under the Paperwork Reduction Act.

* * * * *

------------------------------------------------------------------------

 40 CFR citation OMB Control No.

------------------------------------------------------------------------

 * * * * *

------------------------------------------------------------------------

 Protection of Human Subjects

------------------------------------------------------------------------

26.1125.................................. 2070-0169

26.1303.................................. 2070-0169

 * * * * *

------------------------------------------------------------------------

* * * * *

PART 26--[AMENDED]

? 2. Part 26 is amended as follows:

? a. 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); 

section 201 of Public Law No. 109-54; and 42 U.S.C. 300v-1(b).

? b. By redesignating Sec. Sec. 26.101 through 26.124 as subpart A and 

adding a new subpart heading to read as follows:

Subpart A--Basic EPA Policy for Protection of Subjects in Human 

Research Conducted or Supported by EPA

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? c. By adding new subparts B through Q as follows:

Subpart B--Prohibition of Research Conducted or Supported by EPA 

Involving Intentional Exposure of Human Subjects who are Pregnant Women 

or Children

Sec.

26.201 To what does this subpart apply?

26.202 Definitions.

26.203 Prohibition of research conducted or supported by EPA 

involving intentional exposure of any human subject who is a 

pregnant woman (and therefore her fetus) or child.

Subpart C--Observational Research: Additional Protections for Pregnant 

Women and Fetuses Involved as Subjects in Observational Research 

Conducted or Supported by EPA

26.301 To what does this subpart apply?

26.302 Definitions.

26.303 Duties of IRBs in connection with observational research 

involving pregnant women and fetuses.

26.304 Additional protections for pregnant women and fetuses 

involved in observational research.

26.305 Protections applicable, after delivery, to the placenta, the 

dead fetus, or fetal material.

Subpart D--Observational Research: Additional Protections for Children 

Involved as Subjects in Observational Research Conducted or Supported 

by EPA

26.401 To what does this subpart apply?

26.402 Definitions.

26.403 IRB duties.

26.404 Observational research not involving greater than minimal risk.

26.405 Observational research involving greater than minimal risk 

but presenting the prospect of direct benefit to the individual subjects.

26.406 Requirements for permission by parents or guardians and for 

assent by children.

Subpart E--[Reserved]

Subpart F--[Reserved]

Subpart G--[Reserved]

Subpart H--[Reserved]

Subpart I--[Reserved]

Subpart J--[Reserved]

Subpart K--Basic Ethical Requirements for Third-Party Human Research 

for Pesticides Involving Intentional Exposure of Non-pregnant Adults

26.1101 To what does this subpart apply?

26.1102 Definitions.

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26.1103--26.1106 [Reserved]

26.1107 IRB membership.

26.1108 IRB functions and operations.

26.1109 IRB review of research.

26.1110 Expedited review procedures for certain kinds of research 

involving no more than minimal risk, and for minor changes in 

approved research.

26.1111 Criteria for IRB approval of research.

26.1112 Review by institution.

26.1113 Suspension or termination of IRB approval of research.

26.1114 Cooperative research.

26.1115 IRB records.

26.1116 General requirements for informed consent.

26.1117 Documentation of informed consent.

26.1118--26.1122 [Reserved]

26.1123 Early termination of research.

26.1124 [Reserved]

26.1125 Prior submission of proposed human research for EPA review.

Subpart L--Prohibition of Third-Party Research for Pesticides Involving 

Intentional Exposure of Human Subjects who are Pregnant Women or Children

26.1201 To what does this subpart apply?

26.1202 Definitions.

26.1203 Prohibition of research involving intentional exposure of 

any pregnant woman, fetus, or child.

Subpart M--Requirements for Submission of Information on the Ethical 

Conduct of Completed Human Research

26.1301 To what does this subpart apply?

26.1302 Definitions.

26.1303 Submission of information pertaining to ethical conduct of 

completed human research.

Subpart N--[Reserved]

Subpart O--Administrative Actions for Noncompliance

26.1501 To what does this subpart apply?

26.1502 Lesser administrative actions.

26.1503 Disqualification of an IRB or an institution.

26.1504 Public disclosure of information regarding revocation.

26.1505 Reinstatement of an IRB or an institution.

26.1506 Debarment.

26.1507 Actions alternative or additional to disqualification.

Subpart P--Review of Proposed and Completed Human Research

26.1601 EPA review of proposed human research.

26.1602 EPA review of completed human research.

26.1603 Operation of the Human Studies Review Board.

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Subpart Q--Ethical Standards for Assessing Whether to Rely on the 

Results of Human Research in EPA Actions

26.1701 To what does this subpart apply?

26.1702 Definitions.

26.1703 Prohibition of reliance on research involving intentional 

exposure of human subjects who are pregnant women (and therefore 

their fetuses) or children.

26.1704 Prohibition of reliance on unethical human research with 

non-pregnant adults conducted before April 7, 2006.

26.1705 Prohibition of reliance on unethical human research with 

non-pregnant adults conducted after April 7, 2006.

26.1706 Criteria and procedure for decisions to protect public 

health by relying on otherwise unacceptable research.

Subpart B--Prohibition of Research Conducted or Supported by EPA 

Involving Intentional Exposure of Human Subjects who are Pregnant 

Women or Children.

Sec. 26.201 To what does this subpart apply?

 (a) This subpart applies to all research involving intentional 

exposure of any human subject who is a pregnant woman (and her fetus) 

or a child conducted or supported by the Environmental Protection 

Agency (EPA). This includes research conducted in EPA facilities by any 

person and research conducted in any facility by EPA employees.

 (b) The requirements of this subpart are in addition to those 

imposed under the other subparts of this part.

Sec. 26.202 Definitions.

 The definitions in Sec. 26.102 shall be applicable to this 

subpart as well. In addition, the definitions at 45 CFR

[[Page 6169]]

46.202(a) through (f) and at 45 CFR 46.202(h) are applicable to this 

subpart.

 (a) Research involving intentional exposure of a human subject 

means a study of a 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.

 (b) A child is a person who has not attained the age of 18 years.

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Sec. 26.203 Prohibition of research conducted or supported by EPA 

involving intentional exposure of any human subject who is a pregnant 

woman (and therefore her fetus) or child.

 Notwithstanding any other provision of this part, under no 

circumstances shall EPA conduct or support research involving 

intentional exposure of any human subject who is a pregnant woman (and 

therefore her fetus) or child.

Subpart C--Observational Research: Additional Protections for 

Pregnant Women and Fetuses Involved as Subjects in Observational 

Research Conducted or Supported by EPA

Sec. 26.301 To what does this subpart apply?

 (a) Except as provided in paragraph (b) of this section, this 

subpart applies to all observational research involving human subjects 

who are pregnant women (and therefore their fetuses) conducted or 

supported by the Environmental Protection Agency (EPA). This includes 

research conducted in EPA facilities by any person and research 

conducted in any facility by EPA employees.

 (b) The exemptions at Sec. 26.101(b)(1) through (b)(6) are 

applicable to this subpart.

 (c) The provisions of Sec. 26.101(c) through (i) are applicable to 

this subpart. References to State or local laws in this subpart and in 

Sec. 26.101(f) are intended to include the laws of federally 

recognized American Indian and Alaska Native Tribal Governments.

 (d) The requirements of this subpart are in addition to those 

imposed under the other subparts of this part.

Sec. 26.302 Definitions.

 The definitions in Sec. Sec. 26.102 and 26.202 shall be applicable 

to this subpart as well. In addition, observational research means any 

human research that does not meet the definition of research involving 

intentional exposure of a human subject in Sec. 26.202(a).

Sec. 26.303 Duties of IRBs in connection with observational research 

involving pregnant women and fetuses.

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

Sec. 26.304 Additional protections for pregnant women and fetuses 

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involved in observational research.

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

Sec. 26.305 Protections applicable, after delivery, to the placenta, 

the dead fetus, or fetal material.

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

Subpart D--Observational Research: Additional Protections for 

Children Involved as Subjects in Observational Research Conducted 

or Supported by EPA

Sec. 26.401 To what does this subpart apply?

 (a) This subpart applies to all observational research involving 

children as subjects, conducted or supported by EPA. References to 

State or local laws in this subpart and in Sec. 26.101(f) are intended 

to include the laws of federally recognized American Indian and Alaska 

Native Tribal Governments. This includes research conducted in EPA 

facilities by any person and research conducted in any facility by EPA 

employees.

 (b) Exemptions at Sec. 26.101(b)(1) and (b)(3) through (b)(6) are 

applicable to this subpart. The exemption at Sec. 26.101(b)(2) 

regarding educational tests is also applicable to this subpart. 

However, the exemption at Sec. 26.101(b)(2) for research involving 

survey or interview procedures or observations of public behavior does 

not apply to research covered by this subpart, except for research 

involving observation of public behavior when the investigator(s) do 

not participate in the activities being observed.

 (c) The exceptions, additions, and provisions for waiver as they 

appear in Sec. 26.101(c) through (i) are applicable to this subpart.

Sec. 26.402 Definitions.

 The definitions in Sec. 26.102 shall be applicable to this subpart 

as well. In addition, the following terms are defined:

 (a) For purposes of this subpart, 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 by the Administrator.

 (b) Assent means a child's affirmative agreement to participate in 

research. Mere failure to object should not, absent affirmative 

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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.

 (f) Observational research means any research with human subjects 

that does not meet the definition of research involving intentional 

exposure of a human subject in Sec. 26.202(a).

 (g) Minimal risk means that the probability and magnitude of harm 

or discomfort anticipated in the research are not greater in and of 

themselves than those ordinarily encountered in daily life or during 

the performance of routine physical or psychological examinations or tests.

Sec. 26.403 IRB duties.

 In addition to other responsibilities assigned to IRBs under this 

part, each IRB shall review observational research covered by this 

subpart and approve only research that satisfies the conditions of all 

applicable sections of this subpart.

Sec. 26.404 Observational research not involving greater than 

minimal risk.

 EPA will conduct or fund observational 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 permission of their parents or 

guardians, as set forth in Sec. 26.406.

Sec. 26.405 Observational research involving greater than minimal risk 

but presenting the prospect of direct benefit to the individual subjects.

 If the IRB finds that an intervention or procedure presents more 

than minimal risk to children, EPA will not conduct or fund 

observational research that includes such an intervention or procedure 

unless the IRB finds and documents that:

 (a) The intervention or procedure holds out the prospect of direct 

benefit to the individual subject or is likely to contribute to the 

subject's well-being;

 (b) The risk is justified by the anticipated benefit to the subjects;

 (c) The relation of the anticipated benefit to the risk is at least 

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as favorable to the subjects as that presented by available alternative 

approaches; and

 (d) Adequate provisions are made for soliciting the assent of the 

children and

[[Page 6170]]

permission of their parents or guardians, as set forth in Sec. 26.406.

Sec. 26.406 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 observational 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 

observational research. Even where the IRB determines that the subjects 

are capable of assenting, the IRB may still waive the assent 

requirement under circumstances in which consent may be waived in 

accord with Sec. 26.116(d).

 (b) In addition to the determinations required under other 

applicable sections of this subpart, the IRB shall determine, in 

accordance with and to the extent that consent is required by Sec. 

26.116, that adequate provisions are made for soliciting the permission 

of each child's parents or guardian. Where parental permission is to be 

obtained, the IRB may find that the permission of one parent is 

sufficient for research to be conducted under Sec. 26.404 or Sec. 26.405.

 (c) In addition to the provisions for waiver contained in Sec. 

26.116, if the IRB determines that a research protocol is designed for 

conditions or for a subject population for which parental or guardian 

permission is not a reasonable requirement to protect the subjects (for 

example, neglected or abused children), it may replace the consent 

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requirements in subpart A of this part and paragraph (b) of this 

section with provided an appropriate, equivalent 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, equivalent mechanism would depend upon the nature and 

purpose of the activities described in the protocol, the risk and 

anticipated benefit to the research subjects, and their age, maturity, 

status, and condition.

 (d) Permission by parents or guardians shall be documented in 

accordance with and to the extent required by Sec. 26.117.

 (e) When the IRB determines that assent is required, it shall also 

determine whether and how assent must be documented.

Subpart E--[Reserved]

Subpart F--[Reserved]

Subpart G--[Reserved]

Subpart H--[Reserved]

Subpart I--[Reserved]

Subpart J--[Reserved]

Subpart K--Basic Ethical Requirements for Third-Party Human Research for 

Pesticides Involving Intentional Exposure of Non-pregnant Adults

Sec. 26.1101 To what does this subpart apply?

 (a) Except as provided in paragraph (b) of this section, subpart K 

of this part applies to all research initiated after April 7, 2006 

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 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. 

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136 et seq.) or section 408 of the Federal Food, Drug, and Cosmetic Act 

21 U.S.C. 346a).

 (b) Unless otherwise required by the Administrator, research is 

exempt from this subpart if it involves only the collection or study of 

existing data, documents, records, pathological specimens, or 

diagnostic specimens from previously conducted studies, and if these 

sources are publicly available or if the information is recorded by the 

investigator in such a manner that subjects cannot be identified, 

directly or through identifiers linked to the subjects.

 (c) The Administrator retains final judgment as to whether a 

particular activity within the scope of paragraphs (a) and (b) of this 

section is covered by this subpart.

 (d) Compliance with this subpart requires compliance with pertinent 

Federal laws or regulations which provide additional protections for 

human subjects.

 (e) This subpart does not affect any State or local laws or 

regulations which may otherwise be applicable and which provide 

additional protections for human subjects. Reference to State or local 

laws in this subpart is intended to include the laws of federally 

recognized American Indian and Alaska Native Tribal Governments.

 (f) This subpart does not affect any foreign laws or regulations 

which may otherwise be applicable and which provide additional 

protections to human subjects of research.

 (g) For purposes of determining a person's intent under paragraph 

(a) 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.

Sec. 26.1102 Definitions.

 (a) For purposes of this subpart, Administrator means the 

Administrator of the Environmental Protection Agency (EPA) and any 

other officer or employee of EPA to whom authority has been delegated.

 (b) Institution means any public or private entity or agency 

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(including Federal, State, and other agencies).

 (c) Legally authorized representative means an individual or 

judicial or other body authorized under applicable law to consent on 

behalf of a prospective subject to the subject's participation in the 

procedure(s) involved in the research.

 (d) Research means a systematic investigation, including research, 

development, testing and evaluation,

[[Page 6171]]

designed to develop or contribute to generalizable knowledge. 

Activities which meet this definition constitute research for purposes 

of this subpart, whether or not they are considered research for other 

purposes. For example, some demonstration and service programs may 

include research activities.

 (e) Human subject means a living individual about whom an 

investigator (whether professional or student) conducting research obtains:

 (1) Data through intervention or interaction with the individual, 

or

 (2) Identifiable private information.

 (3) ``Intervention'' includes both physical procedures by which 

data are gathered (for example, venipuncture) and manipulations of the 

subject or the subject's environment that are performed for research 

purposes. Interaction includes communication or interpersonal contact 

between investigator and subject. ``Private information'' includes 

information about behavior that occurs in a context in which an 

individual can reasonably expect that no observation or recording is 

taking place, and information which has been provided for specific 

purposes by an individual and which the individual can reasonably 

expect will not be made public (for example, a medical record). Private 

information must be individually identifiable (i.e., the identity of 

the subject is or may readily be ascertained by the investigator or 

associated with the information) in order for obtaining the information 

to constitute research involving human subjects.

 (f) IRB means an institutional review board established in accord 

with and for the purposes expressed in this part.

 (g) IRB approval means the determination of the IRB that the 

research has been reviewed and may be conducted at an institution 

within the constraints set forth by the IRB and by other institutional 

and Federal requirements.

 (h) Minimal risk means that the probability and magnitude of harm 

or discomfort anticipated in the research are not greater in and of 

themselves than those ordinarily encountered in daily life or during 

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the performance of routine physical or psychological examinations or tests.

 (i) Research involving intentional exposure of a human subject 

means a study of a 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.

 (j) Person means any person, as that term is defined in FIFRA 

section 2(s) (7 U.S.C. 136), except:

 (1) A federal agency that is subject to the provisions of the 

Federal Policy for the Protection of Human Subjects of Research, and

 (2) A person when performing human research supported by a federal 

agency covered by paragraph (j)(1) of this section.

Sec. Sec. 26.1103 through 26.1106 [Reserved]

Sec. 26.1107 IRB membership.

 (a) Each IRB shall have at least five members, with varying 

backgrounds to promote complete and adequate review of research 

activities which are presented for its approval. The IRB shall be 

sufficiently qualified through the experience and expertise of its 

members, and the diversity of the members, including consideration of 

race, gender, and cultural backgrounds and sensitivity to such issues 

as community attitudes, to promote respect for its advice and counsel 

in safeguarding the rights and welfare of human subjects. In addition 

to possessing the professional competence necessary to review specific 

research activities, the IRB shall be able to ascertain the 

acceptability of proposed research in terms of institutional 

commitments and regulations, applicable law, and standards of 

professional conduct and practice. The IRB shall therefore include 

persons knowledgeable in these areas. If an IRB regularly reviews 

research that involves a vulnerable category of subjects, such as 

prisoners or handicapped or mentally disabled persons, consideration 

shall be given to the inclusion of one or more individuals who are 

knowledgeable about and experienced in working with these subjects.

 (b) Every nondiscriminatory effort will be made to ensure that no 

IRB consists entirely of men or entirely of women, including the 

institution's consideration of qualified persons of both sexes, so long 

as no selection is made to the IRB on the basis of gender. No IRB may 

consist entirely of members of one profession.

 (c) Each IRB shall include at least one member whose primary 

concerns are in scientific areas and at least one member whose primary 

concerns are in nonscientific areas.

 (d) Each IRB shall include at least one member who is not otherwise 

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affiliated with the institution and who is not part of the immediate 

family of a person who is affiliated with the institution.

 (e) No IRB may have a member participate in the IRB's initial or 

continuing review of any project in which the member has a conflicting 

interest, except to provide information requested by the IRB.

 (f) An IRB may, in its discretion, invite individuals with 

competence in special areas to assist in the review of issues which 

require expertise beyond or in addition to that available on the IRB. 

These individuals may not vote with the IRB.

Sec. 26.1108 IRB functions and operations.

 In order to fulfill the requirements of this subpart each IRB shall:

 (a) Follow written procedures:

 (1) For conducting its initial and continuing review of research 

and for reporting its findings and actions to the investigator and the 

institution;

 (2) For determining which projects require review more often than 

annually and which projects need verification from sources other than 

the investigator that no material changes have occurred since previous 

IRB review;

 (3) For ensuring prompt reporting to the IRB of proposed changes in 

research activity; and

 (4) For ensuring that changes in approved research, during the 

period for which IRB approval has already been given, may not be 

initiated without IRB review and approval except where necessary to 

eliminate apparent immediate hazards to the human subjects.

 (b) Follow written procedures for ensuring prompt reporting to the 

IRB, appropriate institutional officials, and the Environmental 

Protection Agency of:

 (1) Any unanticipated problems involving risks to human subjects or 

others;

 (2) Any instance of serious or continuing noncompliance with this 

subpart of the requirements or determinations of the IRB; or

 (3) Any suspension or termination of IRB approval.

 (c) Except when an expedited review procedure is used (see Sec. 

26.1110), review proposed research at convened meetings at which a 

majority of the members of the IRB are present, including at least one 

member whose primary concerns are in nonscientific areas. In order for 

the research to be approved, it shall receive the approval of a 

majority of those members present at the meeting.

Sec. 26.1109 IRB review of research.

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 (a) An IRB shall review and have authority to approve, require 

modifications in (to secure approval), or disapprove all research 

activities covered by this subpart.

[[Page 6172]]

 (b) An IRB shall require that information given to subjects as part 

of informed consent is in accordance with Sec. 26.1116. The IRB may 

require that information, in addition to that specifically mentioned in 

Sec. 26.1116 be given to the subjects when, in the IRB's judgment, the 

information would meaningfully add to the protection of the rights and 

welfare of subjects.

 (c) An IRB shall require documentation of informed consent in 

accordance with Sec. 26.1117.

 (d) An IRB shall notify investigators and the institution in 

writing of its decision to approve or disapprove the proposed research 

activity, or of modifications required to secure IRB approval of the 

research activity. If the IRB decides to disapprove a research 

activity, it shall include in its written notification a statement of 

the reasons for its decision and give the investigator an opportunity 

to respond in person or in writing.

 (e) An IRB shall conduct continuing review of research covered by 

this subpart at intervals appropriate to the degree of risk, but not 

less than once per year, and shall have authority to observe or have a 

third party observe the consent process and the research.

Sec. 26.1110 Expedited review procedures for certain kinds of 

research involving no more than minimal risk, and for minor changes in 

approved research.

 (a) The Secretary, HHS, has established, and published as a Notice 

in the Federal Register, a list of categories of research that may be 

reviewed by the IRB through an expedited review procedure. The list 

will be amended, as appropriate after consultation with other 

departments and agencies, through periodic republication by the 

Secretary, HHS, in the Federal Register. A copy of the list is 

available from the Office for Human Research Protections, HHS, or any 

successor office.

 (b)(1) An IRB may use the expedited review procedure to review 

either or both of the following:

 (i) Some or all of the research appearing on the list and found by 

the reviewer(s) to involve no more than minimal risk,

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 (ii) Minor changes in previously approved research during the 

period (of 1 year or less) for which approval is authorized.

 (2) Under an expedited review procedure, the review may be carried 

out by the IRB chairperson or by one or more experienced reviewers 

designated by the chairperson from among members of the IRB. In 

reviewing the research, the reviewers may exercise all of the 

authorities of the IRB except that the reviewers may not disapprove the 

research. A research activity may be disapproved only after review in 

accordance with the non-expedited procedure set forth in Sec. 26.1108(b).

 (c) Each IRB which uses an expedited review procedure shall adopt a 

method for keeping all members advised of research proposals which have 

been approved under the procedure.

 (d) The Administrator may restrict, suspend, or terminate, an 

institution's or IRB's use of the expedited review procedure for 

research covered by this subpart.

Sec. 26.1111 Criteria for IRB approval of research.

 (a) In order to approve research covered by this subpart the IRB 

shall determine that all of the following requirements are satisfied:

 (1) Risks to subjects are minimized:

 (i) By using procedures which are consistent with sound research 

design and which do not unnecessarily expose subjects to risk, and

 (ii) Whenever appropriate, by using procedures already being 

performed on the subjects for diagnostic or treatment purposes.

 (2) Risks to subjects are reasonable in relation to anticipated 

benefits, if any, to subjects, and the importance of the knowledge that 

may reasonably be expected to result. In evaluating risks and benefits, 

the IRB should consider only those risks and benefits that may result 

from the research (as distinguished from risks and benefits subjects 

would receive even if not participating in the research). The IRB 

should not consider possible long-range effects of applying knowledge 

gained in the research (for example, the possible effects of the 

research on public policy) as among those research risks that fall 

within the purview of its responsibility.

 (3) Selection of subjects is equitable. 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 prisoners, mentally disabled persons, 

or economically or educationally disadvantaged persons.

 (4) Informed consent will be sought from each prospective subject 

or the subject's legally authorized representative, in accordance with, 

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and to the extent required by Sec. 26.1116.

 (5) Informed consent will be appropriately documented, in 

accordance with, and to the extent required by Sec. 26.1117.

 (6) When appropriate, the research plan makes adequate provision 

for monitoring the data collected to ensure the safety of subjects.

 (7) When appropriate, there are adequate provisions to protect the 

privacy of subjects and to maintain the confidentiality of data.

 (b) When some or all of the subjects are likely to be vulnerable to 

coercion or undue influence, such as prisoners, mentally disabled 

persons, or economically or educationally disadvantaged persons, 

additional safeguards have been included in the study to protect the 

rights and welfare of these subjects.

Sec. 26.1112 Review by institution.

 Research covered by this subpart that has been approved by an IRB 

may be subject to further appropriate review and approval or 

disapproval by officials of the institution. However, those officials 

may not approve the research if it has not been approved by an IRB.

Sec. 26.1113 Suspension or termination of IRB approval of research.

 An IRB shall have authority to suspend or terminate approval of 

research that is not being conducted in accordance with the IRB's 

requirements or that has been associated with unexpected serious harm 

to subjects. Any suspension or termination of approval shall include a 

statement of the reasons for the IRB's action and shall be reported 

promptly to the investigator, appropriate institutional officials, and 

the Administrator of EPA.

Sec. 26.1114 Cooperative research.

 In complying with this subpart, sponsors, investigators, or 

institutions involved in multi-institutional studies may use joint 

review, reliance upon the review of another qualified IRB, or similar 

arrangements aimed at avoidance of duplication of effort.

Sec. 26.1115 IRB records.

 (a) An IRB shall prepare and maintain adequate documentation of IRB 

activities, including the following:

 (1) Copies of all research proposals reviewed, scientific 

evaluations, if any, that accompany the proposals, approved sample 

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consent documents, progress reports submitted by investigators, and 

reports of injuries to subjects.

 (2) Minutes of IRB meetings which shall be in sufficient detail to 

show attendance at the meetings; actions taken by the IRB; the vote on 

these actions including the number of members voting for, against, and 

abstaining; the basis for requiring changes in or disapproving 

research; and a written summary of the

[[Page 6173]]

 discussion of controverted issues and their resolution.

 (3) Records of continuing review activities.

 (4) Copies of all correspondence between the IRB and the investigators.

 (5) A list of IRB members identified by name; earned degrees; 

representative capacity; indications of experience such as board 

certifications, licenses, etc., sufficient to describe each member's 

chief anticipated contributions to IRB deliberations; and any 

employment or other relationship between each member and the 

institution, for example, full-time employee, a member of governing 

panel or board, stockholder, paid or unpaid consultant.

 (6) Written procedures for the IRB in the same detail as described 

in Sec. 26.1108(a) and Sec. 26.1108(b).

 (7) Statements of significant new findings provided to subjects, as 

required by Sec. 26.1116(b)(5).

 (b) The records required by this subpart shall be retained for at 

least 3 years, and records relating to research which is conducted 

shall be retained for at least 3 years after completion of the 

research. All records shall be accessible for inspection and copying by 

authorized representatives of EPA at reasonable times and in a 

reasonable manner.

Sec. 26.1116 General requirements for informed consent.

 No investigator may involve a human being as a subject in research 

covered by this subpart unless the investigator has obtained the 

legally effective informed consent of the subject or the subject's 

legally authorized representative. An investigator shall seek such 

consent only under circumstances that provide the prospective subject 

or the representative sufficient opportunity to consider whether or not 

to participate and that minimize the possibility of coercion or undue 

influence. The information that is given to the subject or the 

representative shall be in language understandable to the subject or 

the representative. No informed consent, whether oral or written, may 

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include any exculpatory language through which the subject or the 

representative is made to waive or appear to waive any of the subject's 

legal rights, or releases or appears to release the investigator, the 

sponsor, the institution or its agents from liability for negligence.

 (a) Basic elements of informed consent. In seeking informed consent 

the following information shall be provided to each subject:

 (1) A statement that the study involves research, an explanation of 

the purposes of the research and the expected duration of the subject's 

participation, a description of the procedures to be followed, and 

identification of any procedures which are experimental;

 (2) A description of any reasonably foreseeable risks or 

discomforts to the subject;

 (3) A description of any benefits to the subject or to others which 

may reasonably be expected from the research;

 (4) A disclosure of appropriate alternative procedures or courses 

of treatment, if any, that might be advantageous to the subject;

 (5) A statement describing the extent, if any, to which 

confidentiality of records identifying the subject will be maintained;

 (6) For research involving more than minimal risk, an explanation 

as to whether any compensation and an explanation as to whether any 

medical treatments are available if injury occurs and, if so, what they 

consist of, or where further information may be obtained;

 (7) An explanation of whom to contact for answers to pertinent 

questions about the research and research subjects' rights, and whom to 

contact in the event of a research-related injury to the subject; and

 (8) A statement that participation is voluntary, refusal to 

participate will involve no penalty or loss of benefits to which the 

subject is otherwise entitled, and the subject may discontinue 

participation at any time without penalty or loss of benefits to which 

the subject is otherwise entitled.

 (b) Additional elements of informed consent. When appropriate, one 

or more of the following elements of information shall also be provided 

to each subject:

 (1) A statement that the particular treatment or procedure may 

involve risks to the subject (or to the embryo or fetus, if the subject 

may become pregnant) which are currently unforeseeable;

 (2) Anticipated circumstances under which the subject's 

participation may be terminated by the investigator without regard to 

the subject's consent;

 (3) Any additional costs to the subject that may result from 

participation in the research;

 (4) The consequences of a subject's decision to withdraw from the 

research and procedures for orderly termination of participation by the 

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subject;

 (5) A statement that significant new findings developed during the 

course of the research which may relate to the subject's willingness to 

continue participation will be provided to the subject; and

 (6) The approximate number of subjects involved in the study.

 (c) The informed consent requirements in this subpart are not 

intended to preempt any applicable Federal, State, or local laws which 

require additional information to be disclosed in order for informed 

consent to be legally effective.

 (d) Nothing in this subpart is intended to limit the authority of a 

physician to provide emergency medical care, to the extent the 

physician is permitted to do so under applicable Federal, State, or 

local law.

 (e) If the research involves intentional exposure of subjects to a 

pesticide, the subjects of the research must be informed of the 

identity of the pesticide and the nature of its pesticidal function.

Sec. 26.1117 Documentation of informed consent.

 (a) Informed consent shall be documented by the use of a written 

consent form approved by the IRB and signed by the subject or the 

subject's legally authorized representative. A copy shall be given to 

the person signing the form.

 (b) The consent form may be either of the following:

 (1) A written consent document that embodies the elements of 

informed consent required by Sec. 26.1116. This form may be read to 

the subject or the subject's legally authorized representative, but in 

any event, the investigator shall give either the subject or the 

representative adequate opportunity to read it before it is signed; or

 (2) A short form written consent document stating that the elements 

of informed consent required by Sec. 26.1116 have been presented 

orally to the subject or the subject's legally authorized 

representative. When this method is used, there shall be a witness to 

the oral presentation. Also, the IRB shall approve a written summary of 

what is to be said to the subject or the representative. Only the short 

form itself is to be signed by the subject or the representative. 

However, the witness shall sign both the short form and a copy of the 

summary, and the person actually obtaining consent shall sign a copy of 

the summary. A copy of the summary shall be given to the subject or the 

representative, in addition to a copy of the short form.

Sec. Sec. 26.1118 through 26.1122 [Reserved]

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Sec. 26.1123 Early termination of research.

 The Administrator may require that any project covered by this 

subpart be terminated or suspended when the

[[Page 6174]]

Administrator finds that an IRB, investigator, sponsor, or institution 

has materially failed to comply with the terms of this subpart.

Sec. 26.1124 [Reserved]

Sec. 26.1125 Prior submission of proposed human research for EPA review.

 Any person or institution who intends to conduct or sponsor human 

research covered by Sec. 26.1101(a) shall, after receiving approval 

from all appropriate IRBs, submit to EPA prior to initiating such 

research all information relevant to the proposed research specified by 

Sec. 26.1115(a), and the following additional information, to the 

extent not already included:

 (a) A discussion of:

 (1) The potential risks to human subjects;

 (2) The measures proposed to minimize risks to the human subjects;

 (3) The nature and magnitude of all expected benefits of such 

research, and to whom they would accrue;

 (4) Alternative means of obtaining information comparable to what 

would be collected through the proposed research; and

 (5) The balance of risks and benefits of the proposed research.

 (b) All information for subjects and written informed consent 

agreements as originally provided to the IRB, and as approved by the IRB.

 (c) Information about how subjects will be recruited, including any 

advertisements proposed to be used.

 (d) A description of the circumstances and methods proposed for 

presenting information to potential human subjects for the purpose of 

obtaining their informed consent.

 (e) All correspondence between the IRB and the investigators or 

sponsors.

 (f) Official notification to the sponsor or investigator, in 

accordance with the requirements of this subpart, that research 

involving human subjects has been reviewed and approved by an IRB.

Subpart L--Prohibition of Third-Party Research for Pesticides 

Involving Intentional Exposure of Human Subjects who are Pregnant 

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Women or Children

Sec. 26.1201 To what does this subpart apply?

 Subpart L applies to any person who, after April 7, 2006, conducts 

or supports research with a human subject intended:

 (1) For submission to EPA for consideration in connection with any 

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 be held 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).

 (b) For purposes of determining a person's intent under paragraph 

(a) 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.

Sec. 26.1202 Definitions.

 The definitions in Sec. 26.1102 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. In 

addition, a child is a person who has not attained the age of 18 years.

Sec. Sec. 26.1203 Prohibition of research involving intentional 

exposure of any pregnant woman, fetus, or child.

 Notwithstanding any other provision of this part, under no 

circumstances shall a person conduct or sponsor research covered by 

Sec. 26.1201 that involves intentional exposure of any human subject 

who is a pregnant woman (and therefore her fetus) or child.

Subpart M--Requirements for Submission of Information on the 

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Ethical Conduct of Completed Human Research

Sec. 26.1301 To what does this subpart apply?

 This subpart applies to any person who submits a report containing 

the results of any human research if:

 (a) The report is submitted after April 7, 2006, and

 (b) The report is submitted for consideration in connection with 

any 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).

Sec. 26.1302 Definitions.

 The definitions in Sec. 26.102 shall apply to this subpart as well.

Sec. 26.1303 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 provide at the time of submission 

information concerning the ethical conduct of such research. To the 

extent available to the submitter and not previously provided to EPA, 

such information should include:

 (a) Copies of all of the records relevant to the research specified 

by Sec. 26.1115(a) to be prepared and maintained by an IRB.

 (b) Copies of all of the records relevant to the information 

identified in Sec. 26.1125(a) through (f).

 (c) Copies of sample records used to document informed consent as 

specified by Sec. 26.1117, but not identifying any subjects of the 

research.

 (d) If any of the information listed in paragraphs (a) through (c) 

of this section is not provided, the person shall describe the efforts 

made to obtain the information.

Subpart N--[Reserved]

Subpart O--Administrative Actions for Noncompliance

Sec. 26.1501 To what does this subpart apply?

 This subpart applies to any human research subject to subparts A 

through L of this part. References to State or local laws in this 

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subpart are intended to include the laws of federally recognized 

American Indian and Alaska Native Tribal Governments.

Sec. 26.1502 Lesser administrative actions.

 (a) If apparent noncompliance with the applicable regulations in 

subparts A through L of this part concerning the operation of an IRB is 

observed by an officer or employee of EPA or of any State duly 

designated by the Administrator during an inspection. EPA may 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 reasonable 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

[[Page 6175]]

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 of 

the deficiencies in the operation of the IRB.

 (c) The parent institution is presumed to be responsible for the 

operation of an IRB, and EPA will ordinarily direct any administrative 

action under this subpart against the institution. However, depending 

on the evidence of responsibility for deficiencies, determined during 

the investigation, EPA may restrict its administrative actions to the 

IRB or to a component of the parent institution determined to be 

responsible for formal designation of the IRB.

Sec. 26.1503 Disqualification of an IRB or an institution.

 (a) Whenever the IRB or the institution has failed to take adequate 

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steps to correct the noncompliance stated in the letter sent by the 

Agency under Sec. 26.1502(a) and the EPA Administrator determines that 

this noncompliance may justify the 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 from studies subject to this part 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 L 

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 L of this 

part, that was reviewed by an IRB or conducted at an institution during 

the period of disqualification, unless the IRB or the parent 

institution is reinstated as provided in Sec. 26.1505, or unless such 

research is deemed scientifically sound and crucial to the protection 

of public health, under the procedure defined in Sec. 26.1706.

Sec. 26.1504 Public disclosure of information regarding revocation.

 A determination that EPA has disqualified an institution from 

studies subject to this part and the administrative record regarding 

that determination are disclosable to the public under 40 CFR part 2.

Sec. 26.1505 Reinstatement of an IRB or an institution.

 An IRB or an institution may be reinstated to conduct studies 

subject to this part 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 has taken or 

plans to take, that the IRB or institution has provided adequate 

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assurance that it will operate in compliance with the standards set 

forth in this part. Notification of reinstatement shall be provided to 

all persons notified under Sec. 26.1502(c).

Sec. 26.1506 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 L of this part, EPA may 

recommend that institution or investigator be declared ineligible to 

participate in EPA-supported research (debarment). Debarment will be 

initiated in accordance with procedures specified at 40 CFR part 32.

Sec. 26.1507 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 P--Review of Proposed and Completed Human Research

Sec. 26.1601 EPA review of proposed human research.

 (a) EPA shall review all protocols submitted under Sec. 26.1125 in 

a timely manner. With respect to any research or any class of research, 

the Administrator may recommend additional conditions which, in the 

judgment of the Administrator, are necessary for the protection of 

human subjects.

 (b) In reviewing proposals covered by this subpart, the 

Administrator may take into account factors such as whether the 

applicant has been subject to a termination or suspension under Sec. 

26.123(a) or Sec. 26.1123 and whether the applicant or the person or 

persons who would direct or has/have directed the scientific and 

technical aspects of an activity has/have, in the judgment of the 

Administrator, materially failed to discharge responsibility for the 

protection of the rights and welfare of human subjects (whether or not 

the research was subject to Federal regulation).

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 (c) When research covered by subpart K takes place in foreign 

countries, procedures normally followed in the foreign countries to 

protect human subjects may differ from those set forth in subpart K. 

(An example is a foreign institution which complies with guidelines 

consistent with the World Medical Assembly Declaration of Helsinki, 

issued either by sovereign states or by an organization whose function 

for the protection of human research subjects is internationally 

recognized.) In these circumstances, if the Administrator determines 

that the procedures prescribed by the institution afford protections 

that are at least equivalent to those provided in subpart K, the 

Administrator may approve the substitution of the foreign procedures in 

lieu of the procedural requirements provided in subpart K.

 (d) 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.

 (e) EPA shall notify the submitter of the proposal of the results 

of the EPA and Human Studies Review Board reviews.

[[Page 6176]]

Sec. 26.1602 EPA review of completed human research.

 (a) When considering data under FIFRA or FFDCA from research 

involving intentional exposure of humans, EPA shall review the material 

submitted under Sec. 26.1303 and other available, relevant information 

and document its conclusions regarding the scientific and ethical 

conduct of the research.

 (b) EPA shall submit its review of data from human research covered 

by subpart Q, together with the available supporting materials, to the 

Human Studies Review Board if EPA decides to rely on the data and:

 (1) The data are derived from research initiated after April 7, 

2006, or

 (2) The data are derived from research initiated before April 7, 

2006, and the research was conducted for the purpose of identifying or 

measuring a toxic effect.

 (c) In its discretion, EPA may submit data from research not 

covered by paragraph (b) of this section to the Human Studies Review 

Board for their review.

 (d) EPA shall notify the submitter of the research of the results 

of the EPA and Human Studies Review Board reviews.

Sec. 26.1603 Operation of the Human Studies Review Board.

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 EPA shall establish and operate a Human Studies Review Board as follows:

 (a) Membership. The Human Studies Review Board shall consist of 

members who are not employed by EPA, who meet the ethics and other 

requirements for special government employees, and who have expertise 

in fields appropriate for the scientific and ethical review of human 

research, including research ethics, biostatistics, and human toxicology.

 (b) Responsibilities. The Human Studies Review Board shall comment 

on the scientific and ethical aspects of research proposals and reports 

of completed research with human subjects submitted by EPA for its 

review and, on request, advise EPA on ways to strengthen its programs 

for protection of human subjects of research.

Subpart Q--Ethical Standards for Assessing Whether to Rely on the 

Results of Human Research in EPA Actions

Sec. 26.1701 To what does this subpart apply?

 This subpart applies to EPA's decisions whether to rely in its 

actions taken 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) on scientifically valid and relevant 

data from research involving intentional exposure of human subjects.

Sec. 26.1702 Definitions.

 The definitions in Sec. 26.1102 and Sec. 26.1202 shall apply to 

this subpart as well.

Sec. 26.1703 Prohibition of reliance on research involving 

intentional exposure of human subjects who are pregnant women (and 

therefore their fetuses) or children.

 Except as provided in Sec. 26.1706, in actions within the scope of 

Sec. 26.1701, EPA shall not rely on data from any research involving 

intentional exposure of any human subject who is a pregnant woman (and 

therefore her fetus) or child.

Sec. 26.1704 Prohibition of reliance on unethical human research with 

non-pregnant adults conducted before April 7, 2006.

 Except as provided in Sec. 26.1706, in actions within the scope of 

Sec. 26.1701, EPA shall not rely on data from any research initiated 

before April 7, 2006, if there is clear and convincing evidence that 

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the conduct of the 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. This prohibition is in addition to the prohibition in Sec. 

26.1703.

Sec. 26.1705 Prohibition of reliance on unethical human research with 

non-pregnant adults conducted after April 7, 2006.

 Except as provided in Sec. 26.1706, in actions within the scope of 

Sec. 26.1701, EPA shall not rely on data from any research initiated 

after April 7, 2006, unless EPA has adequate information to determine 

that the research was conducted in substantial compliance with subparts 

A through L of this part, or if conducted in a foreign country, under 

procedures at least as protective as those in subparts A through L of 

this part. This prohibition is in addition to the prohibition in Sec. 

26.1703.

Sec. 26.1706 Criteria and procedure for decisions to protect public 

health by relying on otherwise unacceptable research.

 This section establishes the exclusive criteria and procedure by 

which EPA may decide to rely on data from research that is not 

acceptable under the standards in Sec. Sec. 26.1703 through 26.1705. 

EPA may rely on such data only if all the conditions in paragraphs (a) 

through (d) of this section are satisfied:

 (a) EPA has obtained the views of the Human Studies Review Board 

concerning the proposal to rely on the otherwise unacceptable data,

 (b) EPA has provided an opportunity for public comment on the 

proposal to rely on the otherwise unacceptable data,

 (c) EPA has determined that relying on the data is crucial to a 

decision that would impose a more stringent regulatory restriction that 

would improve protection of public health, such as a limitation on the 

use of a pesticide, than could be justified without relying on the 

data, and

 (d) EPA publishes a full explanation of its decision to rely on the 

otherwise unacceptable data, including a thorough discussion of the 

ethical deficiencies of the underlying research and the full rationale 

for finding that the standard in paragraph (c) of this section was met.

[FR Doc. 06-1045 Filed 2-3-06; 8:45 am]

BILLING CODE 6560-50-S 

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