*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 1 of 56 [RIN 2070-AJ76] EO12866_HumanSubjectsRevisions_NPRM_ 2010

- 09

- 17 2011-01-18 .docx

Revised to address Interagency Co mments received under EO 12866 Review.

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 thir d parties who conduct or support research for with pesticides involving intentional exposure of human subjects and to persons who submit the results of human research for with pesticides to EPA. EPA agreed to propose thes e amendments as a result of a settlement agreement resolving a judicial challenge to the promulgation 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 with pesticides submitted to EPA under any regulatory statute it administers . They would also disallow participation in third-party pesticide studies by subjects who cannot consent for themselves. Finally they the proposed amendments would identify specific considerations to be addressed in EPA science and ethics reviews of proposed and completed human research for with pesticides, drawn from the recommendations of the National Academy of Sciences (NAS ) ). In seeking comments on these proposed amendments, EPA does not imply that the current Federal Policy for the Protection of Human Subjects (the “Common Rule”), which gove rns research with human subjects conducted or supported by EPA and many other Federal departments and from the Nuremberg Code. agencies, is inadequate. Indeed, the amendmen ts proposed here would make no changes to the Common Rule or EPA’s codification of the Common Rule. Rather, EPA is proposing these amendments to other portions of its regulation as a result of a settlement agreement, and is now seeking comment on these proposed amendments. The settlement agreement makes clear that EPA retains full discretion concerning what amendments are proposed, and what, if any, amendments are finalized. Furthermore, no research has been identified th at is outside the scope of EPA’s current rule, but that would be within the scope of these proposed amendments. EPA seeks comments on the need for and value of the proposed changes.

DATES: Comments must be received on or before [insert date 60 days after date of publication in the Federal Register ].*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 2 of 56 [RIN 2070-AJ76] 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 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 3 of 56 [RIN 2070-AJ76] 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 with 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 sponsor or conduct human research for with pesticides.

• Other entities (NAICS code 541710) that sponsor or conduct human research for with pesticides, and Institutional Review Boards who review human research for with pesticides to ensure it meets applicable standards of et hical 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 redacted 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.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 4 of 56 [RIN 2070-AJ76] 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.

II. Background

A. What w W ould the proposed amendments do Proposed Amendments Do ?

The proposed amendments would change the 2006 rule, published in the Federal Register on issue of 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 CF R part 26, in the following substantive 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 consent 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, subparts 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 recommendations of the NAS in their its 2004 r R eport to EPA, and from the Nuremberg Code.

The amendments proposed here would make no changes to the Federal Policy for the Protection of Human Subjects of Research (the “Common Rule”), wh ich 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 5 of 56 [RIN 2070-AJ76] 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).

• 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 substantial new clar ifying 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 opportunity 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.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 6 of 56 [RIN 2070-AJ76] 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

. (71 FR 6138, February 6, 2006)(FRL-7759-8). These proposed amendments to that rule rest upon the same lega l authority. In particular, the legal authority for expanding the 2006 rule to cover research involvi ng the intentional e xposure of a human subject to a pesticide submitted under any EPA regulatory statute is provi ded by section 201 of the Department of the Interior, Environment, and Related Agencies Appropriations Act, 2006, Public Law 109-54 (2006 Appropriations Act), and FIFRA.

The 2006 Appropriations Act directly mandates th at EPA promulgate a rule on “thirdparty intentional dosing human t oxicity studies for pesticides . . .” without limiting the rule to pesticide 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) that is not already covered by the Common Rule absent compliance with the applicable rules in 40 CFR part 26, as proposed. The importance of these rules to the protection of human subjects is demonstrated in the 2004 r R eport from the National Research Council of the NAS

, en titled “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scient ific and Ethical Issues .” ” (2004 NAS Report) (http://www.nationalacademies.org).

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 e xposure of human subjects to registered pesticides will serve this end

. fall within that purview. FIFRA provides that a pesticide ma y not be registered unless use of the pesticide under its labeling wi ll not cause unreasonable risks to humans or the environment, 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 nature, purpose, and physical and mental health consequences of th e testing and freely volunteer. (See 7 U.S.C. 136(bb), 136a(c)(5), 136j(a)(2)(G), 136j(a)(2)(P)). The 2006 rule and the amendments proposed in this document i e nsure that these provisions regarding use of registered pesticides in a manner that does not cause unreasonable risk and full and free consent in human testing with pesticides are effectuated.

III. EPA’s Human Subjects Protection Rules*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 7 of 56 [RIN 2070-AJ76] A. Overarching p P rinciples

EPA is committed to relying on scientifically sound research that is ethically conducted, and to transparency in its review processes and decisionmaking

. decision-making. EPA issued the 2006 rule to further these commitments

. As is discussed later in this Unit , experience since 2006 has shown clearly that the rule has contributed to the soundness of EPA decisions, the scientific soundness of new human research, and the ethical treatment of the su bjects of new research

. This experience has also demonstrated the fundamental compatibility of sound science and high ethical standards

.

The nothing in the amendments proposed in this document will not alter the A gency ’ 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 protec ting human subjects of research

.

that. These proposed amendments , however, will increase can be seen as increasing the transparency of EPA decisionmaking, EPA’s decision-making process by clarifying the scope and applicability of the requirements in 40 CFR part 26, codifying the scope and approach used in EPA’s science and ethics reviews of human research involving pesticides , and refining the standards that huma n research with pesticides must meet to be relied upon by EPA in its actions under any of the regulatory statute s 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 p art 26

. The Common Rule defines the core protections for human subjects in any research conducted, supported, or otherwise subject to regulation by any F ederal 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 Appropriations Act (P ub lic L aw 93

- 348), signed into law on July 12, 1974

. The report, entitled “Ethical Principles and Guidelines for the Protection of Human Su bjects of Research” and widely known as the Belmont Report, put forth three basic principles governing the use of hu mans as research subjects: respect for persons, beneficence, and justice

. In the years since the publication of the Belmont Report, its principles have gained wide international and cross

- cultural acceptance

.
The regulatory application of the Belmont principles 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 su pported 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 HSRR O is an independent, senior EPA official with responsibility for overs eeing all EPA activities involving research with*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 8 of 56 [RIN 2070-AJ76] human subjects

. It is EPA policy that no human subject may be recruited or enrolled in any research conducted or supported by the Agency until that research has been reviewed by the EPA HSRRO and either approved or determined to be exempt from the Common Rule.

When EPA promulgated the of 2006 rule adding new subparts to 40 CFR part 26, EPA’s codification of the Comm on Rule was redesignated

— w ithout change

— as 40 CFR part 26, subpart A

. T h e 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 intramural research, the Agency makes grants to academic and
not

- for

- profit scientific institutions to conduc t research under its STAR (Science To Achieve Results) program

. See http://www.epa.gov/ncer/grants

. The Agency also conducts r esearch jointly with other F ederal agencies

. Although it represents only a portion of EPA’s overall research effort, so me of this research i nvolves human subjects, and is thus governed by the Common Rule

. Since promulgation of the Common Rule in 1991, EPA has worked diligently to ensure its human research complies fully with all requirements of the Common Rule.

In 2006 E PA defined new regulatory re quirements in 40 CFR part 26

, subparts B, C, and D that provide additional safeguards fo r specific groups of vulnerable subjects

. These regulations complement longstand ing internal operati ng procedures designed to ensure the in terests of human participants in research th at EPA conducts or supports are fully protected.

Subpart B of 40 CFR part 26 categorically prohibits EPA research involving the intentional exposure of child ren or of pregnant or nur sing women to any substance

. Subpart C defines additional protections for pregnant women (and indirectly their fetuses) involved as subjects in EPA observational research

. Subpart D of 40 CFR part 26 defines additional protections for children involve d as subjects in EPA observation al research

. The major thrust of these subparts is to limit the risk to which th e subjects covered by the subparts may be exposed

. Taken together, the provisi ons in the Common Rule ( 40 CFR part 26, subpart A) and in subparts B, C, and D of 40 CFR part 26 establish the strongest 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 EPA Order 1000.17, “ Policy and Procedures on Protection of Human Research Subjects in EPA Conducted or Supported Research ,” all research involving human subjects proposed to be conducted or supported by EPA must receive approval (or be determined to be ex empt 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 envi ronmental substances raises scientific and ethical issues differing from those raised by other types of human research

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

Page 9 of 56 [RIN 2070-AJ76] 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 : “ Scientific and Ethical Approaches for Observat ional Exposure Studies. ” Available online at http://www.epa.gov/nerl/sots/SEAOES_doc20080707.pdf

. EPA strongly encourages i nvestigators conducting observational research to consider and ap ply this guidance.

D

. Past C ontroversy over Third

- Party H uman R esearch with P esticides

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 factor to increase protection of children

. Soon after passage of FQPA a pesticide industry group issued a white paper noting that the toxic effect serving as the point of departure for most risk assessments of the widely used organophosphate and carbamate pesticides

— cholinesterase inhibition

— was reversible and easily measured

. This white paper recommended testing to directly measure cho linesterase inhibition in humans

. Such data, the paper suggested, could be used by EPA in risk assessments without employing another tenfold uncertainty factor that EPA customarily applie s when estimating safe exposures for humans based on animal toxicity endpoints

. A few studies of cholinesterase inhibition in humans had already been conducted or initiated when the 199 6 amendments were enacted, and several more were initiated soon afterward.

A n environmental advocacy group learned of this testing and pu blished 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 com panies 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 s hould never consider it

. Others argued that although some human tes ting was ethical, EPA should never consider unethical data

. Still others argued that it would be uneth ical not to rely on the best and most relevant scientific data, regardless of how they were obtained.

EPA so ught guidance from an advisory panel co nvened under the joint auspices of the EPA Science Advisory Board and the FIFRA Scientific 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 complex sc ientific and ethical issues posed b y EPA’s possible use of third

- party studies which intentionally dose human subj ects 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 10 of 56 [RIN 2070-AJ76] that this policy statement had the effect of a rule without having been issued through notice

- and

comment rulemaking

. I n its June 2003 decision, the United States Court of Appeals for the District of Columbia vacat ed the policy and direct ed EPA to reinstate “ the agency’s previous practice of considering third

- party human studies on a case

- by

- case basis, applying statutory requirements, the Common Rule, and high ethical standards as a guide

. . . unless and unt il it is replaced by a lawfully promulgated regulation. ” Crop L ife America v

. EPA

, 329 F.3d 876 , 879 (D.C

. Cir

. 2003).

By the time of the CropLife decision, EPA had already be gun 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 Studies 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:

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 in the Federal Register issue of September 12, 2005 (70 FR 53838) (FRL

- 7728-2), accepted public comment until December 12, 2005, and promulgated on February 6, 2006 (71 FR 6138) (FRL 7759

- 8 )

, , a final rule which took effect on April 6, 2006

. (71 FR 6138) (FRL-7759-8). The 2006 rule, as subsequently amended 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 III.E. and is now being furthe r amended by this proposed rule.

E C

. EPA’s 2006 Rule

1. Summary of contents. The 2006 rule established a comprehens ive set of new protections for people participating as s ubjects in third-party human research for with pesticides. (In this context “third-party” research is resear ch neither conducted (“fi rst-party”) nor supported (“second-party”) by EPA or another Federal Common Rule Federal department or agency.) The 2006 rule bans all third-party research on pesticid es involving intentional exposure of children or of pregnant or nursing women. It further forb ids EPA itself to conduct or support any research involving intentional exposur e of pregnant or nursing women or of children to any substance. EPA was required to promulgate the 2006 rule by the 2006 Appropriations Act.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 11 of 56 [RIN 2070-AJ76] The 2006 rule also extends the ethical protections in the Common Rule to third-party studies of non-pregnant, non-nursi ng adult subjects of research involving intentional
exposure intentionally exposed to pesticides. The key provisions of the 2006 rule significantly strengthens and expand s on the se protections for participants in third

- party research by include :

• Requiring pre-implementation submission to EPA of protocols and related information about proposed research to ensu re any future studies 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 in the 2004 NAS ’ report NAS Report

.

2. Implementation e xperience

. Because 2. Research with pesticides si nce promulgation of the 2006 rule. Contrary to some predictions, the 2006 rule has not led to an upsur ge in human research with pesticides for submission to EPA under FIFRA or FFDCA. Si nce promulgation of the 2006 rule EPA has received no proposals at all for re search on the toxicity of a pest icide to human subjects, and has received significantly fewer than were projected proposals for new resear ch of other kinds (e.g., insect repellent studies). In the analyses supporting the 2006 rule, EPA estimated 33 new intentional exposure studies would be submitted each year; in fact, only 26 proposals for new research on pesticides for submission to EP A under FIFRA and FFDCA have been submitted over a span of approximately 5 y ears, or just over 5 per year.

3. Overview of HSRB reviews. EPA’s experience in implementing the 2006 rule is critical to understanding the amen dments 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 th e 2006 rule can be best characterized 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 complete d research and proposals for new research. Specifically, the HSRB has reviewed:

• Completed reports of pre- 2006 rule research reporting t oxic endpoints. These have included intentional exposure toxicity tests ini tiated both before and afte r passage of FQPA in 1996, as well as therapeutic trials of substances used both as dr ugs and as pesticides, reporting side effects relevant to EPA pesticide risk assessments.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 12 of 56 [RIN 2070-AJ76] • Proposals for and reports of new research involving intentional exposure to materials used in the research as pesticides.

Since issuance of the 2006 rule, a ll proposals for new res earch involving intenti onal exposure to pesticides have fallen in to one of two 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 occupat ional exposure of pesticide handlers as they mix, load, or apply pesticides 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 et hically acceptable by both EPA and the HSRB

. Although several of the more complex exposure studies 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 re search 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. We summarize the disposition of each of the 42 studies in the following paragraphs, and additional details may be accesse d in the study specific reports available on the HSRB website at http://www.epa.gov/hsrb/index.htm.

Twenty-nine of the 37 non-therapeutic studies reviewed by the HSRB were initiated before the passage of FQPA in 1996; all reported toxic endpoints. EPA conducted both science and ethic reviews of these st udies prior to submission of the studies to HSRB. EPA science reviewers proposed to rely on 17 of these 29 studies ; the

. HSRB found 13 of these 17 studies scientifically acceptable

. under the applicable st andards of the 2006 rule. EPA ethics reviewers found 5 of the 17 clearly acceptable, and deferred to the HSRB concerning whether the shortcomings noted in the conduct of the remaini ng 12 studies rose to the level of “significant” deficiencies relative to prevailing st andards of ethical research conduct. The HSRB found 15 of those 17 studies ethically acceptable under th e applicable standa rds of the 2006 rule—§26.1703 and §26.1704. The HSRB found 1 study ethically unacceptable because of deficiencies in risk minimization procedures that c ould have led to serious harm to subjects , and another unacceptable because incomplete information provi ded to subjects concerning previous studies seriously 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 subsequently relied on any studies deemed either scientifically or ethically unacceptable by the HSRB.

The 12 remaining pre-FQPA studies that EPA science reviewers also had proposed to reject the remaining 12 studies, all published reports concerning concerned dichlorvos (DDVP). These reports 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 to reduce the inter-species factor*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 13 of 56 [RIN 2070-AJ76] since a dose response could not be calculat ed due to numerous technical weaknesses. HSRB concurred. Because the reported research wa s 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 Turning to the 8 post-FQPA toxicity studies that EPA presented to the HSRB

. These 8 , we note that they were among a group of about 20 studies at the center of controversy before promulgati on of the 2006 rule. Other post-FQPA human toxicity studies were deemed by EPA science reviewers to be irrele vant 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 to set a point of departure because no effect was measured from the single dose level tested 1 , and deferred to the HSRB with respect to the scientific acceptability of the last one. The HSRB concurred that the first six studies were scientifica lly acceptable, and found both the others unacceptable. EPA ethics re viewers found four of th e eight studies clearly acceptable, one clearly unacceptable, and deferred 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 prevaili ng standards of ethical conduct. T he 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 unacceptable 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 pesticide risk assessments were not the main objective of the research, but they were reported side effects of treatment with the when a test material (which is sometimes used as a pesticide) was administered as a medication. The HSRB concurred with the EPA science reviews in four of that these cases four studies were scie ntifically unacceptable , but found one study scientifically unacceptable for the purpo se EPA proposed. EPA ethics reviewers and the HSRB both found all five of these studies to be ethically acceptable under the standards of the 2006 rule.

The In summary, EPA and HSRB concurred with EPA’s scientific assessments of these 42 studies in all but a handful of instances

. Whenever worked through the HSRB has recommended against accep tance of any of these backlog of pre-rule studies for either scientific or ethical reasons of pesticide toxicity awaiting review when the 2006 rule was promulgated. EPA and HSRB agreed about the acceptability of these studies in most cases; when there was disagreement , EPA has accepted and acted on the HSRB ’s HSRB recommendation , and has

. Some pre-rule studies th at met the scientific and ethical st andards defined in the 2006 rule have been relied upon by EPA in actions under the pesticide laws, although EPA has not relied on any studies found unacceptable by HSRB. Meanwhile, as EPA completed the reassessment of tolerances mandated by FQPA, it found human toxicity testing to be relevant to only a handful of

1 For more details on this finding, see the study report available on the HSRD website at http://www.epa.gov/hsrb/index.htm

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

Page 14 of 56 [RIN 2070-AJ76] those assessments.

the HSRB

.

ii. New research involving inte ntional exposure of human subjects. The second broad category of topics addressed by the HSRB since 2006 is In addition to reviewing pre-2006 rule research, HSRB has reviewed proposals for new research invo lving intentional exposure of human subjects. To ensure the thoroughness of its scientific and ethics reviews of these proposals, a nd to ensure as well that the a pplicable recommendations of the NAS in its 2004 report were taken fully into consideration, EPA developed a detailed “f ramework” for its reviews of these proposals

. (see the HSRB website at http://www.epa.gov/hsrb/index.htm ). 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 a ddressing concerns identified in the 2004 NAS r R eport and subsequently by the HSRB has been attached to each EPA review of a proposal for new re search 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.

Close scrutiny by both EPA and HSRB of pr oposals 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 complian ce with the standards of the 2006 rule. These studies provide essential information about repe llent performance and worker exposure that is not available except from well designed, ethica lly conducted research involving intentional exposure of human subjects to pesticides.

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 pests 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 identified enough scientif ic and 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 proposal s 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 their 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 15 of 56 [RIN 2070-AJ76] 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 execution of a completed field mosquito 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 EPA 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 June 2006. The These proposals were from the Agricultural Handlers Exposure Task Force (AHETF). HSRB review was highly critical, and called for substantially greater information fr om both the consortium and from EPA concerning the overall design of the research program, the st atistical design of the proposed studies, the uses to which the resulting data would be put by EPA, and many other aspects of the proposed research. All five of these propos als were subsequently withdrawn so that HSRB criticisms could be addressed prior to resubmission

.
Since that initial review, the overall designs of the umbrella monitoring programs of AHETF and the designs from the Antimicrobial Exposure Assessment Task Force (AEATF II) and the A gricultural Handlers Exposure Task Force (A HETF ) have been fully documented and*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 16 of 56 [RIN 2070-AJ76] presented to the HSRB. The HSRB continues to review the design of individual monitoring studies, but the soundness of the overall appro aches 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 common 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 reports of completed AEATF II exposure research were submitted to EPA in the fall of 2010, and are 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 EPA and the HSRB. These scenarios invol ve application of liquid pe sticides 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 i mplementation of the 2006 r ule

. 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 cases; wh en there was disagreement, EPA has accepted and acted on the advice of the HSRB

. S ome pre

- rule 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 reassessment of tolerances mandate d by FQPA, it found human toxicity testing to be rele vant to only a handful of those assessments.

• C lose 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 inves tigators proposing these studies have learned how to design and execute them efficiently and in full compliance with th e high standards of the 2006 rule

. These studies provide essential information about repe llent performance and worker exposure that is*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 17 of 56 [RIN 2070-AJ76] simply not available except from well design ed, ethically conducted research involving intentional exposure of human sub jects to pesticides.

• C ontrary to some predictions, the 2006 rule has not led to a n upsurge in human research for pesticides

. Since promulgation of the 2006 rule EPA has received no proposals at all for research on the toxicity of a pesticide to human subjects , and has received significantly fewer proposals for new research of other kinds than were projected

. In the analyses supporting the 2006 rule EPA estimated 33 new intentional exposure 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 D

. 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 did not bar all pesticide research with pregnant women and children, was inconsistent with the 2004 NAS Report, and was inconsiste nt with the Nuremburg Code. The following paragraphs describe the Petitioner’s ar guments in greater detail.

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 2004 NAS r R eport. The 2006 Appropriations Act required EPA’s rule to be consistent with the principles proposed in the 2004 NAS r R eport. Petitioners argued that in citing th e “principles” of the 2004 NAS r R eport, Congress was referring to the 17 recommendations in that report. Petitioners furt her argued that the 2006 rule was inconsistent with several specific recommendations in the r eport 2004 NAS Report

.
First, Petitioners argued that the 2006 rule did not incorporate NAS Recommendations 3- 1 and 5-1 from the 2004 NAS Report , which recommend factors to be considered in the scientific evaluation of human research, including that such studies should have “adequate statistical power” and involve “r epresentative populations for the endpoint in question.”*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 18 of 56 [RIN 2070-AJ76] Second, Petitioners argued that th e 2006 rule did not incorporate NAS Recommendations 4-1 and 4-2 from the 2004 NAS Report , which suggest ethical considerations relevant to evaluation of human studies.

Third, Petitioners argued that by adding qua lifying language to the acceptance standard for pre-rule research suggested in NAS Recommendation 5-7 from the 2004 NAS Report , EPA made it inconsistent with the 2004 NAS Report. Petitioners argued that EPA’s addition of the word “significantly” to the recommended accepta nce standard, which permits EPA to rely on research not “significant ly” deficient relative to prevailing st andards, made the criterion in the 2006 rule unlawfully inconsistent with the NAS recommendation recommendations in the 2004 NAS Report

.
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 from the 2004 NAS Report

.

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 the Nuremburg Code.

First, Petitioners argu ed that although the Nuremberg Code specifies that consent must be given by the human subject, the 2006 rule inconsistently permits consent to be given in certain situations by a legally authorized repres entative of the subject.

Second, Petitioners argued that , by adopting the Common Rule’s requirements for informed consent, the 2006 rule was inconsistent with th e 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 2006 rule consent requirements were inadequate to ensure fully informed consent in the context of res earch involving pesticides

.
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 Nuremburg Code’s requirement 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 19 of 56 [RIN 2070-AJ76] 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 E

. Settlement of the 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 finalized on June 18 November 3 , 2010, EPA agreed to conduct notice-and-comment rulemaking 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 substantia lly consistent with la nguage negotiated between the parties and attached to the settlement agreement as Exhibit A. This agreement, including Exhibit A, is available in the docke t for this action as described under ADDRESSES

.
The settlement agreement further provi des that EPA will propose the negotiated amendments within seven months of f iling the agreement with the Second Circuit Court of Appeals no later than January 18, 2011, and that EPA will take final action on the amendments within no later than December 18 months of th is filing , 2011 . The settlement agreement
, however, make s clear that EPA retains full discre tion concerning what amendments are proposed, and what, if any, amendments are finalized.

Although they differ the wording of the amendments pr oposed in this document differs in a few details of construction and wording, t he amendments proposed in this document they are substantially consistent with the regulatory language negotiated with Petitioners, and EPA considers these amendments to address the Petitioners’ major arguments outlined in Unit III. F D

. 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 recommendations from the 2004 NAS Report cited by Petitioners in their challenge to the 2006 rule, as well as ot her pertinent recommendations from the 2004 NAS Report.

• The proposed amendments address Petiti oners’ arguments concerning the Nuremberg Code by dropping from 40 CFR part 26, subpart K

, all 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 d from a settlement agreement, EPA is believes that proposing these amendments because they are is consistent with the language and*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 20 of 56 [RIN 2070-AJ76] purposes of the applicable statutes and because they further the 2006 rule’s goal of ensuring that EPA does not rely on research involving intentio nal exposure of human subjects to pesticides that is not ethically conducted or that is not scientifically sound. M any EPA believes that 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 , but welcomes comment on these interpretations . EPA will fully re-evaluate the appropriateness of the proposed amendments in light of all comments received in response to this proposed rule

. before making a final determination. In particular, EPA seeks commen t on the relative merits of the proposed changes compared to retaining the curr ent scope and content (i.e., current wording) of the 2006 rule.

IV. P rovisions of this Proposed Rule and Amendments, Rationale , and Request for Comment

This Unit provides a description of each pr oposed change, the rationale for the proposed change, and the anticipated effects of each change relative to the current regulatory text (i.e., the 2006 rule). EPA specifically requests comment on each of these proposed changes, as well as on the changes in the aggregate. In particular, EPA asks for comment on its conclusions regarding the effect of these proposed ch anges, including the effect of these proposed changes on the volume of studies covered by the rule, the likely statutes under which studies may be submitted, and the impact on activities covere d by those other statutes, relative to the scope of the 2006 rule.

A. Redefining the Scope and Applicability of 40 CFR part 26, subparts K, L, M, P, and O

1. Summary of proposed changes. EPA is proposing amendments that would modify the scope and applicability of se veral subparts of the 2006 rule. The proposed changes would 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 intenti ons of the sponsor or in vestigator in conducting the research or the intentions of the pe rson submitting the research to EPA.

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. More sp ecifically, these change s alter the scope as follows: instead of covering substances under FIFRA, the proposed amendments would cove r pesticides under all
statutes.

In general, the proposed revisions amendments would shift the focus from whether the research on the substance was intended for EPA’s considerat ion and use under the pesticide laws, FIFRA and FFDCA, to whether the resear ch was conducted with a pesticide and was intended for EPA’s consideration and use in c onnection with an action under any regulatory statute administered by EPA. The proposed am endments also would add a new section 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 ch anges in 40 CFR part 26, subpart K.

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

Page 21 of 56 [RIN 2070-AJ76] focus in the 2006 Appropriations Act on intentional dosing human toxicity studies for pesticides

. 2. Summary of anticipated effects. Although almost all studies with pesticides are conducted and submitted to EPA for considerati on under FIFRA or FFDCA, it is possible that some pesticide studies may be considered by EPA only under other re gulatory authorities

. and not be considered under FIFRA and FFDCA. If studies involving intentional exposure of humans to a pesticide are submitted or cons idered under other EPA regulatory statutes, EPA believe s with the proposed amendment, such studies sh w ould be subject to the same requirements that would have applied had they been s ubmitted or considered under FIFRA or FFDCA. In proposing these amendments, EPA finds that these ch anges in scope are consistent with the focus in the 2006 Appropriations Act on intentional do sing human toxicity studies with pesticides

In sum, EPA does not believe that the severa l changes to the “scop e” sections of 40 CFR part 26, subparts K and L—§26.1101 and §26.1201—and a new definition of “pesticide” at §26.1102(c), that expand the range of human rese arch to which these two subparts apply, will result in a significant increase in the number of studies reviewed under the rule. However, EPA recognizes that this is a possi bility and requests comment on wh ether these proposed changes are clear about which studies would fall under the scope of the rule. EPA knows of no third-party research involving intentional e xposure of a human s ubject to a pesticide that has ever been proposed, conducted, or submitted to EPA under regul atory authorities other than the pesticide laws. The s pecific changes proposed to the scope and applicability sections of 40 CFR part 26, subparts K, L, M, P, and Q are explained here

. Although EPA does not propos e to change the
text of the 2006 rule defining the scope of 40 CFR part 26, s ubpart O

, concerning “Administrative Actions for Noncompliance,” the scope of that subpart would change nonetheless, because its applicability depends on the scope pr ovisions in other subparts that EPA is proposing to change.

1. Subparts The proposed expansion of the scope of these subparts, however, would mean that any such studies that are proposed, conduc ted, or submitted to EPA will be governed by the same standards as pesticide studies submitted under FIFRA or FFDCA section 408.

3. 40 CFR part 26, subparts K and L – basic ethical re quirements and prohibitions applying to third-party research involving intentional exposure of human subjects to a pesticide.

a. Current rule. Subpart K of 40 CFR part 26 extends the basic prot ections of the Common Rule to subjects in ce rtain third-party human research ; subpart L of 40 CFR part 26 forbids new third-party research involving inten tional 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 :

• I t . First, it was initiated after April 6, 2006 (the effective date of the 2006 rule).

• It Second, it is “research involving intentional exposure of a human subject” as defined at §26.1102(i).

• It Third, it was conducted or supported by a “p erson” as defined at §26.1102(j).

• I t Fourth, it was intended by any person conduc ting or supporting the research to be submitted to EPA, or to be held for later inspection by EPA, under the pesticide laws (FIFRA or FFDCA).

The two cited definitions are critical to understanding the scope and applicability of*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 22 of 56 [RIN 2070-AJ76] 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 Federal department or agency. This exclusion is appr opriate because that rese arch is covered by the Common Rule, which provides necessary and appropria te protections for the research subjects. Thus, research already covered by the standards of the Common Ru le is not also subject to subparts K and L. These subparts, in short, apply only to “third-par ty research”—rese arch that is neither conducted (“first-party”) nor s upported (“second-party” ) by EPA or another Federal Common Rule Federal department or agency.

Finally, §26.1101(g) explains how EPA will appr oach determination of the intent of 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.

b. Proposed amendments, rati onale, and anticipated effect. The amendments proposed in this document would not cha nge the definitions of “research involving intentional exposure of a human subject” or of “person.” They would add a new definition of “pesticide” at §26.1102( k), a new definition of “initia tion” of research at §26.1102( c), and would modify the applicability provisions in §26.1101

, as explained later in this Unit of the document.

The first of the four criteria for ap plication 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 effective date of any subsequent amendments.

This proposal includes a new §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 expressed 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 defin ed study initiation as occurring when the first advertisement fo r subjects is issued; EPA’s standard s of Good Laboratory Practice at 40 CFR part 160 define study initiation as occurring when the Study Director signs the protocol

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

Page 23 of 56 [RIN 2070-AJ76] avoid confusion, EPA is considering recast ing this criterion

, stating simply that 40 CFR part 26, subpart s K and L appl y to research in which the first subject is enrolled after the effective date of a final amendment

. Comments on this point are specifically 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 involving inte ntional 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 will nearly always be straightforward. However, EPA recognizes that there may be cases where ma king such a determination may not be as straightforward. EPA will apply this criterion as follows.

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 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 paragraph. This is EPA believes that this would be true even for multiple-use substances that may be used as a pesticide and may also result in human exposure from other commercial uses or as a result of de position in the environment as a waste product.

A good example of how EPA will determine if studies on multi-use substances are studies on a pesticide is presented by sulfur dioxide (SO 2 )—a registered pesticide active ingredient used as a fungicide in grape culture , and also a common 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 involving intentional exposure of*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 24 of 56 [RIN 2070-AJ76] subjects to SO 2 . Most of these studies on their face indicate 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 clas sified as not involving e xposure to a pesticide, because the testing was not conducted or sponsored by a pesticide registrant, the studies do not indicate they were performed in support of FIFR A registration, and there are clearly other major sources of human exposure to SO 2 in addition to whatever pe sticide exposure occurs. Thus, these studies would not come within the scope of the 2006 rule if the scope is modified as proposed.

EPA specifically requests comment on the implic ations of this change for the volume of studies that may need to be revi ewed under such a proposed amendment

The amendments proposed in this document would not change the applicability of 40 CFR part 26, subparts K and L

, to “persons” or the definition of that term at §26.1102(j). Thus the third of the four criteria would not be affected by these proposed 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 , putting aside the propos ed amendment to refer to “pesticides,” is the reference to actions taken “unde r any regulatory statute administered by EPA.” Research intended for submission under FIFRA or FFDCA is covered by the 2006 rule and would continue to be covered unde r proposed §26.1101(a)(1). Proposed §26.1101(a)(2) would broaden the scope of subparts K and L of 40 CFR part 26 to apply as well to research involving intentional exposure of a human subject to a pesticide which is intended for submission to EPA for consideration in connecti on 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), th e Comprehensive Environmental Response, Compensation and Liability Act (CERCLA, or the Superfund law), or other similar statutes. EPA specifically seeks comment on the scope of th is proposed change (i.e., the frequency with which it might be triggered, including other statut es to which the proposed change would apply) and the implications of the proposed change s on the activities governed by those other regulations. EPA seeks comment on the relative merits of this change compared to retaining the current scope of the 2006 rule. As noted, EPA doe s not expect that these wording changes will result in any substantive changes to the num ber or manner in which studies are currently reviewed.

As an example, EPA’s Office of Water ha s, in the past, set Maximum Contaminant Levels (MCLs) under the SDWA for with pesticides found in drinking water. Under the proposed amendment to the scope of 40 CFR pa rt 26, subpart K, any new third-party study involving intentional expos ure of a human to a pesticide, and intended for submission to the Office of Water for considerati on in setting a MCL, would now be subject to 40 CFR part 26,*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 25 of 56 [RIN 2070-AJ76] subpart K, including the requireme nt of §26.1125 for submission of the proposal for prior review by EPA and the HSRB HSRB. EPA would note that this is a theoretical example in that it is unaware of any such study having been submitted with regard to a MCL

.

EPA actions not taken under the authority of regulatory stat utes would not satisfy this fourth criterion. For example, an EPA comment on another Federal department’s or agency’s Environmental Impact Statement would not constitu te an action 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 pesticide residue in food, or establishing a n a MCL for a pesticide active ingredient under SDWA. N on-regulatory actions include, for example, risk assessments of pesticide active ingredients, recommended (non-bindi ng) safe levels of exposure such as Health Advisory Limits when these pertain to pesticides , or clean-up standards for pesticides 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 40 CFR part 26, subpart L applies to all research subject to 40 CFR part 26, subpart K.

In sum, EPA proposes several chan ges to the “scop e” sections of 40 CFR part 26, subparts K and L

— §26.1101 and §26.1201

— and new definitions of “initiation of research” at §26.1102(c) and of “pesticid e” at §26.1102(k), to expand at the margin the range of human research to which these two subparts apply

. EPA does not believe this expansion will result in a significant increase in the number of st udies reviewed under the rule

. EPA knows of no third

party research involving intentional exposure of a human subject to a p esticide that has ever been proposed, conducted, or submitted to EPA under regul atory authorities other than the pesticide laws. T his expansion of the scope of these subparts, 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 consi stent with the C ongressional directive in the 2006 Appropriations Act.

2

. Subpart 4. 40 CFR part 26, subpart M – requirement for docum entation of the ethical conduct of completed human research submitted to EPA.

a. Current rule. Subpart M of 40 CFR part 26 requi res those who subm it the results of human research to EPA for consideration unde r the pesticide laws to submit information documenting the ethical conduct of the completed research. EPA proposes to broaden the applicability of subpart M by amending §26.1301, while leaving the substantive r equirements of subpart M unchanged

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

Page 26 of 56 [RIN 2070-AJ76] 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 department or agency subject to the Common Ru le) submits the results of human research to EPA. Subpart M does not apply when EPA, on its own initia tive, retrieves published articles or otherwise obtains informa tion derived from hu man research.

b. Proposed amendments and rationale. EPA proposes to broaden the applicability of 40 CFR part 26, subpart M , by amending §26.1301, while leaving th e substantive requirements of subpart M unchanged. Specifically, EPA proposes 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 §26.1102(j) submits after the eff ective date of the amended rule a report containing the results of any human research to EPA for considera tion under FIFRA or FFDCA, or a report containing the results of any human resear ch on or with a pesticide fo r consideration under any other regulatory statute administered 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

, submissions of published sc ientific 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 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 27 of 56 [RIN 2070-AJ76] 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.

c. Anticipated effect. EPA’s concern for the potential bur den of 40 CFR part 26, subpart M

, on members of the public is tempered by its e xperience under the 2006 rule. Since promulgation of the 2006 rule EPA has received very few submissions of reports of human research on or with a pestic ide for consideration under FIFRA or FFDCA, and EPA expects submissions of such studies to EPA for considera tion only under other regula tory 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 5. 40 CFR part 26, subpart P – EPA and HSRB review of proposed and completed human research.

a. Current rule. Subpart P of 40 CFR part 26 app lies to EPA and HSRB reviews of proposals for new research involving intentiona l exposure of a human subject, and EPA and HSRB reviews of reports of completed research involving intentional exposure of a human subject and on which EPA proposes to rely in an action under the pesticid e laws. Unlike other subparts of the 2006 rule, subpart P does not incl ude a “scope” section; its applicability is defined only indirectly by re ferences to other subparts.

b. Proposed amendments and rationale. EPA proposes to make explicit the applicability of 40 CFR part 26, 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 [e ffective date of the amended rule] and, to the extent required by §26.1604, by the Human Studies Review Board, of reports of completed research subject to 40 CFR § 26.1701.”

c. Anticipated effect. Since 40 CFR 26.1125 is in subpart K and 40 CFR 26.1701 is in subpart Q, the broadened scope of these subpa rts as proposed in these amendments would indirectly broaden the scope of 40 CFR part 26, subpart P.

4. Subpart 6. 40 CFR part 26, subpart Q – ethical standards for assessing whether to rely on the results of human research in EPA actions.

a. Current rule. Subpart Q of 40 CFR part 26 defines et hical standards that must be met for EPA to rely on the results of human research in actions taken under the pesticide laws. Specifically, 40 CFR part 26, subpart Q

, applies to EPA decisions to rely on data from completed studies involving intentional e xposure of a human subject, when EPA regards the data as scientifically valid and relevant to an action taken under the pesticide laws.

b. Proposed amendments and rationale. For the same reasons it is proposing to broaden the applicability of 40 CFR part 26, subpart K (discussed in Unit IV.A.1

. ) .), EPA proposes to*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 28 of 56 [RIN 2070-AJ76] amend §26.1701 to broaden the applicability of 40 CFR part 26, subpart Q. Proposed §26.1701(a) would retain without change the applicability of 40 CFR part 26, subpart Q

, to research involving intentional e xposure of human subjects to a ny substance, in the context of EPA actions taken under FIFRA or FFDC A. Proposed §26.1701(b) would extend the applicability of 40 CFR part 26, subpart Q

, to research involving inte ntional exposure of human subjects to a pesticide, in th e context of EPA actions taken un der any other regulatory statute 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 w ould 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.

c. Anticipated effect. EPA expects this change in the scope of 40 CFR part 26, subpart Q

, to affect few, if any, EPA actions. Alt hough such actions may occur in the future, EPA cannot identify any actions taken since 2006 under any regulatory statute other than FIFRA or FFDCA that relied on research invol ving intentional exposure of a huma n subject to a pesticide.

As explained previously, EPA is authori zed to propose this change because it is consistent with the 2006 Appropriations Act. Th is proposal would mean that all intentional human studies involving pesticides submitted to EPA would be reviewed under the same ethical and scientific criteria. On the other hand, EPA has also noted that it expects this change will affect few additional studies and may create some uncertainty as to what studies are covered by the rule.

EPA specifically invites comment on the value of making this change and whether there are additional factors to be considered in evalua ting the appropriateness of the change, such as the frequency with which it might be triggered, including other statutes to which the proposed change would apply, and on the clarity of the proposed changes.

B. Disallowing Consent by a Surrogate ( 40 CFR part 26, Subpart K)

1. Current rule. In its the 2004 report NAS Report to EPA, the NAS recommended use of the Common Rule as the starting point for prot ecting human subjects in research involving intentional exposure. Consistent with this recommendation, 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 su bject’s “legally authorized representative” when the subject lacks the capacity to consent for himself or herself. The Common Rule, drafted to protect subjects in a wide variety of research settings, included thes e provisions to permit research in various situations, incl uding, for example, research into emergency procedures to save lives of unconscious pati ents, into improved care for people suffering psychosis or schizophrenia, and to collect valuable data from research with other subjects who lacked the legal capacity to provide fully info rmed, fully voluntary consent.

In this document, 2. Proposed amendments and rationale. EPA proposes to amend 40*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 29 of 56 [RIN 2070-AJ76] CFR part 26 by deleting from subpart K all refere nces permitting consent by a subject’s legally authorized representative. The sections affect ed are the definition of “legally authorized representative” at §26.1102(c ), ); the “Criteria for IRB approval of research” at §26.1111; the “General requirements for informed cons ent” at §26.1116; and the requirements for “Documentation of informed consent” at §26.1117.

EPA proposes to disallow consent by a representative in third-party studies because it thinks the types of research that investigator s will never need are conducted on pesticides would not use subjects for whom such a procedure for the is needed. (The research covered by 40 CFR part 26, subpart K

—includes research involving intentiona l exposure of non-pregnant, nonnursing adults to a pesticide or research i nvolving intentional expos ure of non-pregnant, nonnursing adults intended for submission under FIFRA or FFDCA

. .)

3. Anticipated effect. EPA has never seen, and cannot envision, any such research in which it could be justified to enroll subjects lack ing 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 Rule. Subpart A 40 CFR part 26, subpart A, applies to a much broader range of research with human subjects conduc ted or supported by EPA including , for example, observational studies with young children

, research for which parental consent on behalf of by a child subject is entirely legally authorized re presentative may be appropriate.

C. Revised Standards for EPA and HSRB Reviews ( 40 CFR part 26, Subpart P)

In 1. Current rule. 40 CFR part 26, subpart P

, defines in largely procedural terms how EPA is to review evaluates 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 member ship and responsibilities of the HSRB.

If all 2. Proposed amendments and rationale. a. Revisions to subpart P generally . The proposed amendments to 40 CFR part 26, subpart P became final, it would

, include:

• A proposed new §26.1601 explicitly defining the appl icability of 40 CFR part 26, subpart P

, to EPA and HSRB reviews of proposals fo r new research submitted under §26.1125 of subpart K and to EPA and HSRB reviews of reports of completed research covered by subpart Q. This change is discussed in Unit IV.A.3.

• A proposed new §26.1602 incorporating by reference references the definitions in 40 CFR part 26, subpart K.

• An expanded • A proposal to expand the discussion of EPA reviews of proposed research in §26.1603, retaining all elements of §26.1601 from the 2006 rule, and including a new §26.1603(b) listing considerations to be addressed by EPA in its science reviews of proposed research, and a new §26.1603(c) listing considerati ons to be addressed by EPA in its ethics reviews of proposed research.

• A proposal to slightly revise d discussion of EPA review s of completed research, redesignating §26.1602 in 40 CFR part 26 as §26. 1604, and revising paragraph (a) to emphasize*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 30 of 56 [RIN 2070-AJ76] the required thoroughness of EPA’s reviews and to extend its applicab ility to reviews 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 would be redesignated as §26.1605, defining the membership and responsibilities of the HSRB.

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

• A proposed new §26.1607 requiring the HSRB in its reviews of completed research to consider both the scientific and ethical merits of the research, and to apply the appropriate acceptance standards in 40 CFR part 26, subpart Q.

The As indicated previously a nd again throughout this discus sion, EPA requests comment on each of these proposed changes, as well as on th e changes in the aggregate. EPA also seeks comments on particular points as provided in the discussion.

b. Section 26.1603—EPA Review of proposed human research . Because the most significant changes proposed are the new lists proposed for inclusion in §26.1603(b) and (c) of considerations to be addressed in EPA reviews of proposed new research , those proposed changes will be discussed in greater detail here . These proposed lists are were derived primarily from the 2004 NAS following recommendations in the 2004 NAS Report (reproduced verbatim here and referenced in th e subsequent discussions):

Recommendation 3-1: Scientific Validity of Intentional Human Dosing Studies EPA should issue guidelines for determining wh ether intentional human dosing studies have been: a. justified, in advance of being conducted, as needed and as scientifically appropriate, in that they could contribute to EPA and from the Nuremberg Code

. M aking the se considerations explicit will codify in a regulation the addressing an important scientific or policy question that cannot be resolved on the basis of animal data or human observational data; b. designed in accordance with cu rrent scientific standards and practices developed by EPA and the HSRB in the course of implementing the 2006 rule , and will to (i) address the research question, (ii) include representative study populations for the endpoint in question, and (iii) meet requirements for adequate statistical power; c. conducted in accordance with recognized good clinical practices, including appropriate monitoring for safety; and d. reported comprehensively to EPA, including the full study protocol, all data produced in the study (including adverse events), and detailed analyses of the data.

Recommendation 4-1: Value of Studies That S eek to Improve the Accuracy of EPA’s Decisions But Do Not Provide a Public Health or Environmental Benefit EPA should consider a human dosing study intended to reduce the interspecies uncertainty factor (for example, a study of a biomarker such as c holinesterase inhibition) as conferring a societal benefit only if it was designed and conducted in a manner that would improve the scientific accuracy of EPA’s extrapolation from animal to human data. Because the anticipated benefit*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 31 of 56 [RIN 2070-AJ76] would not be as great as that conferred by st udies intended to provide a public health or environmental benefit, the study could be justifie d ethically only if the participants’ exposure to the pesticide could reliably be anticipated to pose no identifiable risk or present a reasonable certainty of no harm to study participants.

Recommendation 5-1: Criteria for Scientific and Ethical Acceptability Studies that do not meet the highest scientific and ethical standards should not be carried out or accepted by EPA as input to the regulatory deci sion-making process. Necessary conditions for scientifically and ethically acceptable intentional human dosing studies include: a. prior animal studies and, if available, human observational studies; b. a demonstrated need for the knowledge to be obtained from intentional human dosing studies; c. justification and documentation of a research desi gn and statistical analysis that are adequate to address an important scientific or policy question, including adequate power to detect appropriate effects; d. an acceptable balance of risks and benefits and minimization of risks to participants; e. equitable selection of participants; f. free and informed consent of participants; and g. review by an appropriately cons tituted IRB or its foreign equivalent.

Recommendation 5-2: Participant Selection Criteria IRBs reviewing intentional human dosing studies should ensure that these crucial aspects of the the following conditions are met in selecting research participants: a. Selection should be equitable. b. Selection of persons from vulnerable populati ons must be convincingly justified in the protocol, which also must justify the measures to be taken to protect those participants. c. Selection of individuals with conditions that put them at increased risk for adverse effects in such studies must be convincingly justified in the protocol, which also must justify the measures that investigators will use to decrease the risks to those participants to an acceptable level.

Recommendation 5-3: Payment for Participation IRBs, all relevant review boards, investigat ors, and research sponsors should ensure that payments to participants in intentional human dosing studies are neither so high as to constitute undue inducement nor so low as to be attractive only to individuals who are socioeconomically disadvantaged. Proposed levels of and purposes for remuneration (e.g., time, inconvenience, and risk) should be scrutinized in light of the principles of justice and respect for persons. Moreover, EPA, in conjunction with other federa l agencies, should consider developing further guidance on remuneration for participation in intentional human dosing studies, including guidance regarding whether remuneration should refl ect the level of risk as well as the time and inconvenience involved.

Recommendation 5-5: Compensation for Research-Related Injuries At a minimum, sponsors of or institutions conducting intentional human dosing studies should ensure that participants receive needed medical care for injuries incurred in the study, without cost to the participants. In addition, EPA should study whether broader compensation for research-related injuries should be required.

Recommendation 6-1: IRB Review of All Studies EPA should require that all human research conducted for regulatory purposes be approved in advance by an appropriately constituted IRB or an acceptable foreign*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 32 of 56 [RIN 2070-AJ76] equivalent. Research conducted by EPA scie ntists should be reviewed by an EPAauthorized IRB.

[Taken from pages 7-14 of the 2004 NAS report and the Nuremberg Code continue to be considered in the future by EPA and the HSRB

. Report (http://www.national-academies.org).]

c. Science Reviews— § 26.1603(b). The provisions in proposed §26.1603(b) will e nsure include considerations that unnecessary human research is not conducted, EPA must take into account when conducting its science reviews of proposed research that any research that is conducted is designed so that would be covered by the data collected are likely to a nswer an important research question dispositively, rule. In developing this li st of considerations, EPA relied on recommendations 3-1 and that 5-1 from the conduct of 2004 NAS Report to identify specific items that would be relevant to evaluating the scientific merit of proposed human research. How EPA developed the specifi c language for each provision follows.

 Proposed §26.1603(b)(1): Whether the research would be likely to produce data that address an important scientific or policy questi on that cannot be reso lved on the basis of animal data or human observational research follows

.
This language is a combination of recommenda tions 3-1(a) and 5-1(b) and (c) from the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.). The language “address an important scientific or policy question” reflec ts excerpts taken from recommendation 5-1(c). The language “that cannot be resolved on the basis of animal data or human observation research” is taken from recomm endation 3-1(a). These recomme ndations are intended to avoid unnecessary exposure for human subjects. If anim al data or human obser vational research were available to address an important scientific or policy question, then there would be no scientific need for additional human research. EPA relied primarily on recommendation 5-1 in formulating the proposed language because that recommendation addresses criteria for EPA acceptance of human research, whereas recommenda tion 3-1describes topics that should be covered in EPA guidelines.

Based on recommendation 5-1, EPA has phrased the proposed language as whether the research “addresses” an important scientif ic question rather th an use the phraseology “contributes to addressing” in recommendation 3- 1. The Agency believes its formulation is clearer and intends to interpret this as meaning that the research needs to be designed to obtain data likely to provide si gnificant insight into impor tant research questions.

EPA requests comment on whether its reliance primarily on the language of recommendation 5-1(c) is appropri ate here, or whether it should ha ve used the “contributes to” language from recommendation 3-1(a).

 Proposed §26.1603 ( b)(2): Whether the proposed research is designed in accordance with current scientific standards and practices to: (i) Address the research question. (ii) Include representative study populations fo r the endpoint in question. (iii) Have adequate statistical power to detect appropriate effects.

Again, this language is a combination of r ecommendations 3-1(b) and 5-1(c) from the*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 33 of 56 [RIN 2070-AJ76] 2004 NAS Report (see verbatim text provide d in Unit IV.C.2.b.). The recommendations highlight the need for adequate statistical power and appropriate repres entative study populations to ensure the scientific validity and reliability (and thus ethical conduct) of human research. To accommodate these recommendations, EPA is proposing to adopt language from the recommendations 3-1(b) and 5-1(c).

For the reason stated in th e previous discussion on propos ed §26.1603(b)(1), EPA placed primary reliance on recommendation 5-1. The Agency notes that the proposed (iii), which reflects the language in 5-1(c), differs from the language in 3-1(b), which says “meets requirements for adequate statistical power.” Th e Agency prefers to pr opose the language as contained in 5-1(c) because it do es not believe that there is one specific set of “requirements” with which to evaluate statistical power. The Agen cy intends to evaluate the statistical power of a study while focusing on the ultimate goal of ensu ring that appropriate effects are detected rather than on some arbitrary and undefined set of “requirements.”

EPA requests comment on whether the proposed language is clear and specifically on this language as compared to using the language di rectly from the recommendation in the 2004 NAS Report.

 Proposed §26.1603(b)(3): Whether the investigator proposes to conduct the research in accordance with recognized good research and practices, including, when appropriate, good clinical practices. practice guidelines and monitoring fo r the safety of subjects.

This provision reflects excerpts taken fr om recommendation 3-1(c) from the 2004 NAS Report (see verbatim text provided in Un it IV.C.2.b.). Although the NAS focused on good clinical practice guidel ines, the Agency is proposing to a pply a broader sta ndard “recognized good research practices”, which ma y include good clinical practice guidelines when appropriate. The rationale for this is that some human resear ch – in fact, all human research proposed to EPA to be conducted since promulgation of the 2006 rule -- is not conducted in clinical settings (e.g., field testing of repellents or wo rker exposure) and thus good clin ical practice guidelines would be inappropriate to apply. However, there may be other general good research practices that the research community employs to ensure scientific integrity of their studi es and safety of the subjects that would be relevant for the Agency to consider. One such practice that has currently been developed is the Guidelines for Performa nce Testing of Skin-Applied Insect Repellent issued in October 2008, and incorporated into the OCSPP harmonized test guidelines library in July 2010, entitled “Product Performance Test Gu idelines No. 810.3700: Insect Repellents to be Applied to Human Skin” ( http://www.epa.gov/ocspp/pubs/frs/publicat ions/Test_Guidelines/series810.htm )

.
EPA requests comment on this expansion a nd also welcomes suggestions for other good research practice documents that could be cited here as well.

d. Ethics Reviews— § 26.1603(c). The provisions in propos ed §26.1603(c) address many important ethical concerns

, including , among other things, identification and minimization of risks to participants, equitable selection of participants, and provision of medical care for participants. One critica l consideration for ethica l research, reiterated here , is that the subjects’ participation “follow[s] free and fully informed consent.” The Nuremburg Code eloquently*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 34 of 56 [RIN 2070-AJ76] states the importance of free a nd fully informed consent and de scribes the elements of such
consent: In developing this list of considerations, EPA relied on several recommendations from the 2004 NAS Report, including 4-1, 5-1, 5-2, 5-3, and 5-5 (see verbatim text provided in Unit IV.C.2.b.), to identify specific cons iderations that would be relevant to evaluating the ethics of proposed human research. Each proposed consideration is discussed below.

The voluntary consent of the human subject is absolutely essential

. This mea ns that the person involve d should have legal capacity to give con sent; 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 ulterior 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 e n lightened decision

. . . [ http://ohsr.od.nih.gov/guidelines/nuremberg.html ]

 Proposed §26.1603(c)(1): Whether adequate inform ation is available from prior animal studies or from other sources to assess the potential risks to subj ects in the proposed research.

This provision reflects excerpts taken from recommendation 5-1(a) from the 2004 NAS Report (see verbatim text provided in Unit IV.C .2.b.), which recommends that animal studies be available prior to conducting human studies . This NAS recommendation also suggests consideration of human observa tional studies if available. When EPA conducts its ethics reviews, it does and will conti nue to consider whether there is adequate information from prior animal and human observational studies to understa nd the level of risk thatmay be presented to subjects of the proposed research. Although th e NAS does not specify in its recommendation the specific purpose that the information from prior an imal studies or from ot her sources, including human observational studies if available, serves, EPA believes its use of th ese studies to assess potential risks in evaluating the ethics of a human research propos al subject to this rule is reasonable and an integral part of determining wh ether the benefits of th e research outweigh the risks of the research. The proposed language refers to “information . . . from prior animal studies or from other sources.” EPA intends the re ference to “other sour ces” to include human observational studies, consiste nt with recommendation 5-1.

EPA requests comment on whether the proposed language is clear and specifically on this language as compared to using the language directly from the recommendation in the 2004 NAS Report.

 Proposed §26.1603(c)(2): Whether the rese arch proposal adequately identifies anticipated risks to human subjects and th eir likelihood of occurrence, minimizes identified risks to human subjec ts, and identifies likely benefits of the research and their distribution.

This provision is based on recommendati on 5-1(d) from the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.), which states that the necessary conditions for human research include “an acceptable balance of risk s and benefits and mini mization of risks to participants.” EPA has separated these two conditi ons and addresses minimization of risk in this paragraph and the balance of ri sks and benefits in proposed §26.1603( c)(3). In this paragraph, EPA also proposes to include a consideration of whether the research proposal adequately*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 35 of 56 [RIN 2070-AJ76] identifies anticipated risks to human subjects and their likelihood of o ccurrence and the likely benefits of the research and th eir distribution. These additional considerations are important in understanding the overall risk/benefit picture of proposed human res earch covered by this rule. EPA does not believe that adding these consid erations will impose any additional burden on stakeholders since this information is typically provided with research proposals that are submitted to IRBs and to the Agency. EPA currently reviews human research proposals submitted to it under the 2006 rule with these considerations in mind.

EPA requests comment on whether it is approp riate to address minimization of risk and the risk-benefit balance in separate paragraphs . EPA has chosen this approach because it interprets recommendation 5-1(d) as setting fort h separate and independe nt considerations and, given this interpretation, believe s that repeating the risk-benef it balance language in this paragraph would be duplicative and confusing. EPA also recognizes an alternative view of recommendation 5-1(d) is that se parating the minimization of riskconsideration from the riskbenefit balance consideration a lters the collective context inte nded by recommendation 5-1(d) of the 2004 NAS Report. As such, EPA requests commen ts on both approaches as they apply to the proposed §§26.1603(c)(2) and 26.1603(c)(3).

 Proposed §26.1603(c)(3): Whether the proposed research presents an acceptable balance of risks and benefits. In making this determination for research intended to reduce the interspecies uncertainty factor in a pesticide risk assessment, the Administrator must consider Recommendati on 4-1 in the 2004 Report from the National Research Council of the National Academy of Sciences (NAS), entitled “Intentional Human Dosing Studies for EPA Regulatory Pu rposes: Scientific and Ethical Issues.”

This provision reflects excerpts taken from recommendations 5-1(d) and 4-1 from the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.). For each human research proposal submitted to the Agency that is covered by this rule, in addition to considering whether a study proposal minimizes risks to the human su bjects, EPA is proposing to consider whether the proposed research presents an acceptable ba lance of risks and benefits based on, among other things, the information it considers under the proposed paragraphs (c )(1) and (c)(2) in §26.1603.

Recommendation 5-1(d) al so refers to “the minimization of risks to participants.” EPA addressed that consideration in proposed §26.1603(c)(2). The Agency requests comment on whether another reference to minimization of risk is nonetheless needed in this paragraph for consistency with the 2004 NAS Report.

For research that is intended specifically to reduce the interspecies uncertainty factor in a pesticide risk assessment, the Agency is proposi ng to consider whether that study presents an acceptable balance of risks and benefits in accord ance with process laid out for evaluating that type of study in recommendation 4-1 and the a ttendant discussion in th e 2004 NAS report that informs the application of that recommendation. EPA lacks experience in reviewing proposals for research intended to reduce the interspecies un certainty factor. Since the promulgation of the 2006 rule, EPA has received no proposals for such research and, as noted in Unit IV.A.2. and A.3., EPA knows of no third-party research involving intentional e xposure of a human subject to a pesticide that has ever been proposed, c onducted, or submitted to EPA under regulatory authorities other than the pesticide laws. Howeve r, EPA recognizes that th is is a possibility in*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 36 of 56 [RIN 2070-AJ76] the future.

The Agency asks for comment on how it shoul d consider NAS recommendation 4-1, if this proposed amendment were finalized and EP A received a study proposal for that purpose, and, given the context of the proposed expansion to the scope of the 2006 rule as discussed in Unit IV.A., whether the proposed § 26.1603(c)(3) is clear about how NAS recommendation 4-1 might apply to future studies.

 Proposed §26.1603(c)(4): Whether subject selection will be equitable

. This provision is taken directly from reco mmendations 5-1(e) and 5-2(a) from the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.).

 Proposed §26.1603(c)(5): Whether subjects’ par ticipation would follow free and fully informed consent.

This provision reflects excerpts taken from recommendations 5-1(f) from the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.), which mentions free and informed consent, and the Nuremberg Code 2

. 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.

 Proposed §26.1603(c)(6): Whether an appropriate ly constituted In stitutional Review Board or its foreign equivalent ha s approved the proposed research.

This provision reflects excerpts taken from recommendations 5-1(g) and 6-1 from the 2004 NAS Report (see verbatim text provide d in Unit IV.C.2.b.). Section 26.1125 already requires third-parties covered by the 2006 rule to obtain IRB approval before submitting proposals to EPA under subpart P, and section 26.1601(c) of the curr ent rule allows the Agency to consider whether foreign propos ed research has undergone equiva lent protective procedures.

 Proposed §26.1603(c)(7): If any person from a vulnerable population may become a subject in the proposed research, whether ther e is a convincing justification for selection

2 The Nuremburg Code states the importa nce of free and fully informed consent and describes the elements of such consent: “The voluntary consent of the human subject is abso lutely essential. This means that the person involved should have legal capacity to give consent; should be so s ituated as to be able to exercise free power of choice, without the intervention of a ny element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension 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

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

Page 37 of 56 [RIN 2070-AJ76] of such a person, and whether measures ta ken to protect such human subjects are adequate.

This provision reflects excerpts taken from recommendation 5-2(b) from the 2004 NAS Report (see verbatim text provided in Unit IV .C.2.b.). EPA recognizes that some individuals who may become subjects in human research ma y be more vulnerable to coercion or undue influence, for example, prisoners, persons with mental disabilities, or economically or educationally disadvantaged persons. As suc h, for proposals in which such individuals may become a subject of the research, EPA is proposi ng to consider whether the proposal contains a convincing justification for the se lection of those persons as well as whether any measures taken to protect those persons are ad equate. The specific language of recommendation 5-2(b) states that “IRBs . . . should ensure that the following conditions met in selecting research participants . . . (b) Selection of persons from vulnerable popul ations must be convincingly justified in the protocol, which also must justify the measures to be taken to protect th e participants.” In drafting this provision EPA rephrased recommen dation 5-2(b) to conve rt it to regulatory language. In doing so, EPA first ma de this provision conditional (the “if” clause) because EPA does not expect that vulnerable popul ations will often be included in human research and there is no reason to impose a burden on researchers to justif y a situation when it is inapplicable. EPA also substituted the requirement that measures taken to prot ect such human subjects be “adequate” instead of requiring a “convi ncing justification” for them.

EPA requests comment on whether the proposed language is clear and specifically on this language as compared to using the language di rectly from recommenda tion 5-2(b) in the 2004 NAS Report.

 Proposed §26.1603(c)(8): If any person with a condition that would put them at increased risk for adverse effects may b ecome a subject in the proposed research, whether there is a convincing justification for selection of such a person, and whether measures taken to protect such human subjects are adequate.

This provision reflects excerpts taken from recommendation 5-2(c) from the 2004 NAS Report (see verbatim text provided in Unit IV .C.2.b.). Although EPA anticipates that persons with conditions that put them at increased risk for adverse effects would likely be screened from participating in human research subject to th is rule, there may be circumstances when an exception is warranted. In those instances where such persons may become subjects in research covered by this rule, EPA is proposing to consid er whether the research contains a convincing justification for the selection of those persons as well as whethe r any measures taken to protect those persons are adequate to decrease risks to an acceptable level. The specific language of recommendation 5-2(b) states that “IRBs . . . should ensure that the following conditions met in selecting research particip ants . . . (c) Selection of individua ls with conditions that put them at increased risk for adverse effects in such studies must be convincingly justified in the protocol, which also must justify the measures that inve stigators will use to decrease the risks to those participants to an acceptable level.” For this provision, EPA followed a similar path in converting the NAS recommendation into regul atory language as it did with proposed §26.1603(c)(7), i.e., EPA made the provision conditional and used an adequacy test rather than a convincing justification as to evaluating th e measures to protect the subjects.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 38 of 56 [RIN 2070-AJ76] EPA requests comment on whether the proposed language is clear and specifically on this language as compared to using the language di rectly from recommenda tion 5-2(c) in the 2004 NAS Report.

 Proposed §26.1603(c)(9): Whether any proposed payments to subjects are consistent with the principles of justi ce and respect for persons, and whet her they are so high as to constitute undue inducement or so low as to be attractive only to individuals who are socioeconomically disadvantaged.

This provision reflects excerpts taken fr om recommendation 5-3 from the 2004 NAS Report (see verbatim text provided in Unit IV.C .2.b.). Although this prov ision overlaps slightly with proposed §§26.1603(c)(4) and §26.1603(c)(7), EP A is proposing to enumerate a specific consideration for whether the level of remunera tion for participation in any proposal for human research covered by this rule is appropriate, i.e., consistent with the principles of justice and respect for persons, and whether it is likely to induce participation from individuals from vulnerable populations and affect the equitable selection of subjects. In converting the affirmative statement in recommendation 5-3 into a “whether” statement for regulatory language, EPA dropped the recommendation’s “neither – nor” phrasing because it is potentially confusing. EPA believes that, as drafted, this provision re quires consideration of whether payments are either too high or too low but re quests comment on this point.

EPA requests comment on whether the proposed language is clear and specifically on this language as compared to using the language di rectly from recommendation 5-3 in the 2004 NAS Report.

 Proposed §26.1603(c)(10): Whether the sponsor or investigator would provide needed medical care for injuries in curred in the proposed researc h, without cost to the human subjects.

This provision reflects excerpts taken fr om recommendation 5-5 from the 2004 NAS Report (see verbatim text provided in Unit IV.C.2.b.) . EPA is proposing to consider in its ethics review of proposed human resear ch subject to this rule whet her medical care resulting from participation in the research will be provi ded without cost to the human subjects.

As noted throughout this section, EPA reque sts comment on whether the provisions of proposed §26.1603 are consistent with the recommendations from the 2004 NAS Report and whether the regulatory language c hosen by EPA adequately captures EPA’s intended goal and is otherwise clear and easily understood.

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

In addition to broadening the scope of 40 CFR part 26, subpart Q to apply to research relied on by EPA under regulator y statutes other than FIFRA or FFDCA , EPA propos es to amend the substantive standards in §26.1 703, §26.1 704, and §26.1 705 for determining the acceptability of completed research involv ing intentional exposure of a human subject to a pesticide

. Subpart Q) If a covered study does not meet the app licable standards in 40 CFR part 26, subpart Q, EPA would be prohibited from relyin g on the data in any action it takes under any*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 39 of 56 [RIN 2070-AJ76] of its regulatory authorities excep t under the extremely restrictive conditions defined in §26.1706.

Subpart Q of the 2006 rule established 1. Overview. a. Current rule. 40 CFR part 26, subpart Q, establishes standards governing reliance by EP A under the pesticide laws on “scientifically valid and relevant data from research involving intent ional exposure of human subjects.” Section 26.1703 forbids EPA to rely on any research involvi ng intentional exposure of a subject who was a pregnant woman, a nur sing woman, or a child. Section 26.1704 forbids EPA to rely on research initiated before the eff ective date of the 2006 rule in the face of clear and convincing evidence that “t he conduct of the research was fundamentally unethical (e.g., the research was intended to seriously harm participants or failed to obtain informed consent), or was significantly deficient relative to the ethical standards prevailing at the time the research was conducted.” Section 26.1705 forbids EPA to rely on re search initiated after the effective date of the 2006 rule unless EPA has “adequate informa tion to determine that the research was conducted in substantial compliance with subpa rts A through L . . .” Section 26.1706 permits EPA to rely on the results of human resear ch unacceptable under the standards of §§ 26.1703 - 26.1705 only if EPA determines, after public not ice and comment and consultation with the HSRB, that reliance on the research is necessa ry to support “a more stringent regulatory restriction that would improve pr otection of public health . . . than could be justified without relying on the data.” The Agency is no t proposing to amend the substance of §26.1706.

b. Summary of proposed changes. In addition to broadeni ng the scope of 40 CFR part 26, subpart Q, to apply to research relied on by EPA under regulatory statutes other than FIFRA or FFDCA, EPA proposes to amend the substantive standards in §§26.1703, 26.1704, and 26.1705 for determining the acceptab ility of completed research involving intentional exposure of a human subject to a pesticide. As noted throughout this document, EPA requests comment on each of these proposed changes, as well as on the changes in the aggreg ate. In particular, EPA seeks comment on its conclusions regarding th e effect of these propo sed changes relative to the scope of the 2006 rule, incl uding the effect of these pr oposed changes on the volume of studies covered by the rule, the likely statutes under which studies may be submitted, and the impact on activities covered by those other statutes.

c. Anticipated effects. If a covered study does not meet th e applicable standards in 40 CFR part 26, subpart Q, EPA woul d be prohibited from relying on the data in any action it takes under any of its regulatory authorities except unde r the extremely restrict ive conditions defined in §26.1706. 1. Proposed Changes to §26.1703 : S tandards A pplicable to A ll C overed R esearch

. Consistent with the changes proposed in 40 CFR part 26, subpart P

2. §26.1703: Standards applicable to all covered research. a. Proposed changes and rationale. Consistent with the changes proposed in 40 CFR part 26, subpart P, and discussed in Unit IV.C., EPA proposes to add in §26.1703(a) an explicit prohibition against reliance on data from completed research “unless EPA determines th at the data are relevant to a scientific or policy question important for EPA decision-making, th at 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 40 of 56 [RIN 2070-AJ76] research:

• Whether the research was designed and conducted according to “appropriate scientific 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 Observed Effect Level (NOEL) or a No Observed Adverse Effect Level

, (NOAEL), some dose level elicited a biological effect.

The concern for these These four aspects of the research is are derived from NAS Recommendations 3–1 and 5–1 from the 2004 NAS Report . They do not establish fixed criteria for acceptance or rejection of a study, but they iden tify specific aspects of a study that EPA must consider in determining that it is relevant, scien tifically valid and reliab le, and appropriate for a particular use.

b. Anticipated effect. As noted previously, 40 CFR part 26, subpart Q of the 2006 rule

, applies to EPA decisions to rely on “scientific ally valid and relevant data” from covered research. Since 2006 the Agency’s , EPA’s practice in reviewing re ports of covered human research has been to examine carefully the scientific rel iability merit of the reported studies and to refuse to rely on use research deemed invalid or irrele vant. EPA proposes to delete these factors from the scope of 40 CFR part 26, subpart Q

, as defined in §26.1701, and to codify them as factors in §26.1703(a) to ensure that they remain central to determinations of scientific validity and relevance. If this proposed rule amendment is finalized, EPA will revise would likely make minor revisions to its internal review documentation standards procedures to highlight the consideration given to th ese four aspects of the research.

2. Changes to 3. §26.1704 : a A cceptance standards for research not subject to §26.1705

. a. Proposed changes and rationale

. The Agency based the ethical acceptability standard in §26.1704 on Recommendation 5-7 in from the 2004 NAS r R eport, 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 consent), or was significantly deficient relative to the ethical standards prevailing at the time the research was conducted.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 41 of 56 [RIN 2070-AJ76] EPA adopted the NAS recommendation from the 2004 NAS Report nearly verbatim, with the notable insertion of th e word “significantly” before “d eficient.” EPA explained in the preamble to the 2006 rule (at 71 FR 6161) th at this was to allow it the flexibility to consider the impact on subjects of any ethical shortcomings in the conduct of the research. EPA stated in that preamble (at 71 FR 6161) that “EPA expects [the meaning of “significantly”] to acquire greater clarity over time, through HSRB a nd 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 characteriz ing proposing instead to characterize explicitly the kinds of deficiencies that would make a study unacceptable. P roposed §26.1 704 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 i ts conduct “placed participants at increased risk of harm (based on knowledge available at the time the study was conducted) or impair ed their informed consent.”

This language is derived from the advice of the Human Studies Review Board HSRB as they have applied the standard of §26.1704 in the 2006 rule. See, for example, their comments on studies involving aldicarb, methomyl, oxamyl, 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 de ficiencies 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 informati on provided to participants seri ously 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.

3. Changes to §26.1705 standards b. Anticipated effect. 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 participants at increased risk of harm (based on knowledge available at the ti me the study was conducted) or impaired their informed consent.” EPA specifically requests co mment on the incremental value of this change as well as the extent to which this change might inappropriately reduce EPA’s access to human research.

4. §26.1705: Standards for completed research conduc ted under 40 CFR Part 26 or another codification of the Common Rule. a. Proposed changes and rationale. The standard in 40 CFR part 26 applying to completed research initi ated after the effective date of the rule is §26.1705, based on NAS Recommendation 5-6 from the 2004 NAS Report , which states 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 42 of 56 [RIN 2070-AJ76] 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 applies to any scientif ically 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 the 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 would 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 th is 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 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 43 of 56 [RIN 2070-AJ76] §26.1705(b)(2), corresponding changes are made app licable to research conducted in foreign countries.

Finally, in a new paragraph (c) in §26.1705 (c)

, , EPA 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.

b. Anticipated effect. Taken together, these proposed changes in §26.1705 reflect the interpretations and methods used by EPA and the HSRB since 2006 in reviewing completed, post-rule research. Codifying these interpretations will ensure consistency and transparency in future decision-making and is consistent with the 2006 Appropriations Act

.

E. Request for Public Comment on Possible Re-codification of 40 CFR part 26, Subparts K-Q

1. Current rule. 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 research agency. Subparts K-Q of 40 CFR part 26 apply to pestic ide research with human subjects that is conducted by regulated third parties, and to EPA’s regulatory oversight of that research. So me stakeholders have suggested that this important di stinction would be clearer if 40 CFR part 26 contained only those subparts applying to EPA as a research agency, and if 40 CFR part 26, subparts K-Q

, were moved to a different section of EPA’s regula tions, within the range where other pesticidespecific regulations are found.

2. Proposed amendments and rationale. EPA is not now proposing such a recodification, but invites public comment on th e idea. Although it would necessitate many nonsubstantive revisions—mainly of internal cr oss-references—re-codification would not be difficult to accomplish. 40 CFR part 26 would retain current 40 CFR part 26, subparts A-D, and at least parts of current 40 CFR part 26, subpart O. A previously unus ed part within 40 CFR, within the numerical range of parts 150-180 where other pesticid e-related regulations appear, would include current 40 CFR part 26, subparts K, L, M, O, P, and Q. Subpart 40 CFR part 26, subpart O potentially applies to both EPA research a nd to third-party research and would need to be adapted to fit into both parts of a separated codification in 40 CFR.

3. Anticipated effect. Although this proposed re-codi fication may better distinguish those requirements applying to EPA as a resear ch agency, and those applying to third-party studies, it would only change the location of the regulation within 40 CFR, and would not otherwise have any effect on the requirements.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 44 of 56 [RIN 2070-AJ76] V. FIFRA Review Requirements

[Note to reviewers: this section will be fi lled in once FIFRA review is completed , which is scheduled to occur during the EO 12866 review process .]

In accordance with FIFRA section 25(a), EPA has submitted a draft of the proposed rule to the FIFRA SAP, Scientific Advisory Panel (SAP), the Secretary of Agriculture (USDA), and appropriate Congressional Committees. The FIFR A SAP waived its review of this proposal on [insert date]

, October 12, 2010, because the significant scientific issues involved have already been reviewed by the SAP and additional review isn’t is not necessary. Comments on the draft proposal received from USDA have been addressed [or revise to say they did not comment. Or say...USDA responded without comments, but participated fully in the interagency review process under Executive Order 12866 , during which EPA and USDA discussed [ent er 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 identifi ed as a “significan t regulatory action ” because it may raise novel legal or policy issues

. .” Accordingly, 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 recomm endations 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 45 of 56 [RIN 2070-AJ76] $45,927 per study, for a total estimated annual burden for affected entities of 20,332 hours at an 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 significant 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 RFA 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 46 of 56 [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 requireme nts that 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 research ing involving subjects who are ch ildren, or pregnant or nursing women. These provisions would not be affected by the proposed amendments.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 47 of 56 [RIN 2070-AJ76] H. Affect on Energy Supply, Distribution

, or Use

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, Administrative practice and procedures, Human research, Pesticides and pests.

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

Page 48 of 56 [RIN 2070-AJ76] § 26.1101 To what does this subpart apply?

(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. EPA shall must 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 In § 26.1102 as follows:

a

. Revise paragraph (a);

b

. Remove paragraph (c); and

c

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

§ 26.1102 Definitions.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 49 of 56 [RIN 2070-AJ76] (a) Administrator means the Administrator of the Environmental Protection Agency (EPA) and any other officer or employee of EPA to whom authority has been delegated.

* * * * *

(c) Initiation of research involv ing human subjects is defined as occur ring with the enrollment of the first subject in the research.

* * * * *

(k

(c ) Pesticide means any substance or mixture of substances meeting the definition in 7 U.S.C. 136(u) [Federal Insecticide, Fungi cide, and Rodenticide Ac t, section 2(u)].

§ 26.1111 [ Amended]

. AMENDED]

4. Amend In § 26.1111 by r emoving remove from paragraph (a)(4 ) the phrase “or the subject’s legally authorized representative”.

5. Amend In § 26.1116 by revising revise the introductory text of the section and 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 le gally effective informed consent of the subject. An investigator shall must seek such consent only under ci rcumstances that provide the prospective subject sufficient oppo rtunity to consider whether or not to participate and that minimize the possibility of coercion or undue influe nce. The information that is given to the subject shall must be in language understandable to the s ubject. No informed consent, whether oral or written, may include any exculpatory la nguage through which th e subject is made to waive or appear to waive any of the subject’s legal rights, or rele ases or appears to release the investigator, 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 must be documented by the use of a written consent form approved by the IRB and signed by the subject. A copy shall be gi ven 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 50 of 56 [RIN 2070-AJ76] by § 26.1116. This form may be read to the su bject, but in any event, the investigator shall must give 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 must be a witness to the oral presentation. Also, the IRB sh all approve a written summary of what is to be said to the s ubject. Only the short form itself is to be signed by the subject. However, the witness shall must sign both the short form and a copy of the summary, and the person actually obtaining consent shall must sign a copy of the summary. A copy of the
summary shall must be given to the subject, in add ition to a copy of the short form.

7. Revise the title heading for subpart 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 [ Am ended]

. AMENDED]

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

. .”

§ 26.1502 [ Amended]

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

Page 51 of 56 [RIN 2070-AJ76] b. In the second sentence of para graph (a) remove the phrase “The a A gency” and add in its place “EPA.”

c. In the last sentence of the introductory text of paragra ph (b) remove the phrase “The

a A gency” and add in its place “EPA.”

§ 26.1505 [ Am ended]

. AMENDED]

12. Amend In § 26.1505 by removing remove from the last sentence

, the phrase “§ 26.1502(c)” and add ing in its place “§ 26.1502(b)(4).”

§ 26.1507 [ Amended]

. AMENDED]

13. Amend the last sentence of In § 26.1507 by re moving remove from the last sentence, the phrase “The a A gency” and add ing in its place “EPA”.

§ 26.1601- 26. 1603 [ Redesignated]

. 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 newly 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 must review all proposals for new human research submitted under §*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 52 of 56 [RIN 2070-AJ76] 26.1125 in a timely manner.

(b) In reviewing proposals for new hu man research submitted under § 26.1125, the EPA Administrator shall must consider and make determinations regarding the 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 research submitted under § 26.1125, the EPA Administrator shall must consider and make determinations regarding 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 interspecies uncertainty factor in a pesticide risk assessment, the Administrator shall must consider Recommendation 4-1 of in the 2004 Report from the National Research Council as contained in its 2004 report of the National Academy of Sciences (NAS), entitled “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientif ic 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 Inst itutional Review Board IRB 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 53 of 56 [RIN 2070-AJ76] 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.

(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 any class of research, the EPA Administrator may recommend additional conditions wh ich, in the judgment of the EPA Administrator, are necessary for the protection of human subjects.

* * * * *

(h) EPA s hall must provide the submitter of the propos al copies of the EPA and Human Studies Review Board reviews.

17. Amend newly redesignated § 26.1604 by revising para graph (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 exposu re of humans to a pesticide, EPA shall must thoroughly review the material submitted under § 26.1303, if any, and other available, relevant information and document its conclusions regarding the scie ntific and ethical c onduct 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 must consider the scientific merits and ethical aspects of the proposed research, including all elements listed in § 26.1603(b) and (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 must consider the scientific mer its and ethical aspects of the completed research, and shall must apply the appropriate standards in subpart Q of this part.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 54 of 56 [RIN 2070-AJ76] 19. Revise the heading for subpart Q to read as follows:

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 scie ntifically invalid research. EPA shall must not rely on data from research subject to this subpart unless EPA 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 must 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 must 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.*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 55 of 56 [RIN 2070-AJ76] § 26.1704 Prohibition of reliance on unethical human research with non-pregnant, nonnursing adults which is not subject to § 26.1705.

(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 must not rely on data from any research subject to this section if there is clear and c onvincing evidence that:

(1) The conduct of the research was funda mentally unethical (e.g., the research was intended to seriously harm participants or failed to obtain 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 6 , 2006, and 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 Federal Policy for the Protection of Human Subjects in Human Research Conducted or Supported by a Federal Agency , generally referred to as the “Common Rule.”

(b) Except as provided in § 26.1706, EPA shall must not rely on data from any research subject to this section unless EPA determines that the resear ch 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 must not rely on data from any research subject to this section unless EPA determines that the resear ch 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*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review ***

Page 56 of 56 [RIN 2070-AJ76] 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 must not rely on that data.

(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 In paragraph (d) by removing of § 26.1706, remove the phrase “publishes” and add ing in its place “has published.”

[Note to reviewers: We are double checking for any cross references in the CFR that might need to be corrected as a result of these am endments. If any are found, amendatory text to correct them will be added here.]

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