*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 1 of 44 [RIN 2070-AJ76] EO12866_HumanSubjectsRevisio ns_NPRM_2010-09-17.docx

BILLING CODE 6560–50–P

ENVIRONMENTAL PRO TECTION AGENCY

40 CFR Part 26

[EPA–HQ–OPP–2010–0785; FRL– XXXX

– X ]

RIN 2070–AJ76

Revisions to EPA’s Rule on Protections for Subjects in Human Research Involving

Pesticides

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA proposes to amend the portions of its rules for the protection of human subjects of research applying to third parties who conduct or support research for pesticides involving intentional exposure of human subjects and to persons who submit the results of human research for pesticides to EPA. EPA agreed to propose these amendments as a result of a settlement agreement resolving a judicial challenge to the pr omulgation of these rules in 2006, and is now seeking comment on these proposed amendments. The proposed amendments would broaden the applicability of the rules to cover human testing for pesticides submitted to EPA under any regulatory statute. They would also disallow participation in pesticide studies by subjects who cannot consent for themselves. Fina lly they would identify specific considerations

to be addressed in EPA science and ethics re views of proposed and completed human research for pesticides, drawn from the recommendations of the National Academy of Sciences (NAS) and from the Nuremberg Code.

DATES: Comments must be receive d on or before [INSERT DATE 60 DAYS AFTER DATE

OF PUBLICATION IN THE FEDERAL REGISTER ].

ADDRESSES: Submit your comments, identified by doc ket identification (ID) number EPA– HQ–OPP–2010–0785, by one of the following methods:

• Federal eRulemaking Portal : http://www.regulations.gov . Follow the on-line instructions for submitting comments.

• Mail : Office of Pesticide Programs (OPP) Regulatory Public Docket (7502P), Environmental Protection Agency, 1200 Pe nnsylvania Ave., NW., Washington, DC 20460–

0001.

• Delivery : OPP Regulatory Public Do cket (7502P), Environmental Protection Agency, Rm. S–4400, One Potomac Yard (South Bldg.), 2 777 S. Crystal Dr., Arlington, VA. Deliveries*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 2 of 44 [RIN 2070-AJ76] are only accepted during the Docket Facility’s no rmal hours of operation (8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays). Special arrangements should be made for deliveries of boxed information. The Docket Facility telephone number is (703) 305–5805.

Instructions : Direct your comments to docke t ID number EPA–HQ–OPP–2010–0785. EPA's policy is that all comments received will be included in the docket without change and may be made available on-line at http://www.regulations.gov , including any personal information provided, unless the comment include s information claimed to be Confidential Business Information (CBI) or other information w hose disclosure is restri cted by statute. Do not submit information that you consider to be CBI or otherwise protected through regulations.gov or e-mail. The regulations.gov website is an “anonymous access” system, which means EPA will not know your identity or contac t information unless you provide it in the body of your comment. If you send an e-mail co mment directly to EP A without going through regulations.gov, your e-mail address will be automati cally captured and included as part of the comment that is placed in the docket and made available on the Internet. If you submit an electronic comment, EPA recomme nds that you include your name and other contact information in the body of your comment and with any disk or CD-ROM you submit. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment . Electronic files should avoid the use of special characters, any form of encryption, and be free of any defects or viruses.

Docket : All documents in the docket are list ed in the docket index available at http://www.regulations.gov . Although listed in the index, so me information is not publicly available, e.g., CBI or other information whose disc losure is restricted by statute. Certain other material, such as copyrighted material, is not pl aced on the Internet and will be publicly available only in hard copy form. Publicly available docket materials are av ailable either in the electronic

docket at http://www.regulations.gov , or, if only available in ha rd copy, at the OPP Regulatory Public Docket in Rm. S–4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The hours of operation of this Docket Fa cility are from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal ho lidays. The Docket Facility telephone number is (703) 305–

5805.

FOR FURTHER INFORMATION CONTACT: Kelly Sherman, Immediate Office of the Director (7501P), Office of Pesticide Pr ograms, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460–0001; telephone number: (703) 305-8401; fax number: (703) 308-4776; e-mail address: sherman.kelly@epa.gov

.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be potentially affected by this ac tion if you sponsor, conduct, review, or submit to EPA research for pesticides involving human subjects. Potentially affected entities may include, but are not limited to:

• Pesticide and other agri cultural chemical manufactur ers (NAICS code 325320) who*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 3 of 44 [RIN 2070-AJ76] sponsor or conduct human re search for pesticides.

• Other entities (NAICS code 541710) that sponsor or conduct human research for pesticides, and Institutional Revi ew Boards who review human rese arch for pesticides to ensure it meets applicable standards of ethical conduct.

This listing is not intended to be exhaustiv e, but rather provides a guide for readers regarding entities likely to be aff ected by this action. Other types of entities not listed in this unit

could also be affected. The North American I ndustrial Classification Sy stem (NAICS) codes are provided to assist you and others in determining whether this action might apply to certain entities. If you have any questions regarding the applicab ility of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT

.

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

1. Submitting CBI . Do not submit confidential business information (CBI) to EPA through regulations.gov or e-mail. Clearly mark th e part or all of the in formation that you claim

to be CBI. For CBI information in a disk or CD -ROM that you mail to EP A, mark the outside of the disk or CD-ROM as CBI and then identify electronically within th e disk or CD-ROM the specific information that is claimed as CBI. In addition to one complete version of the comment that includes information claimed as CBI, a reda cted copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2.

2. Tips for preparing your comments . When submitting comments, remember to:

i. Identify the document by docket ID number and other identifying information (subject heading, Federal Register date and page number).

ii. Follow directions. The Agency may ask you to respond to specific questions or organize comments by referencing a Code of Federal Regulations (CFR) part or section number.

iii. Explain why you agree or disagree; suggest alternatives and substitute language for your requested changes.

iv. Describe any assumptions and provide a ny technical information and/or data that you

used.

v. If you estimate potential costs or burdens, explain how you arrived at your estimate in sufficient detail to allow for it to be reproduced.

vi. Provide specific examples to illustrate your concerns and suggest alternatives.

vii. Explain your views as cl early as possible, avoiding the use of profanity or personal

threats.

viii. Make sure to submit your comments by the comment period deadline identified.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 4 of 44 [RIN 2070-AJ76] II. Background

A. What would the proposed amendments do?

The proposed amendments would change the 200 6 rule, published in the Federal Register on February 6, 2006 (71 FR 6138) (FRL 7759-8), subsequently amended on June 23, 2006 (71 FR 36171) (FRL 8071-6), and codified at 40 CFR part 26, in the following s ubstantive respects:

• By broadening the applicability of 40 CFR part 26, subparts K, L, M, and Q so these subparts would apply not only to research submitte d to or considered by EPA under the pesticide laws, but also to research i nvolving a “pesticide” (as defined in the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) (7 U.S.C. 136(u)) which is submitted to or considered by EPA under any other regulat ory statute it administers.

• By incorporating the definition of “pestici de” from FIFRA, as a substance or mixture of substances intended for pesticidal effect.

• By deleting from 40 CFR part 26, subpart K all references to cons ent on behalf of a subject in research involving intentional exposure to a pes ticide by a subject’s “legally authorized representative.”

• By incorporating into 40 CFR part 26, s ubparts P and Q factors to be considered by EPA and the Human Studies Review Board (HSRB) in their review of proposed and completed research, derived from the reco mmendations of the NAS in their 2004 report to EPA, and from the Nuremberg Code.

The amendments proposed here would make no changes to the Federal Policy for the Protection of Human Subj ects of Research (the “Common Ru le”), which governs research with human subjects conducted or supported by EP A and many other Federal departments and agencies. EPA’s codification of the Common Rule appears as subpart A in 40 CFR part 26.

Subparts B, C, and D of 40 CFR part 26 would also be unchanged by these proposed amendments. These subparts categorically prohibit any EPA research involving intentional exposure to any substance of human subjects w ho are children or pregna nt or nursing women (40 CFR part 26, subpart B), and provi de extra protections for pregnant women and for children who are the subjects of observational research conducted or supported by EPA (40 CFR part 26, subparts C and D).

The proposed amendments would retain without substantive change the core provisions of the 2006 rule applying to the conduct of hum an pesticide research by third parties—i.e., research neither conducted nor supported by EPA or another Common Rule Federal department or agency. These substan tively unchanged provisions:

• Categorically prohibit new research i nvolving intentional expos ure of pregnant or nursing women or of children to a pe sticide (40 CFR pa rt 26, subpart L).*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 5 of 44 [RIN 2070-AJ76] • Apply the provisions of the Common Rule to third-party human research involving intentional exposure of non-pregna nt, non-nursing adults to a pest icide (40 CFR part 26, subpart K).

• Require submission to EPA of proposals for new covered research before it is initiated (40 CFR part 26, subpart K, §26.1125).

• Require persons who submit to EPA reports of completed human research on pesticides

to document the ethical conduct of that research (40 CFR part 26, subpart M).

• Establish an independent HSRB to review and advise EPA concerning both proposals for new human research involving intentional exposure to a pes ticide and reports of completed research on which EPA proposes to rely in its actions (40 CFR part 26, subpart P).

The proposed amendments would make only mi nor editorial revisions to 40 CFR part 26, subpart O, which defines administrative actions available to EPA to address non-compliance with 40 CFR part 26, subparts A through L.

The proposed amendments would retain the es sential structure of 40 CFR part 26, subpart P, which defines the processes of EPA and HSRB review of proposed and completed research. The amendments, however, would also add substa ntial new clarifying language to 40 CFR part 26, subpart P as discussed in detail in Unit IV.C. of this document.

The proposed amendments would retain the es sential structure of 40 CFR part 26, subpart Q, which defines the standards to be applied wh en EPA proposes to rely on data from completed research involving intentional e xposure of human subjects to a pesticide. The amendments, however, would also add substa ntial new clarifying language to 40 CFR part 26, subpart Q as

discussed in detail in Unit IV.D. of this document.

The proposed amendments would not change the provision in 40 CFR part 26, subpart Q forbidding EPA to rely on any otherwise unacceptab le research involving intentional exposure of human subjects to a pesticide, except under ex tremely restrictive conditions. These conditions require a public review by the HSRB, an opportun ity for public comment, and a showing by EPA

that to do so would result in a more protective regulato ry standard than coul d be justified without

reliance on the unethical research.

B. What is the Agency's Au thority for Taking this Action?

The legal authority for the 2006 rule on human research is set forth in the preamble to that final rule. These proposed amendments to th at rule rest upon the same legal authority. In particular, the legal authority for expanding th e 2006 rule to cover research involving the intentional exposure of a human subject to a pesticide submitted under any EPA regulatory statute is provided by section 201 of the Departme nt of the Interior, Environment, and Related Agencies Appropriations Act, 2006, Public Law 109- 54 (2006 Appropriations Act), and FIFRA.

The Appropriations Act directly mandates that EPA promulgate a rule on “third-party intentional dosing human toxi city studies for pesticides . . .” without limiting the rule to pesticide*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 6 of 44 [RIN 2070-AJ76] studies submitted under FIFRA or section 408 of the Federal Food, Drug and Cosmetic Act (FFDCA) (21 U.S.C. 346a).

Additionally, under FIFRA, EPA has the aut hority to issue regulations as to both unregistered and registered pesticides used in research involving the in tentional exposure of a human subject, whether or not that research is conducted for submission under FIFRA. Section 3(a) of FIFRA authorizes EPA 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 th e economic, social, and environmental costs and benefits of the use of any pesticide”). EPA conc ludes that there would be an unreasonable risk to humans if unregistered pesticides were used in research involving intentional exposure of human subjects (or sold and distributed for such use) absent compliance with the applicable rules in 40 CFR part 26, as proposed. The importance of thes e rules to the protecti on of human subjects is demonstrated in the 2004 report from the NAS titled “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientif ic and Ethical Issues.”

Section 25(a) of FIFRA author izes EPA to “prescribe regulations to carry out the provisions of [FIFRA].” (7 U.S.C. 136w(a)). Regulations protecting huma n subjects in research involving the intentional exposure of human subjects to registered pesticides will serve this end. FIFRA provides that a pesticide may not be re gistered unless use of the pesticide under its labeling will not cause unreasonable risks to humans or the environm ent, that a pesticide may not be used inconsistent with its label, and that a pesticide may not be used in human testing unless the subjects are fully informed regarding the na ture, purpose, and physical and mental health consequences of the testing and freely vol unteer. (See 7 U.S.C. 136(bb), 136a(c)(5), 136j(a)(2)(G), 136j(a)(2)(P)). Th e 2006 rule and the amendments proposed in this document insure that these provisions regard ing use of registered pesticides in a manner that does not cause

unreasonable risk and full and free c onsent in human testing with pesticides are effectuated.

III. EPA’s Human Subjects Protection Rules

A. Overarching principles

EPA is committed to relying on scientifically sound research that is ethically conducted, and to transparency in its review processes a nd decisionmaking. EPA issued the 2006 rule to

further these commitments. As is discussed la ter in this Unit, expe rience since 2006 has shown clearly that the rule has cont ributed to the soundness of EPA decisions, the scientific soundness of new human research, and the ethical treatment of the subjec ts of new research. This experience has also demonstrated the fundament al compatibility of sound science and high

ethical standards.

The amendments proposed in this document will not alter the Agency’s fundamental

commitment to reliance on sound science that is ethically conducted, nor will they change the essential substantive provisions of the 2006 rule for protecting hu man subjects of research.

These proposed amendments, however, will increase the transparency of EPA decisionmaking, by clarifying the scope and appli cability of the requirements in 40 CFR part 26,*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 7 of 44 [RIN 2070-AJ76] codifying the scope and approach used in EPA’s science and ethics revi ews of human research involving pesticides, and refining th e standards that human research with pesticides must meet to be relied upon by EPA in its actions under any of th e regulatory statutes it administers to protect

health and the environment.

B. EPA’s Implementation of the Common Rule

EPA adopted the Common Rule when it was initially promulgated in 1991. It was codified by EPA at 40 CFR part 26. The Common Rule defines the core protections for human subjects in any research conducted, supported, or otherwise subject to regulation by any Federal department or agency that has adopted the Common Rule.

The ethical basis for the Common Rule is the April 18, 1979 repor t of the National Commission for the Protection of Human Subjects of Biomedical and Be havioral Research, a commission established by the National Research Act (Public Law 93-348), signed into law on July 12, 1974. The report, entitle d “Ethical Principles and Guidelines for the Protection of Human Subjects of Research” and widely known as the Belmont Report, put forth three basic principles governing the use of humans as research subjects: respect for persons, beneficence, and justice. In the years since the publication of the Belmont Repor t, its principles have gained

wide international and cro ss-cultural acceptance.

The regulatory application of the Belmont pr inciples in the Common Rule rests on two pillars of protection: the informed consent process and oversight of the research by an independent body known as an institutional review board (IRB). The Common Rule applies to all human research conducted or supported by EPA.

In addition to oversight by a duly constitute d IRB, all human research conducted or supported by EPA is reviewed by the EPA Human Subjects Research Review Official (HSRRO) to ensure compliance with the Common Rule’s requirements. The HSRRO is an independent, senior EPA official with responsibility for overs eeing all EPA activities involving research with human subjects. It is EPA policy that no human subject may be recruite d or enrolled in any research conducted or supported by the Agency un til that research has be en reviewed by the EPA HSRRO and either approved or determined to be exempt from the Common Rule.

When EPA promulgated the 2006 rule addi ng new subparts to 40 CFR part 26, EPA’s

codification of the Common Rule was rede signated—without change—as 40 CFR part 26, subpart A. The amendments to 40 CFR part 26 proposed in this document would again make no changes to 40 CFR part 26, subpart A, EPA’s codification of the Common Rule.

C. Research Sponsored or Supported by EPA

EPA maintains an active research program to support its regulatory programs. In addition to conducting its own intr amural research, the Agency makes grants to academic and not-for-profit scientific institutions to conduct research under its STAR (Science To Achieve Results) program. See http://www.epa.gov/ncer/grants . The Agency also conducts research jointly with other Federal agen cies. Although it represents on ly a portion of EPA’s overall research effort, some of this research involve s human subjects, and is thus governed by the*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 8 of 44 [RIN 2070-AJ76] Common Rule. Since promulgation of the Comm on Rule in 1991, EPA has worked diligently to ensure its human research complies fully with all requirements of the Common Rule.

In 2006 EPA defined new regulatory requirement s in 40 CFR part 26, subparts B, C, and D that provide additional safeguards for speci fic groups of vulnerabl e subjects. These regulations complement longstand ing internal operati ng procedures designed to ensure the interests of human participants in research that EPA conducts or supports are fully protected.

Subpart B of 40 CFR part 26 categorically prohibits EPA research involving the intentional exposure of children or of pregnant or nursing women to any substance. Subpart C defines additional protections for pregnant wome n (and indirectly their fetuses) involved as subjects in EPA observational research. Subpa rt D of 40 CFR part 26 defines additional protections for children involved as subjects in EPA observational research. The major thrust of these subparts is to limit the risk to which the subjects covered by the subparts may be exposed. Taken together, the provisions in the Common Rule (40 CFR part 26, subpart A) and in subparts B, C, and D of 40 CFR part 26 establish the strong est regulatory protections for participants in human research in force by any Federal agency or department.

EPA’s internal operating procedures require a fu rther level of review to complement that mandated by these regulations. Under EP A Order 1000.17, “Policy and Procedures on

Protection of Human Research S ubjects in EPA Conducted or Suppor ted Research,” all research involving human subjects proposed to be conducte d or supported by EPA must receive approval (or be determined to be exempt from Common Rule and 40 CFR part 26, subpart B, C, and D requirements) not only from an IRB, but also from EPA’s HSRRO.

Finally, EPA recognizes that its observational research in to how behavior and other factors may influence human exposure to environmen tal substances raises scientific and ethical issues differing from those raised by other types of human resear ch. The Agency has developed a guidance document for investigators designi ng and conducting observational exposure studies that identifies and recommends approaches for addressing these issues. The HSRB reviewed a draft of this document favorably in Oc tober 2007; its report is available at http://www.epa.gov/osa/hsrb/files/oc tober2007hsrbfinaldraftreport3608.pdf . EPA subsequently revised the document to incorporate the HSRB’s recommendations and published it in final form in May 2008, titled: “S cientific and Ethical Approaches fo r Observational Exposure Studies.”

Available online at http://www.epa.gov/nerl/sots/SEAOES_doc20080707.pdf . EPA strongly encourages investigators conducti ng observational research to cons ider and apply this guidance.

D. Past Controversy over Third-Party Human Research with Pesticides

Amendments to FFDCA made by the Food Quality Protection Act of 1996 (FQPA) required EPA, when evaluating the safety of pesticide residues in food, to employ a new, additional tenfold uncertainty fact or to increase protection of children. Soon after passage of FQPA a pesticide industry group issued a white pape r noting that the toxic effect serving as the point of departure for most risk assessments of the widely used organophosphate and carbamate pesticides—cholinesterase inhibi tion—was reversible and easily measured. This white paper recommended testing to directly measure cholines terase inhibition in hu mans. Such data, the paper suggested, could be used by EPA in risk assessments without employing another tenfold*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 9 of 44 [RIN 2070-AJ76] uncertainty factor that EPA customarily applie s when estimating safe exposures for humans based on animal toxicity endpoint s. A few studies of cholines terase inhibition in humans had already been conducted or initiated when the 199 6 amendments were enacted, and several more

were initiated soon afterward.

An environmental advocacy group learned of this testing and published a report in 1998 charging that the new studies of cholinesterase inhibiti on in human subjects were scientifically weak and fundamentally unethical. Over the next few years fewer than a dozen new studies of this type were completed by pesticide companies and submitted to EPA to support re-registration of their products.

As critics became aware of these new studies the controversy grew. Some argued that all human testing with pesticides was inherently unethical, and EPA shoul d never consider it. Others argued that although some human tes ting was ethical, EPA should never consider unethical data. Still others argue d that it would be unethical no t to rely on the best and most relevant scientific data, regard less of how they were obtained.

EPA sought guidance from an advisory panel convened under the joint auspices of the EPA Science Advisory Board and the FIFRA Scientif ic Advisory Panel. The final report of this group, “Comments on the Use of Data from the Testing of Human Subjects: A Report by the Science Advisory Board and The FI FRA Scientific Advisory Panel,” was issued in September 2000, but left important issues unresolved. In December 2001, EPA asked NAS to conduct “an expeditious review of the comple x scientific and ethical issues posed by EPA’s possible use of third-party studies which intentionally dose human subjects with toxicants to identify or quantify their effects.” At the same time EPA promis ed that, while the NAS review was underway and until a policy was in place, it would not “consider or rely on any such human studies in its regulatory decision making, whether previously or newly submitted.”

A trade association for agricultural pesticid e companies sued EPA in early 2002, seeking to overturn the Agency’s interim commitment not to consider or rely on human studies, arguing that this policy statement had the effect of a rule without ha ving been issued through notice-andcomment rulemaking. In its June 2003 decision, the United States Court of Appeals for the District of Columbia vacated the policy and dire cted EPA to reinstate “the agency’s previous practice of considering third-party human studi es on a case-by-case basi s, applying statutory requirements, the Common Rule, and high ethical st andards as a guide . . . unless and until it is replaced by a lawfully pr omulgated regulation.” CropLife America v. EPA , 329 F.3d 876, 879 (D.C. Cir. 2003).

By the time of the CropLife decision, EPA had already begun the rulemaking process, publishing on May 7, 2003 an Advance Notice of Proposed Rulemaking on the matter, soliciting public comment on a wide range of issues (68 FR 24410) (FRL 7302-8). In April 2004, the NAS issued its report, “Intentional Human Dosing St udies for EPA Regulatory Purposes: Scientific

and Ethical Issues.”

In August 2005, in the 2006 Appropriations Ac t, which appropriated funds for EPA and other Federal departments and agencies for FY 2006, Congress included at section 201 the following provision:*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 10 of 44 [RIN 2070-AJ76] None of the funds made available by this Act may be used by the Administrator of the Environmental Protection Agency to accept, cons ider 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 issu es 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 subject s; 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 Subject s Review Board. The final rule shall be issued no later than 180 days after enactment of this Act.

In response, EPA published a proposed rule on September 12, 2005 (70 FR 53838) (FRL 7728-2), accepted public comment until Decemb er 12, 2005, and promulgated on February 6, 2006 (71 FR 6138) (FRL 7759-8), a final rule which took effect on April 6, 2006. The 2006 rule, as subsequently amende d on June 23, 2006 to extend special protections to nursing women as well (71 FR 36171) (FRL 8071-6), is discussed in the next Unit and is now being further amended by this proposed rule.

E. EPA’s 2006 Rule

1. Summary of contents. The 2006 rule established a comprehensive set of new protections for people participating as subjects in third-party human resear ch for pesticides. (In this context “third-party” resear ch is research neither conducted (“first-party”) nor supported (“second-party”) by EPA or another Federal Co mmon Rule department or agency.) The 2006 rule bans all third-party research on pesticides involving intenti onal exposure of children or of pregnant or nursing women. It further forbids EPA itself to conduct or support any research involving intentional exposur e of pregnant or nursing women or of children to any substance.

The 2006 rule also extends the ethical protect ions in the Common Rule to non-pregnant, non-nursing adult subjects of re search involving intentional ex posure to pesticides. The 2006 rule significantly strengthens and expands on thes e protections for partic ipants in third-party research by:

• Requiring submission to EPA of protocol s and related information about proposed research to ensure any future studi es meet high ethical standards.

• Establishing an independent HSRB to obtai n expert peer review of both proposals for new research intended for submission to EPA and reports of completed human research involving intentional exposure on which EPA propos es to rely in an action taken under the pesticide laws.

• Prohibiting EPA from relying on the results of research in its actions under the pesticide

laws unless EPA determines that the research meets acceptance standards derived from the recommendations of the 2004 NAS’ report.

2. Implementation experience. Because EPA’s experience in implementing the 2006 rule*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 11 of 44 [RIN 2070-AJ76] is critical to understand ing the amendments proposed in this document, that history is recounted

in some detail.

The public meetings of the HSRB have served as key milestones in the implementation of the 2006 rule, and the implementation of the 2006 ru le can be best charact erized by summarizing what the HSRB has been called upon to review.

The HSRB met for the first time in April 2006, immediately after th e 2006 rule became effective, and has met 14 times since then, most recently in October 2010. At these meetings the HSRB has reviewed both reports of completed research and proposals for new research. Specifically, the HSRB has reviewed:

• Completed reports of pre-rule research reporting toxic endp oints. These have included intentional exposure toxic ity tests initiated both before a nd after passage of FQPA in 1996, as well as therapeutic trials of subs tances used both as drugs and as pesticides, reporting side effects

relevant to EPA risk assessments.

• Proposals for and reports of new research involving intentional exposure to materials used in the research as pesticides.

Since issuance of the 2006 ru le, all proposals for new res earch involving intentional exposure to pesticides have fallen into one of tw o categories. Some have been studies of the performance of skin-applied repellents intended to keep mosquitoes, ticks and other pests away from treated skin; others have been studies monitoring occupational exposure of pesticide handlers as they mix, load, or apply pestic ides in well-defined use scenarios.

All but one of the repellent st udies reviewed as a proposal by the HSRB has subsequently been amended to incorporate EPA and HSRB recommendations, executed, reported, submitted to EPA, and found both scientifically and ethi cally acceptable by both EPA and the HSRB. Although several of the more complex exposure st udies have been executed in the field, final reports have not yet been reviewed by the HSRB.

i. Pre-rule research reporting toxic endpoints. At its first two meetings in April and May 2006 the HSRB reviewed 28 reports of pre-rule research conducted with 11 substances. At all its subsequent meetings combined the Board has reviewed 14 more such reports. Half of these 42 reports were published; the rest were unpublished reports submit ted directly to EPA by pesticide companies. Of the 42 reports, 37 reported non-therapeutic research, and 5 were published reports of therapeutic tr ials that described side effect s relevant to pesticide risk

assessments.

Twenty-nine of the 37 non-therapeutic studi es reviewed by the HSRB were initiated before the passage of FQPA in 1996; all repo rted toxic endpoints. EPA science reviewers proposed to rely on 17 of these 29 studies; the HSRB found 13 of these 17 st udies scientifically acceptable. EPA ethics reviewers found 5 of th e 17 clearly acceptable, and deferred to the HSRB concerning whether the shortcomings noted in the conduct of the remaining 12 studies rose to the level of “significant” deficiencies re lative to prevailing standa rds of ethical research

conduct. The HSRB found 15 of those 17 studies ethically acceptable under the applicable*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 12 of 44 [RIN 2070-AJ76] standards of the 2006 rule—§26.1703 and §26.1704. The HSRB found 1 study ethically unacceptable because of deficiencies in risk mi nimization procedures that could have led to serious harm, and another unacceptable because incomplete information provided to subjects concerning previous studies serious ly impaired their informed consent. These 2 studies found by the HSRB to be ethically unacceptable were among those also found by the HSRB to be scientifically unacceptable. EPA has not subseq uently relied on any studies deemed either scientifically or ethically unacceptable by the HSRB.

EPA science reviewers also proposed to re ject the remaining 12 studies, all published reports concerning dichlorvos (DDVP). These re ports on the effects of dichlorvos had been submitted by the registrant to support a proposal to reduce the inter-species uncertainty factor in

EPA’s DDVP risk assessment. EPA reviewers found all 12 to be scientifically unacceptable; the HSRB concurred. Because the reported research was deemed scientifically unacceptable for the proposed use, neither EPA nor the HSRB explicitly reviewed its ethical conduct. EPA has not relied on any of these 12 studies.

In addition, EPA has presented 8 post-FQPA toxi city studies to the HSRB. These 8 were among a group of about 20 studies at the center of controversy before promulgation of the 2006 rule. Other post-FQPA human t oxicity studies were deemed by EPA science reviewers to be irrelevant to EPA’s risk assessments, and have not been considered further.

Of the eight relevant post-FQPA toxicity studies, EPA scienc e reviewers found six scientifically acceptable and proposed to re ly on them, found one more to be clearly scientifically unacceptable, and deferred to the HS RB with respect to the sc ientific acceptability

of the last one. The HSRB concurred that the firs t six studies were scient ifically acceptable, and found both the others unacceptable. EPA ethics re viewers found four of th e eight studies clearly acceptable, one clearly unacceptable, and defe rred to the HSRB’s judgment whether the shortcomings noted in the conduct of the remain ing three rose to the level of “significant” deficiencies relative to prevai ling standards of ethical conduct. The HSRB found all but one of these eight studies ethically ac ceptable under the applicable sta ndards in the 2006 rule. Studies found either scientifically or ethically unaccep table by the HSRB have not subsequently been relied on by EPA in any actions.

EPA also proposed to rely on five published repo rts of therapeutic tria ls of materials that may be used as either drugs or as pesticide activ e ingredients. In these studies the reported toxic endpoints relevant to EPA risk a ssessments were not the main object ive of the research, but were

side effects of treatment with the material used as a medication. The HSRB concurred with the EPA science reviews in four of these cases, but found one study scientif ically unacceptable for the purpose EPA proposed. EPA ethics reviewer s and the HSRB both found all five of these studies to be ethically acceptable und er the standards of the 2006 rule.

The HSRB concurred with EPA’s scientific a ssessments of these 42 studies in all but a

handful of instances. Whenever the HSRB has r ecommended against acceptance of any of these pre-rule studies for either scientific or ethical reasons, EPA has accepted and acted on the HSRB’s recommendation, and has not relied on any studies found unacceptable by the HSRB.

ii. New research involving inte ntional exposure of human subjects. The second broad*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 13 of 44 [RIN 2070-AJ76] category of topics addressed by the HSRB since 2006 is proposals for new research involving intentional exposure of human subj ects. To ensure the thoroughness of its scientif ic and ethics reviews of these proposals, and to ensure as we ll that the applicable recommendations of the NAS in its 2004 report were taken fully into consideration, EPA developed a detailed “framework” for its reviews of these proposals. This framework has been used to guide all subsequent EPA reviews, and has been refined in detail to incorporate suggestions from the HSRB. A completed framework addressing c oncerns identified in the NAS report and subsequently by the HSRB has been attached to each EPA review of a proposal for new research

under the 2006 rule.

Since promulgation of the 2006 rule EPA ha s received no proposals at all for new research concerning pesticide toxicity or meta bolism in human subjects. All submitted proposals

for new research have been for research involvi ng intentional exposure of human subjects to registered pesticides used for pesticidal purposes in the resear ch itself. This has included proposals for research to measur e the duration of effectivenes s of skin-applied repellents intended to keep mosquitoes, ticks and other pests away from the treated skin of human subjects, and for research monitoring occupational exposure of pesticide handlers as they mix, load, or apply pesticides in a variety of agricultural and non-agricu ltural use scenarios.

a. Repellent performance studies. Repellent performance studies using human subjects have been required by EPA for many years to su pport registration of pesticide products bearing claims to keep mosquitoes, ticks, or other pe sts away from treated human skin. Since 2006 the HSRB has reviewed proposals for 13 new repelle nt performance studies testing a total of 29 repellent formulations. EPA and the HSRB identif ied enough scientific an d ethical deficiencies

in their initial review of the fi rst 2 such proposals that a second review was required. After they were revised and resubmitted, both proposals were reviewed favorably by EPA and the HSRB. All subsequent proposals for new repellent performance studies have been found acceptable, with identified needed refinements, upon th eir first review by EPA and the HSRB.

Five of the 13 proposals have been for labor atory research with cag ed insects or ticks reared in the laboratory and known to be disease-fr ee. The remaining studies have been for field studies of repellency against wild populations of insects. Three of the 13 studies have measured the duration of tick repell ency in the laboratory—2 of them co ncurrently testing repellency to 2 species of ticks. Two more have measured the duration of repellency to biting flies—1 in the laboratory with laboratory-reared stable flies, and another in the fi eld measuring repellency against black flies. The remaining 8 studies ha ve measured the duration of repellency against mosquitoes—7 of them in the field, in areas wh ere previous monitoring has not found evidence of infection of potential disease vectors among the wild insect s present, and 1 in the laboratory with laboratory-reared, pathogen-free mosquitoes.

In all these cases the HSRB has concurred with the EPA science and ethics reviews, in some cases recommending further refinements. One proposal was abandoned by its sponsor after a favorable HSRB review; 11 more have been amended consistent with EPA and HSRB recommendations and executed. Reports of these 11 have been submitted to EPA and reviewed by EPA and the HSRB. The most recent proposal is expected to be executed in the field in 2011.

In one case EPA and the HSRB found the ex ecution of a completed field mosquito*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 14 of 44 [RIN 2070-AJ76] repellency test to have been non-compliant with 40 CFR part 26, subparts A-L. This study protocol was subsequently revised and re-execu ted; the report of the re-executed study was found acceptable by EPA and the HSRB.

Reports of all the other ten completed re pellent performance studies were found both scientifically and ethically acceptable by EP A and the HSRB as first submitted.

b. Studies of occupational exposure of pesticide handlers. All other proposals for new research submitted to EPA since promulgation of the 2006 rule have been for research monitoring exposure of professional pesticide handler s as they mix, load, or apply pesticides in well-defined agricultural and non-ag ricultural use scenarios. In such research, experienced workers performing their usual tasks are typically monitored at different sites, representing the range of variation in use practi ces, equipment, and other factors likely to affect exposure. Potential dermal exposure of the workers is m easured by analyzing residues in special “long

underwear” worn under their normal work clothin g, and by rinsing their hands, face and neck. Potential inhalation exposure is measured with a portable air sampler worn in the breathing zone of each worker. This type of research has also long been required by EPA to support its

assessments of worker risk.

Five proposals for field monitoring of worker exposure submitted to EPA by an industry consortium were presented to the HSRB in J une 2006. The HSRB review was highly critical, and called for substantially greater informa tion from both the consortium and from EPA concerning the overall design of the research pr ogram, the statistical design of the proposed studies, the uses to which the re sulting data would be put by EPA, and many other aspects of the proposed research. All five of these proposals were subsequently withdrawn.

Since that initial review, the overall de signs of the monitoring programs of the Antimicrobial Exposure Assessment Task For ce (AEATF II) and the Agricultural Handlers Exposure Task Force (AHETF) have been fully documented and presented to the HSRB. The HSRB continues to review the design of indivi dual monitoring studies, but the soundness of the overall approaches of both the AEATF II and AHETF programs have been established.

Monitoring studies for four antimicrobial exposure scenarios submitted by the AEATF II have been presented to the HSRB and approved with suggestions for refinements by both EPA

and the HSRB. These four scenarios involve co mmon methods of application of antimicrobial pesticide products, including mopping, wiping dow n surfaces with a pre-soaked ready-to-use wipe, spraying surfaces with a pump spray and wiping them down with a cloth, and spraying surfaces with an aerosol product that does not ne ed to be wiped off. For each scenario, monitoring of workers at three distinctive loca tions was proposed. Af ter amendment of the protocols consistent with EPA and HSRB recommendations, the firs t three of these four studies have been executed; the first complete scenario report was submitted to EPA and reviewed by the HSRB in October 2010. The remaining repor ts of completed AEATF II exposure research were submitted to EPA in the fall of 2010, and ar e scheduled for presentation to the HSRB in early 2011.

Monitoring studies for four agricultural exposure scenarios submitted by the AHETF have been presented to the HSRB and approved, again with suggestions for refinements by both*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 15 of 44 [RIN 2070-AJ76] EPA and the HSRB. These scenar ios involve applicati on of liquid pesticides to trellis and orchard crops using “air-blast” sp ray equipment with closed cabs, application of liq uid pesticides using air-blast spray e quipment with open cabs, mixing and lo ading pesticides sold in watersoluble packaging into a wide variety of application equipment, and application of herbicides to rights-of-way. Each of these scenarios calls for monitoring workers in five different regions of the United States, working with different kinds of equipment and crops. The first two of these four studies have been executed; the first complete scenario report was submitted to EPA and reviewed by the HSRB in October 2010. Reports of the remaining research scenarios will be submitted to EPA and presented to the HSRB in 2011.

3. Summary of implementation of the 2006 rule. EPA’s experience in implementing the 2006 rule can be summarized in these three points:

• EPA and the HSRB quickly worked through the backlog of pre-rule studies of pesticide toxicity awaiting review when the 2006 rule was promulgated. EPA and the HSRB agreed about the acceptability of these studies in most cas es; when there was disagreement, EPA has accepted and acted on the advice of the HSRB. Some pre-ru le studies that met the scientific and ethical

standards defined in the 2006 rule have been relied upon by EPA in actions under the pesticide laws. Meanwhile, as EPA completed the reassess ment of tolerances mandated by FQPA, it found human toxicity testing to be relevant to only a handful of those assessments.

• Close scrutiny by both EPA and the HSRB of proposals for new repellent performance testing and worker exposure monitoring studies has led to steady and substantial improvement both in the scientific design of these studies and in their provision for ethical treatment of subjects. These reviews have led to some delays in field research costly to the study sponsors, but the sponsors and investigators proposing th ese studies have learned how to design and execute them efficiently and in full compliance w ith the high standards of the 2006 rule. These studies provide essential information about repe llent performance and worker exposure that is simply not available except from well design ed, ethically conducted research involving intentional exposure of huma n subjects to pesticides.

• Contrary to some predictions, the 2006 rule has not led to an upsurge in human research for pesticides. Since promulgation of the 2006 ru le EPA has received no proposals at all for research on the toxicity of a pesticide to human subjects, and has receiv ed significantly fewer proposals for new research of other kinds than were projected. In the analyses supporting the 2006 rule EPA estimated 33 new intentional exposu re studies would be submitted each year; in fact, only 26 proposals for new research have been submitted over a span of approximately 5 years, or just over 5 per year.

F. Legal Challenge to the 2006 Rule

In early 2006, the Natural Resources Defens e Council, Inc., Pesticide Action Network North American, Pineros y Campesinos Uni do Del Noroeste, Physicians for Social Responsibility-San Francisco, Farm Labor Or ganizing Committee, ALF-CIO, and Migrant Clinicians Network petitioned for review of the 2006 rule in the United States Court of Appeals for the Second Circuit (Second Ci rcuit Court of Appeals). ( NRDC v. EPA , No. 06-0820-ag (2d Cir.)). The Petitioners argued that the 2006 rule violated the 2006 Appropriations Act because it*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 16 of 44 [RIN 2070-AJ76] did not bar all pesticide research with pregnant women and children, was inconsistent with the 2004 NAS Report, and was inconsistent with the Nuremburg Code.

1. Inadequate bar against research w ith pregnant women and children. Petitioners argued that the scope of the 2006 rule’s ban on re search with pregnant women and children was unlawfully narrow because it was limited to studies intended for submission to EPA under FIFRA or FFDCA–the pesticide regulatory laws EPA administers. Petitioners argued that Congress’s direction to EPA in the Appropriations Act to “not permit the use of pregnant women, infants, or children as subjects” in “intentional dosing human toxicity studies for pesticides” did not allow EPA to distinguish between studies or iginally intended for publication and those intended for submission to EPA, or between studies with pesticides conducted for

consideration under FIFRA or FFDCA and thos e conducted for consideration under the Safe Drinking Water Act or any other regulatory stat ute. Petitioners argued that EPA’s 2006 rule violated the plain language of the 2006 Appropriations Act on this point.

2. Inconsistency with the NAS report. The 2006 Appropriations Act required EPA’s rule to be consistent with the principles proposed in the 2004 NAS report. Peti tioners argued that in citing the “principles” of the NAS report, Congre ss was referring to the 17 recommendations in that report. Petitioners furthe r argued that the 2006 rule was in consistent with several specific recommendations in the report.

First, Petitioners argued that the 2006 ru le did not incorporat e NAS Recommendations 3- 1 and 5-1, which recommend factors to be consid ered in the scientific evaluation of human research, including that such studies should ha ve “adequate statisti cal power” and involve “representative populations for th e endpoint in question.”

Second, Petitioners argued th at the 2006 rule did not in corporate NAS Recommendations 4-1 and 4-2, which suggest ethical considerations relevant to ev aluation of human studies.

Third, Petitioners argued that by adding qua lifying language to the acceptance standard for pre-rule research suggested in NAS Recomm endation 5-7, EPA made it inconsistent with the NAS Report. Petitioners argue d that EPA’s addition of the word “significantly” to the recommended acceptance standard, which permits EP A to rely on research not “significantly” deficient relative to prevailing standards, ma de the criterion in the 2006 rule unlawfully

inconsistent with the NAS recommendation.

Finally, Petitioners argued th at the 2006 rule unlawfully failed to require provision of medical care for study participants, as suggested by NAS Recommendation 5-5.

3. Inconsistency with the Nuremberg Code. The 2006 Appropriations Act also required EPA’s rule to be consistent with the principl es in the Nuremberg C ode pertaining to human experimentation. Petitioners argued that the 2006 rule was inconsiste nt with several principles in

this Code.

First, Petitioners argu ed that although the Nuremberg Code specifies that consent must be given by the human subject, the 2006 rule inconsiste ntly permits consent to be given by a legally authorized representative of the subject.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 17 of 44 [RIN 2070-AJ76] Second, Petitioners argued that, by adopting the Common Rule’s requirements for informed consent, the 2006 rule was inconsistent with the Nuremberg Code principle that a test subject “should have sufficient knowledge and co mprehension of the elements of the subject

matter involved as to enable him to make an understanding and enlightened decision.” Petitioners argued that the Common Rule consent requirements were inadequate to ensure fully

informed consent.

Third, Petitioners argued that the 2006 rule failed to address adequately the Nuremberg Code principle that a subject must be “so situated as to be able to exercise free power of choice, without the intervention of any element of for ce, fraud, deceit, duress, over-reaching, or other

ulterior form of constraint or coercion.” Petitioners argued that the requirement of the 2006 rule that consent should only be sought in circumstances that “minimize the possibility of coercion or

undue influence” did not address th e potential for fraud, deceit, ove r-reaching, or constraint.

Petitioners asserted that constrai nt was a particular problem when prisoners are used as subjects in human studies, and the 2006 rule did not specifi cally address research with prisoners.

Fourth, Petitioners argued that the 2006 rule was inconsistent with the Nuremberg Code because it did not explicitly impose the Code’s re quirement that human studies be “designed and based on the results of animal experimentation.”

Finally, Petitioners argued that the 2006 rule was inconsiste nt with the Nuremberg Code principle that human testing “should be such as to yield fruitful results . . . unprocurable by other methods or means of study, and not random and unnece ssary in nature.” Petitioners argued that the 2006 rule requires no inquiry into whether huma n testing is necessary given other methods of

research.

G. Settlement of Litigation

After briefing and argument, but before a decision was rendered by the Second Circuit Court of Appeals, EPA and Petitioners began ne gotiations to settle th e litigation. In the settlement agreement filed with the Second Circuit Court of Appeals on June 18, 2010, EPA agreed to conduct notice-and-comment rulemaki ng on the issue of whether the 2006 rule should be amended. EPA also agreed to propose, at a minimum, amendments to the 2006 rule that are substantially consistent with language negotiated between the parties and attached to the settlement agreement as Exhibit A. This agreem ent, including Exhibit A, is available in the

docket for this action as described under ADDRESSES

.

The settlement agreement further provi des that EPA will propose the negotiated

amendments within seven months of filing the agreement with the Second Circuit Court of Appeals and that EPA will take fi nal action on the amendments with in 18 months of this filing. The settlement, however, makes clear that EPA retains full discre tion concerning what amendments are proposed, and what, if any, amendments are finalized.

Although they differ in a few details of construction and wording, the amendments proposed in this document are substantially cons istent with the regulat ory language negotiated*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 18 of 44 [RIN 2070-AJ76] with Petitioners, and these amendments addre ss the Petitioners’ major arguments outlined in Unit III.F. Specifically,

• The proposed amendments would retain th e scope of the 2006 rule to cover research submitted to EPA under FIFRA or FFDCA, and extend that scope to cover as well research involving intentional exposure to a pesticide, intended for su bmission to EPA under any other regulatory statute administered by EPA.

• The proposed amendments incorporate language from each of the NAS Recommendations cited by Petiti oners in their cha llenge to the 2006 rule, as well as other pertinent recommendations from the NAS Report.

• The proposed amendments address Petiti oners’ arguments concerning the Nuremberg Code by dropping from 40 CFR part 26, subpart K a ll provisions for consent by a representative, and by requiring EPA to consider whether subjects gave their “free and fully informed consent” to participate in a study, whethe r the design of proposed new huma n research takes into account the knowledge gained in earlier animal testing, and whether pr oposed new human research is

necessary.

Although these proposed amendments emerge from a settlement agreement, EPA is proposing these amendments because they are cons istent with the languag e and purposes of the applicable statutes and because they further th e 2006 rule’s goal of ensuring that EPA does not rely on research involving intentional exposure of human subjects to pe sticides that is not ethically conducted or that is not scientifically sound. Many of the changes proposed in this

document are codifications of the manner in which EPA and the HSRB have interpreted and implemented the 2006 rule. EPA will fully re-eva luate the appropriateness of the proposed amendments in light of all comments rece ived in response to this proposed rule.

IV. Provisions of this Proposed Rule and Rationale

A. Redefining Scope and Applicability

EPA is proposing amendments that would modi fy the scope and app licability of several subparts of the 2006 rule. The proposed changes w ould modify the criteria defining the types of research covered by 40 CFR part 26, subparts K, L, and M–most notably the criteria relating to the intentions of the sponsor or investigator in conducting the research or the intentions of the person submitting the res earch to EPA.

In general, the proposed revisions would shif t the focus from whet her the research was

intended for EPA’s consideration and use unde r the pesticide laws, FIFRA and FFDCA, to whether the research was conducted with a pes ticide and was intended for EPA’s consideration and use in connection with an action under any regulatory statute administered by EPA. The proposed amendments also would add a new sec tion to 40 CFR part 26, subpart P defining its scope and would change the scope and applicability of 40 CFR part 26, subpart Q to parallel the changes in 40 CFR part 26, subpart K.

EPA believes these changes in scope would make the 2006 rule more consistent with the*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 19 of 44 [RIN 2070-AJ76] focus in the 2006 Appropriations Ac t on intentional dosing human toxi city studies for pesticides. Although almost all studies with pesticid es are conducted and submitted to EPA for consideration under FIFRA or FFDCA, it is possi ble that some pesticide studies may be considered by EPA only under other regulatory au thorities. If studies involving intentional exposure of humans to a pesticide are subm itted or considered under other EPA regulatory statutes, EPA believes such studies should be subj ect to the same require ments that would have applied had they been submitted or considered under FIFRA or FFDCA.

The specific changes proposed to the scope a nd applicability secti ons of 40 CFR part 26, subparts K, L, M, P, and Q are explained he re. Although EPA does not propose to change the text of the 2006 rule defining the scope of 40 CFR part 26, subpart O, concerning

“Administrative Actions for N oncompliance,” the scope of that subpart would change nonetheless, because its applicab ility depends on the scope provisi ons in other subparts that EPA is proposing to change.

1. Subparts K and L – basic ethical requireme nts and prohibitions applying to thirdparty research involving intentional expos ure of human subjects to a pesticide. Subpart K of 40 CFR part 26 extends the basic prot ections of the Common Rule to su bjects in certain third-party human research; subpart L of 40 CFR part 26 forbids new thir d-party research involving intentional exposure of children or of pregnant or nursing women. In the 2006 rule these two subparts apply to “research with a human subject” which meets these four criteria: • It was initiated after April 6, 2006 (the effective date of the rule).

• It is “research involvin g intentional exposure of a human subject” as defined at §26.1102(i). • It was conducted or supported by a “person” as defi ned at §26.1102(j). • It was intended by any person conducting or supporting the research to be submitted to EPA, or to be held for later inspection by EP A, under the pesticide laws (FIFRA or FFDCA).

The two cited definitions are critical to understanding the scope and applicability of subparts K and L of 40 CFR part 26. “Research involving intentional exposure of a human subject,” is defined at §26.1102(i) as “a study of a substance in which the exposure to the substance experienced by a human subject participating in the st udy would not have occurred but for the human subject’s participation in the study. ” In applying this definition, EPA considers whether a test subject would have experienced equivalent exposure to a test material had the subject not participated in the re search. If not, the re search is deemed to involve intentional exposure of the subject. Notably this definition encompasses all classes of test substances—not only pesticides.

A “person” is defined at §26.1102( j) to have the same meanin g as in FIFRA section 2(s) (7 U.S.C. 136(s)), except that it excludes Fede ral agencies subject to the Common Rule and any person when performing research supported by a Common Rule agency. Thus research already covered by the standards of the Common Rule is not also subject to subparts K and L. These subparts, in short, apply only to “third-party research”—research th at is neither conducted (“firstparty”) nor supported (“second-party”) by EPA or another Federal Common Rule department or

agency.

Finally, §26.1101(g) explains how EPA will appr oach determination of the intent of*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 20 of 44 [RIN 2070-AJ76] sponsors or investigators to s ubmit research to EPA under the pe sticide laws, or hold it for inspection by EPA under the pesticide laws.

The amendments proposed in this document would not change the definitions of “research involving intenti onal exposure of a human subject” or of “person.” They would add a new definition of “pesticide” at §26.1102(k), a new definition of “initiation” of research at §26.1102(c), and would modify the applicability pr ovisions in §26.1101 as explained later in this

document.

The first of the four criteria for applicati on of 40 CFR part 26, subpart K will change to incorporate the effective date of a final rule amending the 2006 rule. EPA believes it would be inappropriate to apply these proposed amendmen ts retroactively. For example, if post-2006 research newly covered by an am ended rule as proposed in this document were submitted to EPA, its acceptability should notbe judged by its compliance with a rule promulgated after it was conducted. Until the 2006 rule is amended by a final rule, its provisions continue to apply fully to new research. Hence no sponsor or in vestigator subject to the 2006 rule would be relieved by the change in the effective date of any obligation to comply with 40 CFR part 26, subparts K and L for research initiated between April 7, 2006, and the ef fective date of any subsequent amendments.

This proposal includes a ne w §26.1102(c) defining “Initiation of research involving human subjects” as occurring with the enrollment of the first subject in the research. This would codify the interpretation expre ssed in the preamble to the final 2006 rule (71 FR 6165) and applied by EPA in implementing the 2006 rule. In guidance issued under the Common Rule some other Federal agencies have defined st udy initiation as occu rring when the first advertisement for subjects is issued; EPA’s standards of G ood Laboratory Practice at 40 CFR part 160 define study initiation as occurring when the Study Director signs the protocol. To avoid confusion, EPA is considering recasting this criterion, stating simply that 40 CFR part 26, subparts K and L apply to research in which the firs t subject is enrolled afte r the effective date of

a final amendment. Comments on this point are specifi cally requested.

The proposal would modify the second of th e four criteria so that 40 CFR part 26, subparts K and L would apply to research involv ing intentional exposure of a human subject “to a pesticide” when the research is intended for submission to EPA under any regulatory statute

other than FIFRA or FFDCA. The definition of “research involving inte ntional exposure of a human subject” would not change, nor would the a pplicability of these su bparts to all new thirdparty research involving inte ntional exposure of human subj ects which is intended for

submission to EPA under FIFRA or FFDCA.

In determining whether research involves in tentional exposure to a pesticide, EPA will focus, as does the FIFRA definition of a “pesticid e,” on the intended use of the substance. EPA expects that application of this standard wi ll nearly always be straightforward.

Initially, EPA will examine the study on its face . If the study states that it involves the testing of a pesticide, or if the te sted substance is used for pesticidal effect in the study, as it is in insect repellent efficacy testing or in monitoring exposure of pest icide applicators, there can be little question that the study i nvolves exposure to a pesticide. If on the other hand the study*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 21 of 44 [RIN 2070-AJ76] reports testing of another type of substance, such as an industrial chemi cal, waste product, or air pollutant, then absent compelling evidence to the contrary, EPA will not treat the study as involving exposure to a pesticide.

If it is not clear from the face of the study whether it involves expos ure to a pesticide, EPA will look to other objective factors to determ ine whether a substance is being tested as a pesticide. Intent to test a s ubstance as a pesticide could be indicated by evidence that the testing was conducted or supported by an entity regulated under FIFRA or section 408 of FFDCA; the testing was conducted for the purpo se of attaining a FIFRA regi stration or FFDCA tolerance; there are not significant commercial uses for the s ubstance other than as a pesticide; or human exposure to the substance occurs primarily from its use as a pesticide. Absent any such evidence, EPA will generally treat the study as not involving exposure to a pesticide.

EPA expects that in most cases, the questi on of whether the study involves exposure to a pesticide will be quickly resolv able without looking to other obj ective factors such as the four identified in the previous paragr aph. This is true even for mul tiple-use substances that may be used as a pesticide and may also result in hum an exposure from other commercial uses or as a result of deposition in the envir onment as a waste product.

A good example is sulfur dioxide (SO 2 )—a registered pesticide active ingredient used as a fungicide in grape culture, and also a co mmon air pollutant. Thousands of tons of SO 2 are released yearly into the atmosphere by burning of coal and other fossil fuels. In promulgating National Ambient Air Quality Standards (NAAQS) for SO 2 under the Clean Air Act (CAA) in 2010, EPA relied on numerous human studies involvi ng intentional exposure of subjects to SO 2

. Most of these studies on their face in dicate clearly that they tested SO 2 as an industrial air pollutant and not as a pesticide. The few that do not expressly state they tested SO 2 as an air pollutant are, nonetheless, easily classified as not involving exposure to a pesticide, because the testing was not conducted or sponsored by a pestic ide registrant, the stud ies do not indicate they were performed in support of FIFRA registratio n, and there are clearly other major sources of human exposure to SO 2 in addition to whatever pes ticide exposure occurs.

The amendments proposed in this document would not change the applicability of 40 CFR part 26, subparts K and L to “persons” or th e definition of that term at §26.1102(j). Thus

the third of the four criteria would not be affected by these amendments.

The fourth criterion would be broadened by the amendments proposed in this document beyond the scope of the 2006 rule. The 2006 rule applies to research with any substance,

conducted with intent to submit its results to EPA under FIFRA or FFDCA; as proposed here, the rule would apply as well to research with a pesticide, conducted with intent to submit its

results to EPA “for consideration in connection with any action that may be performed under any regulatory statute administered by EPA” other than FIFRA or FFDCA.

The new element in this fourth criterion is the reference to actions taken “under any regulatory statute administered by EPA.” Re search intended for submission under FIFRA or FFDCA is covered by the 2006 rule and would continue to be covered under proposed §26.1101(a)(1). Proposed §26.1101(a)(2) would broade n the scope of subparts K and L of 40 CFR part 26 to apply as well to research involving intentional e xposure of a human subject to a*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 22 of 44 [RIN 2070-AJ76] pesticide which is intended for submission to EPA for consideration in connection with any action that may be performed under any regulatory statute other than FIFRA or FFDCA. Such submission could be made under CAA, the Safe Drinking Water Act (SDWA), the Clean Water Act (CWA), the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response, Compensation and Liabili ty Act (CERCLA, or the Superfund law), or

other similar statutes.

As an example, EPA’s Office of Water ha s, in the past, set Maximum Contaminant Levels (MCLs) under the SDWA for pesticides found in drinking water. Under the proposed amendment to the scope of 40 CFR part 26, s ubpart K, any new third-party study involving intentional exposure of a human to a pesticide, and intended for submission to the Office of

Water for consideration in sett ing a MCL, would now be subject to 40 CFR part 26, subpart K, including the requirement of §26.1125 for submissi on of the proposal for prior review by EPA

and the HSRB.

EPA actions not taken under the authority of regulatory stat utes would not satisfy this fourth criterion. For example, an EPA comm ent on another Federal agency’s Environmental Impact Statement would not constitute an acti on taken under a regulatory statute, and research intended for submission solely for consideration in such a context would not be subject to 40 CFR part 26, subparts K and L.

EPA interprets the word “action” in this context broadly, embracing both regulatory and non-regulatory actions. Regulatory ac tions include, for example, can cellation or registration of a pesticide, establishment of a tolerance for a pes ticide residue in food, or establishing an MCL for a pesticide active ingredient unde r SDWA. Non-regulatory actions include, for example, risk assessments of pesticide active ingredients, recommended (non-bindi ng) safe levels of exposure such as Health Advisory Limits, or cl ean-up standards at a Superfund site.

The amendments proposed in this document in clude two additional editorial revisions to clarify the scope sections of 40 CFR part 26, subp arts K and L. One change would clarify the applicability of 40 CFR part 26, subpart K by moving the exposition of how EPA will determine intent to submit from §26.1101(g), where it appears in the 2 006 rule, to §26.1101(b), immediately following the presentation of the four criteria. The other would amend §26.1201, the scope section of 40 CFR part 26, subpart L, to state simply that subpart L applies to all research subject to subpart K.

In sum, EPA proposes several changes to the “scope” sections of 40 CFR part 26, subparts K and L—§26.1101 and §26.1201—and new definiti ons of “initiation of research” at §26.1102(c) and of “pesticide” at §26.1102(k), to expand at the margin the range of human research to which these two subpa rts apply. EPA does not believe th is expansion will result in a significant increase in the numbe r of studies reviewed under th e rule. EPA knows of no thirdparty research involving intentiona l exposure of a human subject to a pesticide that has ever been proposed, conducted, or submitted to EPA under regul atory authorities other than the pesticide laws. This expansion of the scope of these subpa rts, however, insures that any such studies that are proposed, conducted, or submitted to EPA will be governed by the same standards as pesticide studies submitted under FIFRA or FFDCA section 408. It is also consistent with the Congressional directive in the 2006 Appropriations Act.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 23 of 44 [RIN 2070-AJ76] 2. Subpart M – requirement for documentation of the ethical conduct of completed

human research submitted to EPA. Subpart M of 40 CFR part 26 requires those who submit the

results of human research to EPA for cons ideration under the pesticide laws to submit information documenting the ethical conduct of the completed research. EPA proposes to broaden the applicabil ity of subpart M by amending §26.1301, while leaving the substantive requirements of subpart M unchanged.

Under the 2006 rule, 40 CFR part 26, subpart M applies when a “person” as defined at §26.1102(j) submits after the effectiv e date of the 2006 rule a report containing the results of any

human research to EPA for consider ation under the pest icide laws.

These criteria differ from those defining c overage by 40 CFR part 26, subparts K and L in important ways. First, unlike other s ubparts of the 2006 rule, subpart M applies to

submissions after the effective date of the rule of any and all human rese arch, without regard to who conducted it, when, or for what purpose, or whether or not the reported research involved intentional exposure of a human subject. Second, subpart M applies only when a person (other than a Federal agency subject to the Common Rule) submits the results of human research to EPA. Subpart M does not apply when EPA, on its own initiative, retrieve s published articles or

otherwise obtains information de rived from human research.

EPA proposes to broaden the applicability of 40 CFR part 26, subpart M to include submissions of reports of human research on pesticides for consideration by EPA under regulatory statutes other than FIFRA or FFDCA. Under the proposed amendments, subpart M would apply when a “person” as defined at §26.1 102(j) submits after the effective date of the amended rule a report containing the results of any human research to EPA for consideration under FIFRA or FFDCA, or a report containing the results of any human re search on or with a pesticide for consideration under any other re gulatory statute admini stered by EPA.

The proposed amendments to 40 CFR part 26, subpart M attempt to balance the need for

full information on ethical issues with a concer n that the public not be deterred from submitting

scientific data relevant to EPA informati on requests. Section 26.1303 requires a submitter to provide “information concerning the ethical conduct” of the human research, including copies of relevant IRB records, and copies of records releva nt to the key ethical considerations outlined in §26.1117 and §26.1125(a). This requirement is qualified by the provision that such records need only be provided “[t]o the extent [the records] are available to the submitter and not previously provided to EPA,” but any submitter not providing the information required must “describe the

efforts made to obtain the information.”

To minimize the potential burden on public commenters, EPA considered excluding from the coverage of 40 CFR part 26, subpart M submi ssions of published scie ntific journal articles reporting human research, or of citations to such articles. In some circumstances, however, EPA believes it is important for submitters of even published human research to bear the burden of gathering the information required by §26.1303. Specifically, EPA believes a submitter of published human research who is seeking action unde r a regulatory statute from EPA that would directly benefit the submitter should be obliged to gather records bearing on the conduct of the research, even if the research is described in the public literature. For example, an applicant for a*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 24 of 44 [RIN 2070-AJ76] pesticide registration or a part y petitioning for a pes ticide tolerance should have to exercise

reasonable efforts to obtain records of the ethical conduct of research re lied on to support the EPA action sought, whether or not th e research happens to be descri bed in a scientif ic journal. Reasonable efforts in these circumstances may include seeking relevant records from the research administrator or the overseeing IRB. On the other hand, if a member of the public responds to an EPA request for information on a pesticide by citing or submitting a published study, EPA believes that certification that the submitter did not sponsor, participate in, or otherwise have personal knowledge of or responsibility for the refe renced research would satisfy the submitter’s obligation under 40 CFR part 26, subpart M.

EPA’s concern for the potential burden of 40 CFR part 26, subpart M on members of the public is tempered by its experi ence under the 2006 rule. Sin ce promulgation of the 2006 rule EPA has received very few submissions of reports of human research on or with a pesticide for consideration under FIFRA or FFDCA, and EPA exp ects submissions of such studies to EPA for consideration only under other regulatory statutes will be even less common.

EPA specifically requests comments on this approach to and interpretation of the requirements in 40 CFR part 26, subpart M. Such comments should address whether the proposed rule language is adequate to implement EPA’s interpretation.

3. Subpart P – EPA and HSRB review of proposed and completed human research. Subpart P of 40 CFR part 26 applies to EPA a nd HSRB reviews of proposals for new research involving intentional exposure of a human subject, and EPA and HSRB reviews of reports of completed research involving intentional e xposure of a human subject and on which EPA proposes to rely in an action under the pesticide laws.

Unlike other subparts of the 2006 rule, subpart P does not include a “s cope” section; its applicability is defined only indirectly by refere nces to other subparts. EPA proposes to make explicit the applicabil ity of subpart P in a new §26.1601. This proposed new section provides that 40 CFR part 26, subpart P applies to EPA and HSRB reviews of (1) “proposed research subject to 40 CFR §26.1125,” and (2) “reviews by EPA after [effective date of the amended rule] and, to the extent required by §26.1604, by the Huma n Studies Review Board, of reports of completed research subject to 40 CFR §26.1701.” Since 40 CFR 26.1125 is in subpart K and 40 CFR 26.1701 is in subpart Q, the broadened scop e of these subparts as proposed in these amendments would indirectly broaden the scope of 40 CFR part 26, subpart P.

4. Subpart Q – ethical standards for assessing whet her to rely on the results of human

research in EPA actions. Subpart Q of 40 CFR part 26 define s ethical standards that must be met for EPA to rely on the results of human rese arch in actions taken under the pesticide laws. Specifically, subpart Q applies to EPA decisions to rely on data from completed studies involving intentional exposur e of a human subject, when EPA regards the data as scientifically

valid and relevant to an action ta ken under the pesticide laws.

For the same reasons it is proposing to br oaden the applicability of 40 CFR part 26, subpart K (discussed in Unit IV.A.1.) EP A proposes to amend §26.1701 to broaden the applicability of 40 CFR part 26, subpart Q. Proposed §26.1701(a) would re tain without change the applicability of 40 CFR part 26, subpart Q to research involving in tentional exposure of*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 25 of 44 [RIN 2070-AJ76] human subjects to any substance, in the context of EPA actions taken under FIFRA or FFDCA. Proposed §26.1701(b) would extend the applicability of subpart Q to research involving intentional exposure of human subj ects to a pesticide, in the c ontext of EPA actions taken under any other regulatory statut e administered by EPA.

EPA intends to interpret “action” and “regul atory statute administered by EPA” in 40 CFR part 26, subpart Q just as these terms would be interpreted for 40 CFR part 26, subpart K. To make this scope provision c onsistent with the ot her scope provisions in this proposal, EPA proposes to depart from the language negotiated in the settlement agreemen t and define the scope of 40 CFR part 26, subpart Q in terms of the “research” covered rather than the “decisions”

covered.

EPA expects this change in the scope of 40 CF R part 26, subpart Q to affect few, if any, EPA actions. Although such actions may occur in the future, EPA cannot identify any actions taken since 2006 under any regulat ory statute other than FIFR A or FFDCA that relied on research involving intentional exposure of a human subject to a pesticide.

B. Disallowing Consent by a Surrogate (Subpart K)

In its 2004 report to EPA, the NAS recomm ended use of the Common Rule as the starting point for protecting hu man subjects in research invol ving intentional exposure.

Consistent with this recomme ndation, EPA incorporated much of the text of the Common Rule into subpart K of 40 CFR part 26, including language providing for consent for a subject’s participation in research by the subject’s “lega lly authorized representative” when the subject lacks the capacity to consent for himself or herself. The Common Ru le, drafted to protect subjects in a wide variety of research settings , included these provisions to permit research into emergency procedures to save lives of uncons cious patients, into improved care for people suffering psychosis or schizophren ia, and to collect valuable da ta from research with other subjects who lacked the legal cap acity to provide fully informe d, fully voluntary consent.

In this document, EPA proposes to amend 40 CFR part 26 by deleti ng from subpart K all references permitting consent by a subject’s legally authorized representative. The sections

affected are the definition of “l egally authorized representativ e” at §26.1102(c), the “Criteria for IRB approval of research” at §26.1111; the “Gener al requirements for informed consent” at §26.1116; and the requirements for “Documentati on of informed consent” at §26.1117.

EPA proposes to disallow consent by a repres entative because it thinks that investigators will never need such a procedure for the re search covered by 40 CFR part 26, subpart K— research involving intentional exposure of non-pregnant, non-nursi ng adults to a pesticide or research involving intentional exposure of non-pregnant, non-nursing adults intended for

submission under FIFRA or FFDCA. EPA has never seen, and cannot envision, any such research in which it could be justified to en roll subjects lacking the capacity to consent for themselves. EPA does not propose to modify the provisions of 40 CFR part 26, subpart A,

EPA’s codification of the Common Ru le. Subpart A applies to a much broader range of research with human subjects conduc ted or supported by EPA includi ng, for example, observational studies with young children, for which parental cons ent on behalf of a chil d subject is entirely appropriate.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 26 of 44 [RIN 2070-AJ76] C. Revised Standards for EPA and HSRB Reviews (Subpart P)

In 40 CFR part 26, subpart P defines in largel y procedural terms ho w EPA is to review proposals for new research submitted under §26. 1125 of 40 CFR part 26, subpart K, and how EPA is to review reports of completed researc h. Subpart P of 40 CFR part 26 also defines the membership and responsibil ities of the HSRB.

If all proposed amendments to 40 CFR part 26, subpart P became final, it would include:

• A new §26.1601 explicitly defining the applicability of 40 CFR part 26, subpart P to EPA and HSRB reviews of proposals for new research submitted under §26.1125 of subpart K and to EPA and HSRB reviews of reports of comple ted research covered by subpart Q. This change is discussed in Unit IV.A.3.

• A new §26.1602 incorporating by reference th e definitions in 40 CFR part 26, subpart

K.

• An expanded discussion of EPA reviews of proposed research in §26.1603, retaining all elements of §26.1601 from the 2006 rule, and in cluding a new §26.1603(b) lis ting considerations to be addressed by EPA in its science revi ews of proposed research, and a new §26.1603(c) listing considerations to be a ddressed by EPA in its ethics reviews of proposed research.

• A slightly revised discussion of EPA re views of completed research, redesignating §26.1602 in 40 CFR part 26 as §26.1604, and revising paragraph (a) to em phasize the required thoroughness of EPA’s reviews and to extend its applicability to review s of completed human research on pesticides consider ed under regulatory statutes other than FIFRA or FFDCA.

• The unchanged text of §26.1603 in the 2006 rule redesignated as §26.1605, defining the membership and responsibilities of the HSRB.

• A new §26.1606 requiring the HSRB in its review s of proposed research to consider the same range of scientific, ethical, and other topics addressed by EP A in its reviews under §26.1603.

• A new §26.1607 requiring the HSRB in its revi ews of completed research to consider

both the scientific and ethical merits of the re search, and to apply the appropriate acceptance standards in 40 CFR part 26, subpart Q.

The most significant changes are the new lis ts proposed for inclusion in §26.1603(b) and (c) of considerations to be addressed in EPA re views of proposed new research. These lists are

derived from the 2004 NAS recommendations to EPA and from the Nuremberg Code. Making these considerations explicit will codify in a regulation the practices developed by EPA and the HSRB in the course of implementing the 2006 rule, and will ensure that th ese crucial aspects of the NAS report and the Nuremberg C ode continue to be considered in the future by EPA and the

HSRB.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 27 of 44 [RIN 2070-AJ76] The provisions in proposed §26.1603(b) will ensu re that unnecessary human research is not conducted, that any research that is conducted is designed so that the data collected are likely to answer an important research question dispos itively, and that the c onduct of the research follows good research and clinical practices.

The provisions in proposed §26.1603(c) addr ess many important ethical concerns including identification and minimization of risks to par ticipants, equitable selection of participants, and provision of medical care for participants. One cr itical consideration for ethical research, reiterated here, is th at the subjects’ participation “follow[s] free and fully informed consent.” The Nuremburg Code eloquently states the importance of free and fully informed

consent and describes the elements of such consent:

The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to gi ve consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulte rior form of constraint or coercion; and should have sufficient knowledge and compre hension of the elements of the subject

matter involved as to enable him to make an understanding and enlightened decision . . .
[ http://ohsr.od.nih.gov/guidelines/nuremberg.html ]

Key aspects or indicators of free and fully in formed consent or legally effective consent are set out in detail in §26.1116. They includ e that information be provided in a form understandable to the subject, incl uding information on the purposes and duration of the research as well as on the procedures, risks, and any comp ensation involved in the re search. Further, the subject must be made aware that participation in the research is vol untary, that there is no penalty for not participating, and that the subject may withdraw from the research at any time. The reference in §26.1603(c)(5) to “free and fully informed consent” emphasizes the centrality of this concept to the ethi cs evaluation process.

D. Revised Acceptance Standards for Completed Research (Subpart Q)

In addition to broadening the scope of 40 CF R part 26, subpart Q to apply to research relied on by EPA under regulatory statutes ot her than FIFRA or FFDCA, EPA proposes to amend the substantive standards in §26.1703, §26.1704, and §26.1705 for determining the acceptability of completed research involving in tentional exposure of a human subject to a pesticide. If a covered study does not meet the applicable standards in 40 CFR part 26, subpart Q, EPA would be prohibited from relying on th e data in any action it takes under any of its regulatory authorities except unde r the extremely restrictive c onditions defined in §26.1706.

Subpart Q of the 2006 rule established st andards governing reliance by EPA under the pesticide laws on “scientifically valid and relevant data from research involving intentional exposure of human subjects.” Section 26.1703 fo rbids EPA to rely on any research involving intentional exposure of a subj ect who was a pregnant woman, a nursing woman, or a child. Section 26.1704 forbids EPA to rely on research in itiated before the eff ective date of the 2006

rule in the face of clear and convincing evidence that “the conduct of the research was fundamentally unethical (e.g., the re search was intended to seriously harm participants or failed to obtain informed consent), or was significantly deficient relative to the ethical standards*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 28 of 44 [RIN 2070-AJ76] prevailing at the time the research was conduc ted.” Section 26.1705 forbids EPA to rely on research initiated after the effective date of the 2006 rule unless EPA has “adequate information

to determine that the research was conducted in substantial co mpliance with subparts A through L . . .” Section 26.1706 permits EPA to rely on th e results of human res earch unacceptable under the standards of §§ 26.1703 - 26.1705 only if EPA de termines, after public notice and comment and consultation with the HSRB, that reliance on the research is necessary to support “a more stringent regulatory restriction th at would improve protection of public health . . . than could be justified without relying on the data.” The Agen cy is not proposing to amend the substance of §26.1706.

1. Proposed Changes to §26.1703: Standards Applicable to All Covered Research. Consistent with the changes pr oposed in 40 CFR part 26, subpart P and discussed in Unit IV.C., EPA proposes to add in §26.1703(a) an explicit prohibition ag ainst reliance on data from completed research “unless EPA determines that th e data are relevant to a scientific or policy question important for EPA decision-making, that the data were derived in a manner that makes them scientifically valid and reliable, and that it is appropriate to use the data for the purpose proposed by EPA.”

In making this determination, EPA would be requ ired to assess these four aspects of the

research:

• Whether the research was conducted accordi ng to “appropriate scie ntific standards and practices prevailing at the time the research was conducted.”

• The extent to which the test subjects represent the population w hose response the data will be used to predict.

• The statistical power of the data to s upport the scientific conclusions drawn by EPA.

• Whether, in a study that reports a No Obse rved Adverse Effect Le vel, some dose level elicited a biological effect.

The concern for these four aspects of the research is derived from NAS Recommendations 3–1 and 5–1. They do not establis h fixed criteria for acceptance or rejection of a study, but they identify specific aspects of a study that EPA must c onsider in determining that it is relevant, scientifically valid and re liable, and appropriate for a particular use.

As noted previously, subpart Q of the 2006 ru le applies to EPA decisions to rely on “scientifically valid and relevant data” from c overed research. Since 2006 the Agency’s practice in reviewing reports of covered human research has been to examine car efully the scientific reliability of the reported studies and to refuse to rely on research deemed invalid or irrelevant. EPA proposes to delete these f actors from the scope of subpart Q as defined in §26.1701, and to codify them as factors in §26.1703(a) to ensure th at they remain central to determinations of scientific validity and relevance. If this propos ed rule is finalized, EP A will revise its review documentation standards to highlight the consid eration given to these four aspects of the

research.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 29 of 44 [RIN 2070-AJ76] 2. Changes to §26.1704 acceptance standards for research not subject to§26.1705. The Agency based the ethical acceptability standard in §26.1704 on Recommendation 5-7 in the 2004 NAS report, which states in relevant part:

EPA should accept scientifically valid st udies conducted before its new rules are implemented unless there is clear and convincing evidence that the conduct of those studies was fundamentally unethical (e.g., the studies were intended to seriously harm participants or failed to obtain informed consent) or that the conduct was deficient relative to then-prevailing standards.

Section 26.1704 provides in relevant part (emphasis added):

. . . EPA shall not rely on data from any r esearch initiated before [the effective date of the 2006 rule], if there is clear and convinci ng 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 con sent), or was significantly deficient relative to the ethical standards prevailing at the time the research was conducted.

EPA adopted the NAS recommendation nearly verbatim, with the notable insertion of the word “significantly” before “deficient .” EPA explained in the preamble to the 2006 rule (at 71 FR 6161) that this was to allow it the flexibility to c onsider the impact on subjects of any ethical shortcomings in the c onduct of the research. EPA stated in that preamble “EPA expects [the meaning of “signifi cantly”] to acquire gr eater clarity over time, through HSRB and public review of Agency decisions concerning reliance on completed

human research.”

EPA believes that greater clarity has, ind eed, been achieved through the application of the 2006 rule by EPA and the HSRB. EPA now proposes to revise §26.1704 by deleting the word “significantly,” and by characterizing explicitly the kinds of deficiencies that would make a study unacceptable. Proposed §26.1704 would forbid EPA to rely on research not covered by 40 CFR part 26, subpart K or the Common Rule in the face of clear and convincing evidence that its conduct “placed partic ipants at increased risk of harm (b ased on knowledge available at the time the study was conducted) or impaired their informed consent.”

This language is derived from the advice of the Human Studies Re view Board as they have applied the standard of §26.1704 in the 2006 rule. See, for example, their comments on studies involving aldicarb, methomyl, oxa myl, azinphos-methyl, DDVP, ethephon, sodium cyanide, and amitraz at: http://www.epa.gov/osa/hsrb/files/ meeting-materials/apr-4-6-2006- public-meeting/april200 6mtgfinalreport62606.pdf . For each study they found ethically acceptable, the HSRB found “ no evidence of significant deficiencies in the ethical procedures that could have resulted in serious harm (based on the knowledge available at the time the study was conducted) nor that information provided to participants seriously impaired their informed consent.”

Finally, EPA proposes to redefine the appli cability of §26.1704 in a new paragraph (a) as the complement of the more detailed scope of §26.1705, thereby eliminating any gaps or overlap in the applicability of the two standards.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 30 of 44 [RIN 2070-AJ76] 3. Changes to §26.1705 standards for completed re search conducted under 40 CFR Part 26 or another codification of the Common Rule. The standard in 40 CFR part 26 applying to completed research initiated after the effective date of the rule is §26.1705, based on NAS Recommendation 5-6, which st ates in relevant part (italics in the original; footnote omitted):

EPA should operate on the strong presumption that data obtained in studies conducted after implementation of the new rules that do not meet the ethical standards described in this report will not be considered in its regulatory decisions.

EPA adapted this recommendation in its drafting of §26.1705, which provides in relevant part:

EPA shall not rely on data from any research in itiated after [the effective date of the 2006 rule] unless EPA has adequate information to determine that the research was conducted in substantial compliance with subparts A thr ough L of this part, or if conducted in a foreign country, under procedures as least as protective as those in subparts A through L of this part.

EPA now proposes to amend both the applicability of §26.1705 and the substance of the standard itself. In the 2006 rule §26.1705 app lies to any scientifically valid and relevant research involving intentional exposure of human subjects an d initiated after the effective date of the rule. EPA proposes now to limit application of the §26.1705 st andard to research subject, at the time it was conducted, either to subparts A through L of 40 CFR part 26 or to another Federal department or agency ’s codification of the Common Rule.

EPA recognizes that it could in future wish to rely on data from third-party research

conducted after 2006 but which fell outside the scope of 40 CFR part 26, subpart K, and for

which EPA therefore would not have conducted a protocol review under 40 CFR part 26, subpart

P before the research was conducted. For exam ple, as discussed in Unit IV.A., 40 CFR part 26, subpart K as now proposed would not apply to a new clinical trial evaluating the therapeutic efficacy of a drug that was also a pesticide. Beca use this research would fall outside the scope of 40 CFR part 26, subpart K, investigators would not have submitted the protocol to EPA under 40 CFR part 26, subpart K and EPA and the HSRB w ould not have reviewed it under 40 CFR part 26, subpart P. Yet, if data from such research were to be relied on by EPA, the standards of subpart Q would apply. As §26.1705 is currently worded in 40 CFR part 26, such a study could only be relied on if “EPA has adequate informati on to determine that the research was conducted in substantial compliance with subparts A through L.” But because the protocol would not have been submitted for review by EPA and the HSRB, the research in this example would not have been conducted in substantial complian ce with 40 CFR part 26, subpart K.

EPA believes that it would be inappropriate to reject otherwise meritorious and ethical research for failure to comply with provisions in 40 CFR part 26, subparts A–L that did not apply when the research was conducted. Thus EPA proposes to make §26.1705 applicable only to studies that were initiated after the effective date of the 2006 rule and that were subject to EPA’s rules for the protection of human subjects (40 CFR part 26, subparts A through L) or another codi fication of the Common Rule. A companion change in §26.1704(a) would apply the standard of §26.1704 to all other completed research*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 31 of 44 [RIN 2070-AJ76] considered by EPA under 40 CFR part 26, subpart Q, without regard to when the research

was initiated.

EPA proposes further changes to §26.1705 to help make this clear. Proposed §26.1705(b)(1) defines the applicable standard as either 40 CFR part 26, subparts A through

L of EPA’s rule or another Federal department or agency ’s codification of the Common Rule, whichever set of rules covered the re search when it was conducted. In proposed §26.1705(b)(2), corresponding changes are made app licable to research conducted in foreign

countries.

Finally, in a new paragraph §26.1705(c), EP A proposes to require substantial compliance of covered research with its prot ocol. A study reviewed as a proposal under subpart P of 40 CFR part 26 could be relied on only if it had been c onducted in substantial compliance with the protocol found acceptable by EPA, and if the investigator did not further amend or deviate from the protocol in wa ys that placed particip ants at increased risk of harm (based on knowledge available at th e time the study was conducted) or impaired their informed consent. If a completed study was not reviewed as a proposal under 40 CFR part 26, subpart P, the study could only be re lied on if it had been c onducted in substantial compliance with a protocol that would have been found acceptable, and if the investigator did not amend or deviate from the protocol in wa ys that placed particip ants at increased risk of harm (based on knowledge available at th e time the study was conducted) or impaired

their informed consent.

Taken together, these proposed changes in §26.1705 reflect the in terpretations and methods used by EPA and the HSRB since 2006 in reviewing completed, post-rule research. Codifying these interpretations will ensure cons istency and transparency in future decisionmaking.

E. Request for Public Comment on Possi ble Re-codificati on of Subparts K-Q

Subparts A-D of 40 CFR part 26 all apply to research with human subjects which is conducted or supported by EPA in its role as a re search agency. Subparts K-Q of 40 CFR part 26 apply to pesticide research wi th human subjects that is con ducted by regulated third parties, and to EPA’s regulatory oversight of that research. Some stakehol ders have suggested that this important distinction would be clearer if 40 CF R part 26 contained only those subparts applying to EPA as a research agency, and if subparts K- Q were moved to a different section of EPA’s regulations, within the range where other pesticide-spec ific regulations are found.

EPA is not now proposing such a re-codificati on, but invites public comment on the idea. Although it would necessitate many non-substantiv e revisions—mainly of internal crossreferences—re-codification would not be difficu lt to accomplish. 40 CFR part 26 would retain current subparts A-D, and at leas t parts of current subpart O. A previously unused part within 40 CFR, within the numerical range of parts 150- 180 where other pesticid e-related regulations appear, would include current subpa rts K, L, M, O, P, and Q. Subpart O potentially applies to both EPA research and to third-part y research and would need to be adapted to fit into both parts of a separated codification in 40 CFR.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 32 of 44 [RIN 2070-AJ76] V. FIFRA Review Requirements

[Note to reviewers: this sec tion will be filled in once FIFRA re view is completed, which is scheduled to occur during th e EO 12866 review process.]

In accordance with FIFRA section 25(a), EPA has submitted a draft of the proposed rule to the FIFRA SAP, the Secretary of Agricu lture (USDA), and appr opriate Congressional

Committees. The FIFRA SAP waived its review of this proposal on [insert date], because the significant scientific issues involved have al ready been reviewed by the SAP and additional review isn’t necessary. Comments on the dr aft proposal received from USDA have been addressed [or revise to say they did not comm ent. Or say...USDA participated fully in the interagency review proc ess under Executive Order 12866, during which EPA and USDA discussed [enter major topic areas that were raised and resolved].

VI. Statutory and Executive Order Reviews

A. Regulatory Planning and Review

Under Executive Or der 12866, entitled Regulatory Planning and Review (58 FR 51735, October 4, 1993), this has been identified as a “significant regulatory action” because it may raise novel legal or policy issues. Accordingl y, EPA submitted the draft proposed rule to the Office of Management and Budget (OMB) fo r review under Executive Order 12866 and any changes made in response to OMB recommendati ons have been documented in the public docket for this rulemaking as requi red by the Execu tive Order.

The incremental costs of these proposed am endments both to industry and to EPA are expected to be negligible. EPA has not, theref ore, prepared a new economic analysis for this rulemaking. Because no research has been identif ied that is outside the scope of the 2006 rule

but that would be within the sc ope of these proposed amendments, EPA has no basis on which to revise the cost estimates that were provided in the economic analysis for the 2006 rulemaking or those most recently provided in the 2008 renewa l of the Information Collection Request (ICR) for the existing regulation at 40 CFR part 26. The recent estimates included in the ICR are summarized in Unit VI.B. and a copy of the ICR is available in the docket.

B. Paperwork Reduction Act

This action does not impose any new informa tion collection burden that would require additional review or approval by OMB under th e Paperwork Reduction Act (PRA), 44 U.S.C.

3501 et seq . OMB previously approved the informati on collection requirement s contained in the existing regulations at 40 CFR part 26 under OMB Control No. 2070-0169 (EPA ICR No. 2195). Burden is defined at 5 CFR 1320.3(b).

In its 2008 analysis supporting the most recent renewal of this ICR, EPA estimated that respondents would submit to the Agency some 34 proposals for or reports of research involving intentional exposure of human subjects each year. EPA estimated that preparation of information required by the 2006 rule would requi re about 598 hours per study at a cost of $45,927 per study, for a total estimated annual burden for affected entities of 20,332 hours at an*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 33 of 44 [RIN 2070-AJ76] estimated cost of $1,561,518. In addition, EPA es timated annual submission of 20 reports of research requiring only documentation of ethical conduct at a cost of 12 hours/$879 per report, or 240 hours/$17,580 per year. The tota l estimate of the annual responde nt burden and cost was the sum of these two estimates, or 2,572 hours/$1,579,098.

These paperwork burden and cost estimates in clude activities relate d to initial rule familiarization, as well as activities that resear chers would have to perform even without the Agency’s rulemaking in this area, such as deve loping a protocol and maintaining records.

The average annual burden on EPA for reviewing each of the 34 study submissions was estimated to be 178 hours/$16,850 per study, or 6,052 hours/$572,900 per year. The average annual burden on EPA for reviewing each of the 20 additional submissions was estimated to be 44 hours/$3,158 per study, or 880 hours/$63,160 per ye ar. The total estim ate of the annual

burden on EPA was the sum of these tw o estimates, or 6,932 hours/$636,000 per year.

In no year since promulgation of the 2006 ru le have more than 7 protocols been submitted to EPA by industry; the average annual ra te has been just over 5 for the 5-year period of 2006-2010. Somewhat fewer completed reports have been submitted during this period, so the average of new protocols and finished studies has been about 11 per year, less than a third of the projected 34 per year covered by the ICR. There is no evidence to su ggest an upward trend, and nothing in these amendments is believed likely to lead to a significant change in the rate of protocol and study submissions.

An agency may not conduct or sponsor, a nd a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9.

C. Small Entity Impacts

Pursuant to section 605(b) of the Regulat ory Flexibility Act (RFA), 5 U.S.C. 601 et seq .), the Agency hereby certifies that this action will not have a sign ificant adverse economic impact

on a substantial number of small entities. Under the RFA, small entities include small businesses, small organizations, and small governme ntal jurisdictions. For purposes of assessing the impacts of this proposed rule on small entitie s, small entity is defined in accordance with

section 601 of the RFA as:

1. A small business as defined by the Small Busi ness Administration’s (SBA) regulations at 13 CFR 121.201. 2. A small governmental jurisdiction that is a government of a c ity, county, town, school district or special district w ith a population of less than 50,000. 3. A small organization that is any not-fo r-profit enterprise which is independently owned and operated and is not dominant in its field.

Because no small entities have been identifi ed that are directly regulated by these proposed amendments, EPA has not attempted to reduce the impact of this proposed rule on

small entities. Comments are invited on all as pects of the proposal and its impacts on small

entities.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 34 of 44 [RIN 2070-AJ76] D. Unfunded Mandates

This action does not impose any enforceab le duty, contain any unfunded mandate, or otherwise have any effect on small governments subject to the requireme nts of sections 202, 203, 204, or 205 of the Unfunded Mandates Reform Act (UMRA), 2 U.S.C. 1531-1538. These amendments are unlikely to affect State, local, and tribal governments at all, and are likely to affect the private sector only trivially. The 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 1 year.

E. Federalism

This action does not have federalism implica tions because it is not expected to have substantial direct effects on the States, on the relationship between the national government and the States, or on the distribution of power a nd responsibilities among th e various levels of government, as specified in Executive Order 13132, entitled Federalism (64 FR 43255, August 10, 1999). It makes marginal changes in the scope of an existing rule applying to sponsors and investigators conducting certain kinds of research involving hu man subjects, and refines the standards for EPA oversight of a nd reliance on such research.

In the spirit of Executive Or der 13132, and consistent with EPA policy to promote

communications between EPA and State and lo cal governments, EPA specifically requests comments on this proposed action from State and local officials.

F. Tribal Implications

This action does not have tribal implicat ions as specified in Executive Order 13175,

entitled Consultation and Coordination with Indian Tribal Governments (65 FR 67249, November 9, 2000). This action is not expected to have substantial direct effects on Indian Tribes, will not significantly or uniquely affect the communities of Indian Tribal governments, and does not involve or impose any requirements th at affect Indian Tribes. Thus Executive Order 13175 does not apply to this action.

G. Children’s Health Protection

EPA interprets Executive Order 13045, entitled Protection of Children from Environmental Health Risks and Safety Risks (62 FR 19885, April 23, 1997), as applying only to those regulatory actions that con cern health or safety risks, such that the analysis required under section 5-501 of the Executive Order has the pote ntial to influence the regulation. This action is not subject to Executive Order 13045 because it do es not establish an e nvironmental standard intended to mitigate health or safety risks, no r is it an “economically significant regulatory

action” as defined in Executive Order 12866. The 2006 rule applies to the conduct and review of research involving intentional e xposure of human subj ects, and prohibits the conduct of or EPA reliance on any such researching involving subjects who are child ren, or pregnant or nursing women. These provisions would not be affected by the proposed amendments.

H. Affect on Energy Supply, Distribution or Use*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 35 of 44 [RIN 2070-AJ76] This action is not a “significant energy action” as defined in Executive Order 13211,

entitled Actions Concerning Regulations That Signifi cantly Affect Energy Supply, Distribution,

or Use (66 FR 28355, May 22, 2001), because this action is not likely to have any affect on the supply, distribution, or use of energy.

I. Technical Standards

Because this action does not involve any t echnical standards, section 12(d) of the National Technology Transfer and Advancement Act of 1995 (NTTAA) (15 U.S.C. 272 note), does not apply to this action.

J. Environmental Justice

This action does not entail special considerations of environmental justice related issues as delineated by Executive Order 12898, entitled Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations (59 FR 7629, February 16, 1994). The strengthened protections for human subjects participating in covered research established in the 2006 rule would not be altered by these proposed amendments.

List of Subjects in 40 CFR Part 26

Environmental protection, Hu man research, Pesticides

Dated: _________________

____________________________________ Administrator.

Therefore, it is proposed that 40 CFR chapter I be amended as follows:

PART 26—[AMENDED]

1. The authority citation for part 26 is revised to read as follows:

Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) and 136w(a)(1); 21 U.S.C. 346a(e)(1)(C); sec. 201, Pub. L. 109–54, 119 Stat. 5 31; and 42 U.S.C. 300v–1(b).

2. Amend § 26.1101 as follows:

a. Remove paragraphs (a), (c), and (g);

b. Redesignate paragraphs (b ) as (c), (f) as (g), (e) as (f), and (d) as (e); and

c. Add new paragraphs (a), (b), and (d) to read as follows.

§ 26.1101 To what does this subpart apply?*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 36 of 44 [RIN 2070-AJ76] (a) Except as provided in paragr aph (c) of this section, this su bpart applies to all research initiated after [effective date of final rule] involving intentional exposure of a human subject to:

(1) Any substance if, at any time prior to initiating such rese arch, any person who conducted or supported such research intended either to submit results of the research to EPA for

consideration in connection w ith any action that may be performed by EPA under the Federal Insecticide, Fungicide, and Rode nticide Act (FIFRA) (7 U.S.C. 136-136y) or section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. 346a)

, or to hold the results of the research for later inspection by EPA under FI FRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C. 346a); or

(2) A pesticide if, at any time prior to in itiating such research, any person who conducted or supported such research intended either to submit results of the research to EPA for

consideration in connection with any action that may be perfo rmed by EPA under any regulatory statute administered by EPA other than those statutes designated in paragraph (a)(1) of this section, or to hold the results of the research for later insp ection by EPA under any regulatory statute administered by EPA other than those statutes designated in paragraph (a)(1) of this

section.

(b) For purposes of determining a person’s intent under paragraph (a) of this section, EPA may consider any available and relevant information. EP A shall rebuttably presume the

existence of intent 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 pe ople who, or whose products or activities, are regulated by EPA and, at the time the research wa s initiated, the results of such research would

be relevant to EPA’s exercise of its regulatory authority with re spect to that class of people, products, or activities.

* * * * *

(d) The Administrator retains final judgment as to whether a particul ar activity is covered by this subpart.

* * * * *

3. Amend § 26.1102 as follows:

a. Revise paragraph (a);

b. Remove paragraph (c); and

c. Add new paragraphs (c) and (k) to read as follows:

§ 26.1102 Definitions.

(a) Administrator means the Administrator of the Environmental Protection Agency*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 37 of 44 [RIN 2070-AJ76] (EPA) and any other officer or employee of EPA to whom authority has been delegated.

* * * * *

(c) Initiation of research involving human subjects is defined as occurring with the enrollment of the first subject in the research.

* * * * *

(k) Pesticide means any substance or mixture of s ubstances meeting the definition in 7 U.S.C. 136(u) [Federal Insecticide, Fungicide , and Rodenticide Act, section 2(u)].

§ 26.1111 [Amended].

4. Amend § 26.1111 by removing from paragr aph (a)(4) the phrase “or the subject’s legally authorized representative”.

5. Amend § 26.1116 by revising the introductory te xt of the section a nd paragraph (e) to

read as follows:

§ 26.1116 General requirements for informed consent.

No investigator may involve a human being as a subject in res earch covered by this subpart unless the investigator has obtained the lega lly effective informed consent of the subject. An investigator shall seek such consent only under circumstances that provide the prospective subject sufficient opportunity to consider whethe r or not to participate and that minimize the possibility of coercion or undue influence. The in formation that is given to the subject shall be in language understandable to the subject. No in formed consent, whether oral or written, may include any exculpatory language through which the s ubject is made to waive or appear to waive any of the subject’s legal rights, or releases or appear s to release the inves tigator, the sponsor, the institution or its agents from liability for negligence.

* * * * *

(e) The subjects of the research must be informed of the identity of the pesticide and the nature of its pesticidal function.

6. Revise § 26.1117 to read as follows:

§ 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. A copy shall be given to the subject.

(b) The consent form may be either of the following:

(1) A written consent document that embodies the elements of informed consent required by § 26.1116. This form may be read to the subject, but in any event, the i nvestigator shall give*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 38 of 44 [RIN 2070-AJ76] the subject adequate opportunity to read it before it is signed; or

(2) A short form written consent document statin g that the elements of informed consent required by § 26.1116 have been presented orally to the subject. When this method is used, there shall be a witness to the oral presentation. Al so, the IRB shall approve a written summary of what is to be said to the subject. Only the s hort form itself is to be signed by the subject. 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 th e summary. A copy of the summary shall be given to the subject, in additi on to a copy of the short form.

7. Revise the title for su bpart L to read as follows:

Subpart L—Prohibition of Third-Party Research Involving Intentional Exposure to a Pesticide of Human Subjects Who are Ch ildren or Pregnant or Nursing Women

8. Revise § 26.1201 to read as follows:

§ 26.1201 To what does this subpart apply?

This subpart applies to any research subject to subpart K of this part.

9. Revise § 26.1301 to read as follows:

§ 26.1301 To what does this subpart apply?

This subpart applies to any person who submits to EPA after [effective date of final rule] either of the following:

(a) A report containing the results of any hum an research for consid eration in connection with an action that may be performed by EPA under FIFRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C. 346a).

(b) A report containing the results of any human research on or with a pesticide for

consideration in connection with any action that may be perfo rmed by EPA under any regulatory statute administered by EPA.

§ 26.1302 [Amended].

10. Amend § 26.1302 by removing the word “shall” from this section.

§ 26.1502 [Amended].

11. Amend § 26.1502 as follows:

a. In the first sentence of paragraph (a) remove the period after the phrase “during an inspection” and add in its place a comma; and

b. In the second sentence of paragraph (a) re move the phrase “The ag ency” and add in its*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 39 of 44 [RIN 2070-AJ76] place “EPA.”

c. In the introductory text of paragraph (b) remove the phr ase “The agency” and add in its place “EPA.”

§ 26.1505 [Amended].

12. Amend § 26.1505 by removing from the last sentence the phrase “§ 26.1502(c)” and adding in its place “§ 26.1502(b)(4).”

§ 26.1507 [Amended].

13. Amend the last sentence of § 26.1507 by removing the phrase “The agency” and adding in its place “EPA”.

§ 26.1601-1603 [Redesignated].

14. Amend subpart P of this part by redesignating §§ 26.1601 through 26.1603 as §§ 26.1603 through 26.1605.

15. Add new §§ 26.1601 and 26.1602 to read as follows:

§26.1601 To what does this subpart apply?

This subpart applies to both of the following:

(a) Reviews by EPA and by the Human Studies Review Board of proposals to conduct new research subject to 40 CFR 26.1125.

(b) Reviews by EPA after [effective date of th e final rule] and, to th e extent required by § 26.1604, by the Human Studies Review Board of re ports of completed research subject to 40

CFR 26.1701.

§ 26.1602 Definitions.

The definitions in § 26.1102 apply to this subpart as well.

16. Amend redesignated § 26.1603 as follows:

a. Remove paragraphs (a) and (e).

b. Redesignate paragraphs (b) through (d) as (e) through (g).

c. Add new paragraphs (a), (b), (c ), (d), and (h) to read as follows.

§ 26.1603 EPA review of proposed human research.

(a) EPA shall review all proposals for new human research submitted under § 26.1125 in a timely manner.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 40 of 44 [RIN 2070-AJ76] (b) In reviewing proposals for new hu man research submitted under § 26.1125, the

Administrator shall consider and make determ inations regarding th e proposed research, including:

(1) Whether the research w ould be likely to produce data that address an important scientific or policy question th at cannot be resolved on the basis of animal data or human

observational research.

(2) Whether the proposed research is desi gned in accordance with current scientific standards and practices to:

(i) Address the research question.

(ii) Include representative study popula tions for the endpoint in question.

(iii) Have adequate statistical pow er to detect appropriate effects.

(3) Whether the investigator proposes to conduct the research in accordance with recognized good research practices, including, when appropriate, good clinical practice guidelines and monitoring for the safety of subjects.

(c) In reviewing proposals for new res earch submitted under § 26.1125, the Administrator shall consider and make determinations regard ing ethical aspects of the proposed research including:

(1) Whether adequate information is availabl e from prior animal studies or from other sources to assess the pote ntial risks to subjects in the proposed research.

(2) Whether the research pr oposal adequately identifies anticipated risks to human subjects and their likelihood of occurrence, minimizes identified risks to human subjects, and identifies likely benefits of th e research and their distribution.

(3) Whether the proposed research presents an acceptable balance of risks and benefits. In making this determination for research intende d to reduce the interspeci es uncertainty factor in a pesticide risk assessment , the Administrator shall consid er Recommendation 4-1 of the

National Research Council as contained in it s 2004 report entitled “I ntentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues.”

(4) Whether subject selection will be equitable.

(5) Whether subjects’ par ticipation would follow free and fully informed consent.

(6) Whether an appropriately constituted Institutional Review Board or its foreign equivalent has approved the proposed research.

(7) If any person from a vulnerable populat ion may become a subject in the proposed research, whether there is a convi ncing justification for selecti on of such a person, and whether measures taken to protect such human subjects are adequate.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 41 of 44 [RIN 2070-AJ76] (8) If any person with a c ondition that would put them at increased risk for adverse effects may become a subject in the proposed research, whether there is a convincing justification for selection of su ch a person, and whether measures taken to protect such human subjects are adequate.

(9) Whether any proposed payments to subjec ts are consistent with the principles of justice and respect for persons, and whether they are so high as to constitute undue inducement

or so low as to be attractiv e only to individuals who are so cioeconomically disadvantaged.

(10) Whether the sponsor or investigator w ould provide needed medical care for injuries incurred in the proposed research, wi thout cost to the human subjects.

(d) With respect to any research or a ny class of research, the Administrator may recommend additional conditions which, in the judg ment of the Administrator, are necessary for the protection of human subjects.

* * * * *

(h) EPA shall provide the submitter of the proposal copies of the EPA and Human

Studies Review Board reviews.

17. Amend redesignated § 26.1604 by revisi ng paragraph (a) to read as follows:

§ 26.1604 EPA review of completed human research.

(a) When considering, under any regulatory st atute it administers, data from completed research involving intentional e xposure of humans to a pestic ide, EPA shall thoroughly review the material submitted under § 26.1303, if any, and other available, relevant information and document its conclusions regarding the scien tific and ethical conduc t of the research.

*****

18. Add §§ 26.1606 and 26.1607 to read as follows:

§ 26.1606 Human Studies Review Board review of proposed human research.

In commenting on proposals for new research submitted to it by EPA, the Human Studies

Review Board shall consider the scientific merits and ethical as pects of the proposed research, including all elements listed in § 26.1603(b) a nd (c) and any additional conditions recommended pursuant to § 26.1603(d).

§ 26.1607 Human Studies Review Board review of completed human research.

In commenting on reports of completed re search submitted to it by EPA, the Human

Studies Review Board shall consider the scientif ic merits and ethical aspects of the completed research, and shall apply the appropriate standards in subpart Q of this part.

19. Revise the heading for subpart Q to read as follows:*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 42 of 44 [RIN 2070-AJ76] Subpart Q—Standards for Assessing Whether to Rely on the Results of Human Research

in EPA Actions

20. Revise §§ 26.1701-26.1705 to read as follows:

§ 26.1701 To what does this subpart apply?

(a) For decisions under FIFRA (7 U.S.C. 136-136y) or section 408 of FFDCA (21 U.S.C. 346a), this subpart applies to research involving intentional exposure of human subjects to any

substance.

(b) For decisions under any regulatory statut e administered by EPA other than those statutes designated in paragraph (a) of this section, th is subpart applies to research involving intentional exposure of human subjects to a pesticide.

§ 26.1702 Definitions.

The definitions in § 26.1102 and § 26.1202 apply to this subpart as well.

§ 26.1703 Prohibitions applying to all research subject to this subpart.

(a) Prohibition of reliance on scientifically invalid researc h. EPA shall not rely on data from research subject to this subpart unless EP A determines that the data are relevant to a scientific or policy question impor tant for EPA decision-making, that the data were derived in a manner that makes them scientifically valid and relia ble, and that it is appropriate to use the data for the purpose proposed by EPA. In making such determinations, EPA shall consider:

(1) Whether the research was designed a nd conducted in accordance with appropriate scientific standards and practices prevaili ng at the time the rese arch was conducted.

(2) The extent to which the re search subjects are representa tive of the populations for the endpoint or endpoint s in question.

(3) The statistical power of the data to s upport the scientific conclusion EPA intends to

draw from the data.

(4) In a study that reports only a No Observ ed Effect Level (NOEL) or a No Observed Adverse Effect Level (NOAEL), wh ether a dose level in the study gave rise to a biological effect, thereby demonstrating that the study had adequate sensitivity to detect an effect of

interest.

(b) Prohibition of reliance on research subj ect to this subpart involving intentional exposure of human subjects w ho are pregnant women (and ther efore their fetuses), nursing women, or children. Except as provided in § 26.1706, EPA shall not rely on data from any research subject to this subpa rt involving intentional exposure of any human subject who is a pregnant woman (and therefore her fe tus), a nursing woman, or a child.

§ 26.1704 Prohibition of reliance on unethical human research with non-pregnant, nonnursing adults which is not subject to § 26.1705.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 43 of 44 [RIN 2070-AJ76] (a) This section applies to research subject to this subpart that is not subject to § 26.1705.

(b) Except as provided in § 26.1706, EPA shall not rely on data from any research subject

to this section if there is cl ear and convincing evidence that:

(1) The conduct of the research was funda mentally unethical (e.g., the research was intended to seriously harm pa rticipants or failed to obt ain informed consent), or

(2) The conduct of the research was deficien t relative to the ethical standards prevailing at the time the research was conducted in a way that placed participants at increased risk of harm (based on knowledge available at the time the study was conducted) or impaired their informed

consent.

(c) This prohibition is in addi tion to the prohibitions in § 26.1703.

§ 26.1705 Prohibition of reliance on unethical human research with non-pregnant, nonnursing adults initiated after April 7, 2006, a nd subject to subparts A through L of this part or codification of the Common Rule by another Federal department or agency.

(a) This section applies to resear ch subject to this subpart, that:

(1) Was initiated after April 6, 2006.

(2) Was subject, at the time it was conducted, ei ther to subparts A through L of this part or to another codification of the Basic Policy fo r the Protection of Subj ects in Human Research Conducted or Supported by a Federal Agency, gene rally referred to as the “Common Rule.”

(b) Except as provided in § 26.1706, EPA shall not rely on data from any research subject

to this section unless EPA determines that the research was conducted in substantial compliance

with either:

(1) All applicable provisions of subparts A th rough L of this part or codification of the Common Rule by another Federal department or agency, or

(2) If the research was conduc ted outside the United States, with procedures at least as protective of subjects as those in subparts A through L of this part or codification of the Common Rule by another Federal department or agency.

(c) Except as provided in § 26.1706, EPA shall not rely on data from any research subject

to this section unless EPA determines that the research was conducted in substantial compliance

with either:

(1) A proposal that was found to be accep table under § 26.1603(c), and no amendments to or deviations from that proposal placed par ticipants at increased risk of harm (based on knowledge available at the time the study was conducted) or impaired their informed consent. If EPA discovers that the submitter of the proposal materially misrepresented or knowingly omitted

information that would have altered the outco me of EPA’s evaluation of the proposal under § 26.1603(c), EPA shall not rely on that data.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 44 of 44 [RIN 2070-AJ76] (2) A proposal that would have been found to be acceptable under § 26.1603(c), if it had been subject to review under that section, and no am endments to or deviations from that proposal placed participants at increased risk of harm (based on knowledge available at the time the study was conducted) or impaired their informed consent.

(d) This prohibition is in addi tion to the prohibitions in § 26.1703.

21. Amend § 26.1706 in paragraph (d) by removi ng the phrase “publishes” and adding in its place “has published.”

[Note to reviewers: We are double checking for a ny cross references in the CFR that might need

to be corrected as a result of these amendments . If any are found, amenda tory text to correct them will be added here.]

[FR Doc. ??–????? Filed ??–??–??; 8:45 am]