## Attachment # B
– Review Period: 11/07/11
– 06/08/12

EO 12866 Documentation related to the following action:

Final Rule: EPA's Rule on Protections for Subjects in Human Research Involving Pesticides (RIN 2070

- AJ76; FRL

- 9353

- 4; EPA Docket ID #: EPA

- HQ

- OPP

- 2010

- 0785)

NOTE : Under Executive Order 12866 (58 FR 51735, October 4, 1993), EPA submitted this action to OMB for review under Executive Orders 12866 and 13563 (76 FR 3821, January 21, 2011) on two occasions. As such, the doc umentation for each review is represented as two separate attachments. See docket entry for the full documentation. 02/08/2013

## Attachment # B
– Review Period: 11/07/11
– 06/08/12

(1) A copy of the information that was submitted to OIRA for review under the Executive Order.

02/08/2013*** EO 12866 Draft

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Page 1 of 33 EO 12866_Human Subjects Revisions_RIN 2070

- AJ76 _FRM_2011

- 09

- 15 .doc x 1 BILLING CODE 6560

– 50

– P 2 ENVIRONMENTAL PROTECTION AGENCY 3 40 CFR Part 26 4 [ EPA

– HQ

– OPP

– 20 10

– 0785 ; FRL

– XXXX

– X ] 5 RIN 2070

– AJ76 6 Protections for Subjects in Human Research Involving Pesticides 7 AGENCY: Environmental Protection Agency (EPA). 8 ACTION: Final rule. 9 SUMMARY: EPA is finalizing narrowly

- tailored amendments to the portions of its rules for the 10 protection of human subjects of research apply ing to third parties who conduct or support 11 research with pesticides involving intentional exposure of human subjects and to person s who 12 submit the results of human research with pesticides to EPA

. The amendments broaden the 13 applicability of the rules to cover human testing with pesticides submitted to EPA under any 14 regulatory statute it administers

. They also disallow participation in third

- party pesticide studies 15 by subjects who cannot consent for themselves

. Finally , the amendments identify specific 16 considerations to be addressed in EPA science and ethics reviews of proposed and completed 17 human research with pesticides , drawn from the recommendations of the National Academy of 18 Sciences (NAS)

. Th e amendments make no changes to the Common Rule or EPA’s codification 19 of the Common Rule. 20 DATES : This rule is effective on [ 60 days after publication ] 21 ADDRESSES: EPA has established a docket for this action under docket identification (ID) 22 number EPA

– HQ

– OPP

– 20 10

– 0785

. All documents in the docket are listed in the docket index 23 available at http://www.regulations.gov

. Although listed in the index, some information is not 24*** EO 12866 Draft

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Page 2 of 33 publicly available, e.g., CBI or other information whose disclosure is restricted by statute

. 25 Certain other material, such as copyrighted material, is not placed on the Internet and will be 26 publicly available only in hard copy form

. Publicly available docket materials are available 27 either in the electronic docket at http://www.regulations.gov , or, if only available in hard copy, at 28 the OPP Regulatory Public Docket in Rm

. S

– 4400, One Potomac Yard (South Bldg.), 2777 S

. 29 Crystal Dr., Arlington, VA

. The ho urs of operation of this Docket Facility are from 8:30 a.m

. to 30 4 p.m., Monday through Friday, excluding legal holidays

. The Docket Facilit y telephone 31 number is (703) 305

- 5805. 32 FOR FURTHER INFORMATION CONTACT: Kelly Sherman , Immediate Office of the 33 Directo r (7501P) , Office of Pesticide Programs, Environmental Protection Agency, 1200 34 Pennsylvania Ave., NW., Washington, DC 20460

– 0001; telephone number: (703) 305

- 8401; fax 35 number: (703) 308

- 4776; e

- mail address: sherm an.kelly @epa.gov

. 36 SUPPLEMENTARY INFORMATION: 37 I. Does this Action Apply to Me? 38 You may be potentially affected by this action if you conduct human research on 39 substances regulated by EPA. Potentially affected entities may include, but are not limited to , 40 entities that conduct or sponsor research involving intentional exposure of human subjects that 41 may be submitted to EPA. Although EPA has in the past received such third

- party research from 42 pesticide registrants, other entities could submit such informat ion to EPA. 43

• Pesticide and other Agricultural Chemical Manufacturing (NAICS code 325320) who 44 sponsor or conduct human research with pesticides

. 45

• Other entities (NAICS code 541710) that sponsor or conduct human research with 46 pesticides, and Institutiona l Review Boards who review human research with pesticides to ensure 47*** EO 12866 Draft

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Page 3 of 33 it meets applicable standards of ethical conduct. 48 This listing is not intended to be exhaustive, but rather provides a guide for readers 49 regarding entities likely to be affected by this a ction. Other types of entities not listed in this unit 50 could also be affected. The North American Industrial Classification System (NAICS) codes 51 have been provided to assist you and others in determining whether this action might apply to 52 certain entitie s. If you have any questions regarding the applicability of this action to a particular 53 entity, consult the person listed under FOR FURTHER INFORMATION CONTACT

. 54
I I . General Information 55
A

. What Action is the Agency Taking ? 56 The amendm ents contained in this final rule change the 2006 rule, published in the 57 Federal Register issue of February 6, 2006 ( 71 FR 6138) (FRL

- 7759

- 8 ) , subsequently amended 58 on June 23, 2006 (71 FR 36171) (FRL

- 8071

- 6), and codified at 40 CFR p art 26, in the following 59 substantive resp ects: 60

• By broadening the applicability of 40 CFR part 26, subparts K, L, M, and Q , so these 61 subparts would apply not only to research submitted to or considered by EPA under the pesticide 62 laws, but also to research involving a “pesticide” (as defined in the Federal Insecticide, 63 Fungicide , and Rodenticide Act ( FIFRA ) ( 7 U.S.C

. 136 (u) ) which is submitted to or considered 64 by EPA under any other regulatory statute it administers. 65

• By incorporating the definition of “pesticide” from FIFRA, as a substance or mixture of 66 substances intended for pesticidal effect. 67

• By deleting from 40 CFR part 26, subpart K , all references to consent o n behalf of a 68 subject in research involving intentional exposure to a pesticide by a subject’s “legally 69 authorized representative.” 70*** EO 12866 Draft

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Page 4 of 33 • By incorporating into 40 CFR part 26, subparts P and Q , factors to be considered by 71 EPA and the Human Studies Review Bo ard ( HSRB ) in their review of proposed and completed 72 research, derived from the recommendations of NAS in its 2004 R eport to EPA , and from the 73 Nuremberg Code

. 74
B

. What is the Agency's Authority for Taking this Action? 75 The legal authority for the se amendme nts to the 2006 rule on human research is set forth 76
in detail in the preamble to th e proposed rule. 76 FR 5735, 5736

- 5755 (February 2, 2011)

. In 77 brief, the authority for these amendments is provided by section 201 of the Department of the 78 Interior, Environment, and Related Agencies Appropriations Act, 2006, Public Law 109

- 54 79 ( 2006 Appropriations Act), and sections 3(a)( and 25(a) of FIFRA

. 80
II I . Background 81 As required by section 201 of the 2006 Appropriations Act, EPA promulg at ed a rule 82 establishing a set of protections for people participating as subjects in third

- party human research 83 with pesticides

. (In this context “third

- party” research is research neither conducted (“first

84 party”) nor supported (“second

- party”) by EPA or another Common Rule Fe deral department or 85 agency.) The 2006 rule prohibits EPA from relying on third

- party research on pesticides 86 involving intentional exposure of children or of pregnant or nursing women , unless relying on 87 the data is crucial to a decision that would impose a more stringent regulatory restriction that 88 would improve protection of public health than could be justified without relying on the data

. It 89 further forbids EPA itself to conduct or support any research involving intentional exposure of 90 pregnant or nursi ng women or of children to any substance

. 91
In early 2006 , the Natural Resources Defense Council, Inc., Pesticide Action Network 92 North American, Pineros y Campesinos Unido Del Noroeste, Physicians for Social 93*** EO 12866 Draft

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Page 5 of 33 Responsibility

- San Francisco, Farm Labor Organizing Committee, ALF

- CIO, and Migrant 94 Clinicians Network petitioned for review of the 2006 rule in the United States Court of Appeals 95 for the Second Circuit (Second Circuit Court of Appeals)

. ( NRDC v . EPA , No

. 06

- 0820

- ag (2d 96 Cir

. ))

. The Petitioners argued that the 2006 r ule violated the 200 6 Appropriations Act because it 97 d id not bar all pesticide research with pregnant women and children , w as inconsistent with the 98 2004 NAS Report , and w as inconsistent with the Nuremburg Code

. 99 After briefing and argument , but before a decision was rendered by the Second Circuit 100 Court of Appeals , EPA and P etitioners entered a settlement agreement in which EPA agree d to 101 conduct notice

- and

- comment rulemaking on the issue of wheth er the 2006 r ule should be 102 amended

. EPA also agree d to propose, at a minimum, amendments to the 2006 rule that were 103 substantially consistent with language negotiated between the parties and attached to the 104 settlement agreement as Exhibit A

. This agreemen t , including Exhibit A , is available in the 105 docket for this action as described under ADDRESSES

. The settlement agreement make s clear 106 that EPA retain ed full discretion concerning what amendments wer e proposed, and what, if any , 107 amendments are finalized. 108 Consistent with the settlement agreement, on January 18, 2011, EPA Administrator 109 Lisa Jackson signed a notice of proposed rulemaking for proposed amendments to the 2006 rule

. 110 The proposed amendments were substantially consistent with the regulatory lan guage negotiated 111 with Petitioners. The notice of proposed rule making was published in the Federal Register on 112 February 2, 2011. 113
IV. Public Comments on the Notice of Proposed Rulemaking 114
A. Summary 115 This unit discusses, in general terms, the public comments on the proposed rulemaking 116*** EO 12866 Draft

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Page 6 of 33 and EPA’s responses to those comments. For additional details, please refer to the docket for 117 this action ( EPA

– HQ

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– 0785 ) . The docket includes all of the comments submitted to 118 EPA on this action, as well as a separate document that provides EPA’s detailed responses to the 119
comments. 120
EPA received a total of 10 public comments on the proposed rulemaking during the 60

- 121 day comm ent period

. C omments were submitted by four individual citizens and six different 122 entities

– the Agricultural Handler Exposure Task Force, the American Chemistry Council ( on 123 behalf of the Antimicrobial Exposure Assessment Task Force II ) , Beyond Pesticides , CropLife 124 America, Natural Resources Defense Council, and SC Johnson & Son, Inc. 125
B. Comments within the scope of the proposed rulemaking 126 EPA has identified only two issues raised by the commenters that are within the scope of 127 the proposed rulemaking. T he first issue relate s to the proposed expansion of the scope of the 128 rule to cover human testing with pesticides submitted to EPA under any regulatory statute it 129 administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA. 130
O ne commenter argued that EPA was without authority to expand the scope of the rule and 131 another requested that the scope be even broader. The second issue relate s to new regulatory text 132
at § 26.1603(b)(2)(ii and iii) and § 26.1703(a)(2 and 3) which would require EPA to consider 133 whether proposed and completed research includes representative study populations for the 134 endpoint in question and has adequate statistical power to detect appropriate effects. Several 135 commenters addressed this issue. 136
1. Comments abou t p roposed s cope c hanges 137
Comment: SC Johnson & Son commented that the proposed scope expansion exceeds 138 EPA’s statutory authority

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Page 7 of 33 Response: EPA’s authority for this proposed revision to the rule can be found in the 140 Appropriations Act and in FIFRA. Section 201 of the Appropriations Act gives EPA the 141 authority to issue a rule covering research involving the intentional dosing toxicity studies for 142 pesticides. The Appropriations Act does not expressly limit EPA’s authority to studies 143 conducted with pesticides that are intended to be submitted under only FIFRA and the FFDCA. 144 FIFRA provides additional authority to issue rules covering the use of both unregistered and 145 registered pesticides, regardless of whether that research is conducted for submission under 146 FIFRA. Section 3(a) of FIFRA permits EPA to regulate the distribution, sale, or use of any 147 unregistered pesticide in any State “[t]o the ext ent necessary to prevent unreasonable adv erse 148 effects on the environment

. ” Section 25(a) authorizes EPA to “prescribe regulations to carry out 149 the provisions of [FIFRA].” EPA has determined that this rule ensures that registered pesticides 150 are not used i n a manner that would cause unreasonable adverse effects on the environment, 151 including humans. 152
Comment: Natural Resources Defense Council commented that the scope should be 153 further expanded, asserting that Section 201 of the 2006 Appropriations Act req uires a “clear ban 154 on intentional dosing toxicity stud[ies] on pregnant women or children

. ” Natural Resources 155 Defense Council believes the “intent to submit” requirement in the scope provisions creates a 156 loophole that could allow third parties to conduct i ntentional dosing toxicity studies with 157 pregnant women or children. 158 Response: Notwithstanding the authority provided in the 2006 Appropriations Act and in 159 FIFRA, EPA does not believe that the 2006 Appropriations Act compels the broad ban 160 advocated by NR DC. The human studies that Congress was primarily concerned about during 161 the debates leading up to the passage of the 2006 Appropriations Act were those that involved 162*** EO 12866 Draft

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Page 8 of 33 intentional testing of pesticides on human subjects and EPA’s consideration or reliance o n those 163 studies. EPA was prohibited from relying on any human studies until it issued a rule in 164 accordance with the requirements of the 2006 Appropriations Act. This context implies that a 165 reasonable interpretation of what Congress was requiring EPA to d o was to issue a rule covering 166 human studies involving exposure to pesticides when those studies were submitted to EPA. 167 Nothing in the legislative history indicates that Congress intended EPA’s rule to apply to studies 168 that were outside of EPA’s purview. As mentioned above, EPA has authority, and believes it is 169 reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides 170 that are submitted to EPA under other laws that it administers. This rule covers studies that are 171 within EPA’s purview. However, to expand the 2006 rule to impose prohibitions or conditions 172 on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies 173 involving unregistered pesticides that are conducted outside the Un ited States) is clearly outside 174 EPA’s authority. Moreover, such a prohibition, if enforceable, could have the unintended effect 175 of prohibiting valuable research. 176
2. Comments about revised rule language on representative subjects and statistical 177 analysis 178
Co mment: The American Chemistry Council (for the Antimicrobial Exposure 179 Assessment Task Force II), the Agricultural Handler Exposure Task Force, and CropLife 180 America commented on the new regulatory text at §26.1603(b)(2)(ii and iii) which would require 181
EPA to consider whether the proposed research includes representative study populations for the 182 endpoint in question and has adequate statistical power to detect appropriate effects, and the new 183 regulatory text at §26.1703(a)(2 and 3) which would require EPA t o consider these factors in 184 determining whether to rely on the research . The American Chemistry Council argues that these 185*** EO 12866 Draft

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Page 9 of 33 criteria are “inapposite to the types of exposure research being conducted by AEATF and 186 others...” The Agricultural Handler Exposure Task Force and CropLife America claim that the 187 criteria are “more appropriate for clinical studies and do not translate directly to occupational 188 exposure studies...” All three commenters sought clarification on how the criteria would apply 189 to exposure stu dies. They expressed concern that adding these criteria to the rule would impose 190 additional burdens on sponsors of exposure studies. Specifically, they asked that EPA confirm 191 that it does not expect any effect from the adoption of these criteria on the continued approval of 192 the worker exposure studies. 193 Response: As discussed in the preamble to the proposed rule, this language is a 194 combination of recommendations 3

- 1(b) and 5

- 1(c) from the 2004 Report by the National 195 Research Council of the National Ac ademies of Science (NAS) titled Intentional Human Dosing 196 Studies for EPA Regulatory Purposes (hereafter, NAS Report). EPA disagrees with the assertion 197 that the criteria on representative populations and statistical power are not applicable to exposure 198
stu dies. Although the NAS recommendations on which these criteria are based were drafted 199 with an eye toward toxicological testing, the scientific concepts embodied have broad 200 applicability to scientific testing. Further, the language used by EPA in this rul e is generic in 201 nature and not limited to toxicological testing. Terms such as “effect” or “endpoint,” when used 202 without a modifier, can refer to any result to be examined in a scientific study. Thus, EPA 203 believes the criteria are potentially applicable to all types of intentional exposure human studies 204 covered by this rule. 205 Nonetheless, EPA does not believe that adoption of these criteria will impose additional 206 burdens on sponsors of the type of exposure studies referenced by the commenters. Even thou gh 207 the NAS’ recommendations about representative study populations and adequate statistical 208*** EO 12866 Draft

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Page 10 of 33 power were not specifically articulated in EPA’s 2006 Final Rule (40 CFR 26), EPA has applied 209 the principles underlying these recommendations, as well as the genera l NAS directive that 210 studies should be designed and conducted in accordance with appropriate scientific standards and 211 practices, in its consideration of human research since the promulgation of the rule in 2006. 212 Thus, EPA does not anticipate any effect fr om adding these NAS recommendations to the 2006 213 rule on the Agency’s consideration of ongoing or future worker occupational exposure studies, 214 except that EPA’s consideration of these issues will be even more transparent. As EPA 215 repeatedly noted in the pre amble to the proposed rule, the proposed amendments essentially 216 codify the scope and approach used under the 2006 rule in EPA’s science and ethics reviews of 217 human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this 218 comment response, EPA further clarifies the applicability of the criteria at issue to exposure 219 studies. 220 The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is 221 relevant to any scientific endeavor in which less than the full population is examined or tested 222 and for which valid extrapolation to a larger population is desired. EPA does not agree that the 223 language could be construed as not applying to exposure studies, given that the 224 representativeness of the sample is a rele vant consideration in evaluating, for proposed and 225 completed research, whether the observed effects of the completed study would predict the 226 responses of a larger population. 227 In evaluating what is a representative population for a study, the NAS emphasi zed that 228 EPA should focus on the “objectives of the study” (NAS Report, p. 77). For a study intended to 229 measure worker exposure, representation of the general workforce would be evaluated with 230 respect to, among other characteristics, types of equipment use d, the monitored subjects’ work 231*** EO 12866 Draft

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Page 11 of 33 experience, and work situations that could be defined by factors such as geographic location or 232 crop. The exposure studies to date have been representative of the workforce studied in this 233 manner. As discussed below, EPA c onsiders explicit adoption of the representative population 234 criterion as a codification of existing practice and does not believe that adoption of this criterion 235 will impose any additional burden on sponsors of exposure studies. 236 The commenters appear to be concerned that the representative population consideration 237 will require that a study use a fully statistically random sample imposing additional burdens on 238 sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular 239 meth od for demonstrating representativeness; rather, the rule only requires that EPA, in 240 determining the scientific validity and reliability of proposed and completed studies, “consider” 241 representativeness. Moreover, as noted above, the NAS Report stressed th at representativeness 242 was a study

- specific determination based on the objectives of the study. For exposure studies, a 243 fully statistically random sample may neither be feasible nor, in some cases, desirable. Alternate 244 sampling strategies can produce a s ample which represents a broader range of conditions than 245 would be present in a random sample of similar limited size and thus may produce results that 246 reasonably approximate real world exposures with respect to the overall magnitude and “spread.” 247
For exa mple, the Agricultural Handler Exposure Task Force (AHETF) and the Antimicrobial 248 Exposure Assessment Task Force II (AEATF

- II) are using a “purposive diversity selection” 249 sampling procedure in their exposure research. This procedure attempts to produce a s ample 250 which incorporates some random elements (where feasible); the resulting sample can be more 251 useful from a regulatory perspective in that it more likely represents the range of conditions and 252 situations under which exposure occurs. This approach meets the objectives of the study and is 253 consistent with the representative population consideration requirement. The Agency recognizes 254*** EO 12866 Draft

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Page 12 of 33 that random sampling, in many cases, may be considered to be the “gold

- standard” for 255 demonstrating representativeness in a s tatistical sense. Nonetheless, for the reasons stated above, 256 the use of alternate sampling strategies can, under certain circumstances, produce a sample 257 which is sufficiently representative given the study objectives. 258 The statistical power conside ration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is also a 259 relevant concept for both toxicology and exposure studies. Statistical power evaluates how 260 accurately a study can measure the effect being studied. For example, a toxicity study typically 261 evaluate s whether a chemical causes an effect by comparing the responses of the treated and 262 untreated groups. In some instances , treated and untreated groups will not show different 263 (statistically significant) responses, even though the chemical actually does cau se the effect. 264 The statistical “power” of a toxicological study can be thought of as the ability of the study to 265 detect a difference between treated and untreated groups given that a difference of a defined 266 magnitude does exist. Statistical power can b e an important concept in evaluating the design of 267 toxicity studies since it helps in ascertaining the degree to which the study will be able to find a 268 significant difference between treated and untreated groups , when a difference of defined 269 magnitude does indeed exist. Obviously, for completed toxicological studies, the statistical 270 power of the study is an irrelevant consideration if the study found a statistically significant 271 relationship between exposure and an effect. Conversely, when a completed toxi city study finds 272 no such relationship, evaluating the statistical power of the study design becomes relevant 273 because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of 274 the result. As to exposure studies, statistica l power could have applicability to an exposure study 275 design if, for example, that study attempted to evaluate the relationship between dermal or 276 inhalation exposure and an exposure variable. The statistical power of such an exposure study 277*** EO 12866 Draft

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Page 13 of 33 would also be a consideration if that study was interpreted as showing that there is no 278 relationship between the tested variables. 279 EPA has required various statistical analyses of exposure studies under the 2006 rule 280 other than statistical power analyses. For exampl e, EPA has relied upon standard regression 281 analyses and calculation of summary statistics (e.g. means and percentiles) in evaluating the 282 merit of worker exposure studies. EPA expects that those or similar analyses will, in all 283 probability, suffice going forward under the requirement in the revised rule that researchers have 284 a general obligation to ensure that their research is “designed and conducted in accordance with 285 appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 286 26.1703(a) (EPA must determine that “data were derived in a manner that makes them 287 scientifically valid and reliable”). Therefore, EPA does not believe that the revised rule will 288 impose any additional burden on sponsors of exposure studies with re gard to statistical analyses 289 generally. 290 Finally, even if either or both of these criteria turn out to be inapplicable to some studies 291 covered by the rule, that fact should not result in a significant burden for either EPA, the HSRB, 292 or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 26.1703, if in 293 reviewing a study, EPA or the HSRB determines that either or both of the criteria are not 294 applicable to that particular study, a notation by EPA or the HSRB of the reason for such 295 determ ination would constitute appropriate consideration of the criteria in accordance with the 296 rule. Similarly, for a person submitting a study design or a completed study to EPA and the 297 HSRB for review, an explanation of why certain criteria are inapplicable to the study submitted 298 may satisfy the rule’s requirements. 299
B. Comments outside of the scope of the proposed rulemaking 300*** EO 12866 Draft

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Page 14 of 3 3 The remainder of the public comments address ed issues beyond the sc ope of the 301 proposed rulemaking. These comments included arguments that the burden of the requirements 302 of the 2006 rule (as opposed to any burden connected to this rulemaking) are unjustified, and 303 assertions that EPA ’s i nterpretation in the 2006 rule of t he language “research involving 304 intentional exposure of a human subject” from the 2006 Appropriations act was incorrect. 305 Because these comments were directed at a prior rulemaking and EPA has not reopened these 306 issues for reconsideration in this rulema king, they are beyond the scope of this rulemaking and 307 no response to them is appropriate at this time. EPA’s Response to Comments document, 308 available in the docket for this action, explains in more detail why these comments are outside 309 the scope of the c urrent rulemaking. 310
V . Final Rule 311 As noted above, EPA received relatively few comments on the proposed rule, and most 312 of the comments received did not even address the amendments in the proposal. For the reasons 313 noted above, the comments that did addr ess the proposal do not merit any change to the 314 amendments, as proposed. As explained in the preamble to the proposed rule, EPA proposed 315 these amendments because they further the 2006 rule ’ s goal of ensuring that EPA does not rely 316 on research involving in tentional exposure of human subjects to pesticides that is not ethically 317 conducted or that is not scientifically sound and they are consistent with the language and 318 purposes of the 2006 Appropriations Act. Many of the amendments are codifications of the 319 manner in which EPA and HSRB have interpreted and implemented the 2006 rule. For these 320

reasons , EPA is finalizing the rule as proposed in 7 6 FR 5735, 5736

- 57 55 (February 2, 2011) . A 321 detailed explanation of the amendments is provided in the preamble of the proposed rule. 322
V I . Statutory and Executive Order Reviews 323*** EO 12866 Draft

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Page 15 of 33 A. Executive Order 12866: Regulatory Planning and Review and Executive Order 13563: 324 I mproving Regulation and Regulatory Review 325 326 Under Executive Order 12866 (58 FR 51735, October 4, 1993), th is action is a 327 “significant regulatory action , ” because OMB determined that it would raise novel legal or 328 policy issues arising out of legal mandates, the President’s priorities, or the principles set forth in 329 the Executive Order. Accordingly, EPA submit ted this action to the Office of Management and 330 Budget (OMB) for review under Executive Order s 12866 and 13563 (76 FR 3821, January 21, 331 2011). A ny changes made in response to OMB recommendations have been documented in the 332 docket for this rulemaking as re quired by the Executive Order. 333 The incremental costs of these amendments both to industry and to EPA are expected to 334 be negligible

. EPA has not, therefore, prepared a new economic analysis for this rulemaking

. 335 Because no research has been identified that is outside the scope of the 2006 rule but that would 336 be within the scope of these amendments, EPA has no basis on which to revise the cost estimates 337 that were provided in the economic analysis for the 2006 rule making or those most recently 338 provided in the 2008 renewal of the Information Collection Request (ICR) for the existing 339 regulation at 40 CFR part 26

. The recent estimates included in the ICR are summarized in Unit 340
VI.B and a copy of the ICR is available i n the docket

. 341
B

. Paperwork Reduction Act 342 This action does not impose any new information collection burden that would require 343 additional review or approval by OMB . However, the Office of Management and Budget 344 ( OMB ) has previously approved the information collection requirements contained in the 345 existing regulations at 40 CFR part 26 under the provisions of the Paperwork Reduction Act 346 (PRA) , 44 U.S.C. 3501 et. seq. and has assigned OMB Control No

. 2070

- 0169 (EPA ICR No

. 347
2 195)

. The OMB control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9. 348*** EO 12866 Draft

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Page 16 of 33 In its 2008 analysis supporting the most recent renewal of this ICR, EPA estimated that 349 respondents would submit to the Agency some 34 proposals for or reports of research involving 350 intentional exposure of human subjects each year

. EPA estimated that preparation of 351 information required by the 2006 rule would require about 598 hours per study at a cost of 352 $45,927 per study, for a total estimated annual burden for af fected entities of 20,332 hours at an 353 estimated cost of $1,561,518

. In addition, EPA estimated annual submission of 20 reports of 354 research requiring only documentation of ethical conduct at a cost of 12 hours/$879 per report, or 355 240 hours/$17,580 per year

. The total estimate of the annual respondent burden and cost was the 356 sum of these two estimates, or 2,572 hours/$1,579,098. 357 These paperwork burden and cost estimates include activities related to initial rule 358 familiarization, as well as activities that r esearchers would have to perform even without the 359 Agency’s rulemaking in this area, such as developing a protocol and maintaining records

. 360 The average annual burden on EPA for reviewing each of the 34 study submissions was 361 estimated to be 178 hours/$16,8 50 per study, or 6,052 hours/$572,900 per year

. The average 362 annual burden on EPA for reviewing each of the 20 additional submissions was estimated to be 363 44 hours/$3,158 per study, or 880 hours/$63,160 per year

. The total estimate of the annual 364 burden on EPA was the sum of these two estimates, or 6,932 hours/$636,000 per year. 365 In no year since promulgation of the 2006 rule have more than 7 protocols been 366 submitted to EPA by industry; the average annual rate has been just over 5 for the 5

- year period 367 of 2006

- 2010

. Somewhat fewer completed reports have been submitted during this period, so 368 the average of new protocols and finished studies has been about 11 per year, less than a third of 369 the projected 34 per year covered by the ICR

. There is no evidence t o suggest an upward trend, 370 and nothing in these amendments is believed likely to lead to a significant change in the rate of 371*** EO 12866 Draft

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Page 17 of 33 protocol and study submissions. 372 An agency may not conduct or sponsor, and a person is not required to respond to, a 373 collection of i nformation unless it displays a currently valid OMB control number

. The OMB 374 control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9

. 375
C. Regulatory Flexibility Act 376 The Regulatory Flexibility Act generally requires an Agency to prep are a regulatory 377 flexibility analysis of any rule subject to notice and comment ru lemaking requirements under the 378 Administrative Procedure Act or any other statute unless the agency certifies that the rule will 379
not have a significant economic impact on a s ubstantial number of small entities. Small entities 380 include small businesses, small organizations and small governmental jurisdictions

. 381 For purposes of assessing the impacts of today’s rule on small entities, small entity is 382 defined as: ( 1 ) a small busine ss as defined by the Small Business Administration’s (SBA) 383 regulations at 13 CFR 121.201 , which is based on either the maximum number of employees or 384 on the sales for small bus inesses in each industry sector, as defined by a 6

- digit NAICS code, 385 and for thi s rule is p esticide and other agricultural chemical manufacturers (NAICS code 386 325320) who sponsor or conduct human research with pesticides, or other entities (NAICS code 387 541710) that sponsor or conduct human research with pesticides, and Institutional Rev iew 388 Boards who review human research with pesticides to ensure it meets applicable standards of 389 ethical conduct; ( 2 ) a small governmental jurisdiction that is a government of a city, county, 390 town, school district or special district with a population of less than 50,000 ; or ( 3 ) a small 391 organization that is any not

- for

- profit enterprise which is independently owned and operated and 392 is not dominant in its field

. 393 After considering the economic impacts of this final rule on small entities, I certify that 394*** EO 12866 Draft

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Page 18 of 33 th is action will not have a significant adverse economic impact on a substantial number of small 395 entities. Because no small entities have been identified that are directly regulated by these 396 amendments, EPA has not attempted to reduce the impact of this fin al rule on small entities

. 397 Public c omments were explicitly invited on all aspects of the proposal and its impacts on small 398 entities , but no such comments were received

. 399
D

. Unfunded Mandate s Reform Act 400 This rule does not contain a Federal ma ndate that may result in expenditures of $100 401 million or more for State, local, and tribal governments, in the aggregate, or the private sector in 402 any 1 year. Thus, this rule is not subject to the requirements of sections 202 or 205 of UMRA. 403 This rule is also not subje ct to the requirements of section 203 of UMRA, because it 404 contains no regulatory requirements that might significantly or uniquely affect small 405 governments. These amendments are unlikely to affect State, local, and tribal governments at 406 all, and are likel y to affect the private sector only trivially

. 407
E

. Executive Order 13132 ( Federalism ) 408 This action does not have federalis m implications. It will not have substantial direct 409 effects on the States, on the relationship between the national government and the States, or on 410 the distribution of power and responsibilities among the various levels of government, as 411 specified in Executive Order 13132 (64 FR 43255, August 10, 1999)

. It makes marginal changes 412 in the scope of an existing rule applying to sponsors and investigators conducting certain kinds 413 of research involving human subjects, and refines the standards for EPA oversight of and 414 reliance on such research

. Thus, Executive Order 13132 does not apply to this action. 415 In the spirit of Executive Order 1313 2, and consistent with EPA policy to promote 416 communications between EPA and State and local governments, EPA specifically requested 417*** EO 12866 Draft

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Page 19 of 33 comment s on th e proposed action from State and local officials. EPA did not receive any such 418
comments. 419
F

. Executive Orde r 13175 420 This action does not have tribal implications as specified in Executive Order 13175 (65 421 FR 67249, November 9, 2000)

. This action would not have substantial direct effects on Indian 422 Tribes, will not significantly or uniquely affect the communities of Indian Tribal governments, 423 and does not involve or impose any requirements that affect Indian Tribes

. Thus , Executive 424 Order 13175 does not apply to this action

. 425
G

. Executive Order 13045: Protection of Children from Environmental Health Risks and Safety 426 Risks 427 EPA interprets EO 13045 (62 FR 19885, April 23, 1997), as applying only to those 428 regulatory actions that concern health or safety risks, such that the analysis required under 429 section 5

- 501 of the Order has the potential to influenc e the regulation

. This action is not subject 430 to EO 13045, because it does not establish an environmental standard intended to mitigate health 431 or safety risks, nor is it an “economically significant regulatory action” as defined in Executive 432 Order 12866

. The 2006 rule applies to the conduct and review of research involving intentional 433 exposure of human subjects, and prohibits the conduct of or EPA reliance on any such research 434 involving subjects who are children, or pregnant or nursing women

. These provis ions would not 435 be affected by the amendments. 436
H

. Executive Order 13211: Actions Concerning Regulations That Significantly Affect E nergy 437 Supply, Distribution , or Use 438 This action is not a “significant regulatory action” as defined in Executive Order 13211 439 (66 FR 28355, May 22, 2001), because it is not likely to have a significant adverse e ffect on the 440*** EO 12866 Draft

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Page 20 of 33 supply, distribution, or use of energy. 441
I

. National Technology Transfer and Advancement Act 442 Section 12(d) of the National Technology Transfer and Advancement Act of 1995 443 ( “ NTAA ” ), Public Law No. 104

- 113, 12(d) (15 U.S.C. 272 note) directs EPA to use voluntary 444 consensus standards in its regulatory activities unless to do so would be inconsistent with 445 applicable law or otherwise impractical. Voluntar y consensus standards are technical standards 446 (e.g., materials specifications, test methods, sampling procedures, and business practices) that are 447 developed or adopted by voluntary consensus standards bodies. NTTAA directs EPA to provide 448 Congress, through OMB, explanations when the Agency decides not to use available and 449 applicable voluntary consensus standards. T his action does not involve any technical standards

. 450 Therefore, EPA did not consider the use of any voluntary consensus standards. 451
J

. E xecuti ve O rder 12898: Federal Actions to Address Environmental Justice in Minority 452 Populations and Low

- Income Populations 453 Executive Order (EO) 12898 ( 59 FR 7629, February 16, 1994) establishes federal 454 executive policy on environmental justice. Its main provision directs federal agencies, to the 455 greatest extent practicable and permitted by law, to make environmental justice part of their 456 mission by identifying and addressing, as ap propriate, disproportionately high and adverse 457 human health or environmental effects of their programs, policies, and activities on minority 458 populations and low

- income populations in the United States. 459 EPA has determined that t his final rule will not have disproportionately high and adverse 460 human health or environmental effects on minority or low

- income populations, because it does 461 not affect the level of protection provided to human health or the environment. This rule does 462 not entail special considerati ons o f environmental justice related issues. The strengthened 463*** EO 12866 Draft

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Page 21 of 33 protections for human subjects participating in covered research established in the 2006 rule will 464 not be altered by these amendments

. 465
VI. Congressional Review Act 466 467 The Congressional Review Act, 5 U.S.C. 801 et seq
. , as added by the Small Business 468 Regulatory Fairness Act of 1996, generally provides that before a rule may take ef fect, the 469

a gency promulgating the rule must submit a rule report , which includes a copy of the rule, to 470 each House of the Congress and the Comptroller General of the United States. EPA will submit 471 a report containing this rule and other required information to the U.S. Senate, the U.S. House of 472 Representatives, and the Comptroller General of th e United States prior to publication of the rule 473 in the Federal Register

. A Major rule cannot take effect until 60 days after it is published in the 474 Federal Register

. This action is a not “major rule” as defined by 5 U.S.C. 804(2). 475 List of Subjects in 4 0 CFR P art 26 476 Environmental protection, Administrative practice and procedures, Human r esearch, 477 Pesticides and pests. 478 479 480 Dated:

_________________ 481 482 483 484 485

____________________________________ 486 Administrator. 487 488 489 490 491*** EO 12866 Draft

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Page 22 of 33 Therefore, 40 CFR chapter I will be amended as follows: 492 493 PART 26

— [AMENDED] 494 495 1

. The authority citation for part 26 is revised to read as follows: 496 Authority: 5 U.S.C

. 301; 7 U.S.C

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

. 346a(e)(1)(C); 497

sec . 201 , Pub

. L . 109

– 54, 119 Stat. 531; and 42 U.S.C

. 300v

– 1(b). 498
2

. Amend § 26.1101 as follows: 499

a . Remove paragraphs (a), (c), and (g); 500 b

. Redesignate paragraphs (b) as (c), ( f ) as ( g ), (e) as (f), and ( d ) as ( e ); and 501

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

. 502 § 26.1101 To what does this subpart apply? 503 (a) Except as provided in paragraph (c) of this section, this subpart applies to all research 504 initiated after [effective date of final rule] involving intentional exposure of a human subject to: 505 (1) Any substance if, at any time prior to initiatin g such research, any person who 506 conducted or supported such research intended either to submit results of the research to EPA for 507 consideration in connection with any action that may be performed by EPA under the Federal 508 Insecticide, Fungicide, and Rodenti cide Act (FIFRA) (7 U.S.C

. 136

- 136y) or section 408 of the 509 Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C

. 346a) , or to hold the results of the 510 research for later inspection by EPA under FIFRA (7 U.S.C

. 1 36

- 136y) or section 408 of 511
FFDCA (21 U.S.C

. 346a); or 512 (2) A pesticide if, at any time prior to initiating such research, any person who conducted 513 or supported such research intended either to submit results of the research to EPA for 514 consideration in connection with any action that may be performed by EPA under any regulatory 515
statute administered by EPA other than those statutes designated in paragraph (a)(1) of this 516 section , or to hold the results of the research for later inspection by EPA under any regulatory 517*** EO 12866 Draft

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Page 23 of 33 statute administered by EPA other tha n those statutes desi gnated in paragraph (a)(1) of this 518 section

. 519 (b) For purposes of determining a person’s intent under paragraph (a) of this section , 520 EPA may consider any available and relevant information

. EPA must rebuttably presume the 521 existence of intent if: 522 (1) The person or the person’s agent has submitted or made available for inspection the 523 results of such research to EPA; or 524 (2) The person is a member of a class of people who, or whose products or activities, are 525 regulated by EPA and, at the time the research was initiated, the results of such research would 526 be relevant to EPA’s exercise of its regulatory authority with respect to that class of people, 527 products, or activities. 528
* * * * * 529 (d) The Administrator retains final judgment as to wheth er a particular activity is covered 530 by this subpart. 531
* * * * * 532 3

. In § 26.1102 , r evise paragraph s (a) and (c) to read as follows: 533 § 26.1102 Definitions. 534 (a) Administrator means the Administrator of the Environmental Protection Agency 535 (EPA) and any othe r officer or employee of EPA to whom authority has been delegated. 536
* * * * * 537 (c) Pesticide means any substance or mixture of substances meeting the definition in 7 538
U.S.C

. 136(u) [Federal Insecticide, Fungicide , and Rodenticide Act , section 2(u)]

. 539
§ 26.11 11 [AMENDED] 540*** EO 12866 Draft

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Page 24 of 33 4

. In § 26.1111 r emove from paragraph (a)(4) the phrase “or the subject’s legally 541 authorized representative”

. 542
5

. In § 26.1116 revis e the introductory text of th e section to read as follows: 543 § 26.1116 General requirements for info rmed consent. 544 545 No investigator may involve a human being as a subject in research covered by this 546 subpart unless the investigator has obtained the legally effective informed consent of the subject

. 547 An investigator must seek such consent only under circumstances that provide the prospective 548 subject sufficient opportunity to consider whether or not to participate and that minimize the 549 possibility of coercion or undue influence

. The information that is given to the subjec t must be 550 in language understandable to the subject

. No informed consent, whether oral or written, may 551 include any exculpatory language through which the subject is made to waive or appear to waive 552 any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the 553 institution or its agents from liability for negligence. 554
6

. Revise § 26.1117 to read as follows: 555 § 26.1117 Documentation of informed consent. 556 (a) Informed consent must be documented by the use of a written consent form approved 557 by the IRB and signed by the subject

. A copy shall be given to the subject. 558 (b) The consent form may be either of the following: 559 (1) A written consent document that embodies the elements of informed consent required 560 by § 26.1116

. This form may be read to the subject, but in any event, the investigator must give 561 the subject adequate opportunity to read it before it is signed; or 562 (2) A short form written consent document stating that the elements of informed consent 563 required by § 26. 1116 have been presented orally to the subject

. When this method is used, there 564
must be a witness to the oral presentation

. Also, the IRB shall approve a written summary of 565*** EO 12866 Draft

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Page 25 of 33 what is to be said to the subject

. Only the short form itself is to be signed by the subject

. 566
H owever, the witness must sign both the short form and a copy of the summary, and the person 567 actually obtaining consent must sign a copy of the summary

. A copy of the summary must be 568 given to the subject, in addition to a copy of the short form. 569
7

. Revise the heading for subpart L to read as follows: 570 Subpart L

— Prohibition of Third
- Party Research Involving Intentional Exposure to a 571 Pesticide of Human Subjects W ho are Children or Pregnant or Nursing Women 572
8

. Revise § 26.1201 to read as fol lows: 573 § 26.1201 To what does this subpart apply? 574 This s ubpart applies to any research subject to subpart K of this part. 575 576 9

. Revise § 26.1301 to read as follows: 577 § 26.1301 To what does this subpart apply? 578 This subpart applies to any person who submits to EPA after [effective date of final rule] 579 either of the following: 580 (a) A report containing the results of any human research for consideration in connection 581 with an action that may be performed by EPA under FIFRA (7 U.S.C

. 136

- 136y) or section 408 582 of FFDCA (21 U.S.C

. 346a). 583 (b) A report containing the results of any huma n research on or with a pesticide for 584 consideration in connection with any action that may be performed by EPA under any regulatory 585
statute administered by EPA. 586 § 26.1 3 02 [AMENDED] 587 1 0

. In § 26.1302 remov e the word “shall

. ” 588 § 26.1 5 02 [AMENDED] 589 1 1

. Amend § 26.1502 as follows: 590*** EO 12866 Draft

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Page 26 of 33 a . In the first sentence of p aragraph (a) remove the period after the phrase “during an 591 inspection” and add in its place a comma; and 592 b

. In the second sentence of paragraph (a) remove the phrase “The A gency” and add in 593 its pl ace “EPA.” 594 c. In the last sentence of the introductory text of paragraph (b) remove the phrase “The 595
A gency” and add in its place “EPA.” 596 § 26.1 5 0 5 [AMENDED] 597 1 2

. In § 26.1505 remove from the last sentence , the phrase “§ 26.1502(c)” and add in its 598 place “§ 26.1502(b)(4).” 599 § 26.1 5 0 7 [AMENDED] 600 1 3

. In § 26.1507 re mov e from the last sentence, the phrase “The A gency” and add in its 601 place “EPA”. 602 § 26.1 6 0 1
- 26. 1603 [REDESIGNATED] 603 1 4

. Amend s ubpart P of this part by redesignating §§ 26.1601 through 26.1603 as § § 604 26.1603 through 26.1605. 605

1 5

. Add new §§ 26.1601 and 26.1602 to read as follows: 606 §26.1601 To what does this subpart apply? 607 This subpart applies to both of the following: 608 (a) Reviews by EPA and by the Human Studies Review Board of proposals to conduct 609 new research subject to 40 CFR 26.1125

. 610 (b) Reviews by EPA after [effective date of the final rule] and, to the extent required by 611 § 26.1604, by the Human Studies Review Board of reports of completed research subject to 40 612
CFR 26.1701. 613*** EO 12866 Draft

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Page 27 of 33 § 26.1602 Definitions. 614 The definitions in § 26.1102 apply to this subpart as well. 615 1 6

. Amend newly redesignated § 26.1603 as follows: 616

a . Remove p aragraphs (a) and (e). 617 b

. Redesignate paragraphs (b) thr ough (d) as (e) through (g). 618

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

. 619 § 26.1603 EPA review of proposed human research. 620 (a) EPA must review all proposals for new human research submitted under § 26.1125 in 621 a timely manner. 622 (b) In reviewing proposals for new human research submitte d under § 26.1125, the EPA 623 Administrator must consider and make determinations regarding the proposed research, 624 including: 625 (1) Whether the research would be likely to produce data that address an important 626 scientific or policy question that cannot be reso lved on the basis of animal data or human 627 observational research. 628 (2) Whether the proposed research is designed in accordance with current scientific 629 standards and practices to: 630 (i) Address the research question

. 631 (ii) Include representative study populat ions for the endpoint in question

. 632 (iii) Have adequate statistical power to detect appropriate effects. 633 (3) Whether the investigator proposes to conduct the research in accordance with 634 recognized good research practices, including, when appropriate, good clinical practice 635 guidelines and monitoring for the safety of subjects. 636 (c) In reviewing proposals for new research submitted under § 26.1125, the EPA 637*** EO 12866 Draft

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Page 28 of 33 Administrator must consider and make determinations regarding ethical aspects of the proposed 638 research , including: 639 (1) Whether adequate information is available from prior animal studies or from other 640 sources to assess the potential risks to subjects in the proposed research

. 641 (2) Whether the research proposal adequately identifies anticipated risks to hum an 642 subjects and their likelihood of occurrence, minimizes identified risks to human subjects, and 643 identifies likely benefits of the research and their distribution

. 644 (3) Whether the proposed research presents an acceptable balance of risks and benefits

. 645
I n making this determination for research intended to reduce the interspecies uncertainty factor 646 in a pesticide risk assessment, the Administrator must consider Recommendation 4

- 1 in the 2004 647 Report from the National Research Council of the National Academy of Sciences (NAS) , entitled 648

“ Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues .” 649 (4) Whether subject selection will be equitable

. 650 (5) Whether subjects’ participation would follow free and fully informed consent

. 651 (6) Whether an appropriately constituted IRB or its foreign equivalent has approved the 652 proposed research

. 653 (7) If any person from a vulnerable population may become a subject in the proposed 654 research, whether there is a convincing justification for sele ction of such a person, and whether 655 measures taken to protect such human subjects are adequate

. 656 (8) If any person with a condition that would put them at increased risk for adverse 657 effects may become a subject in the proposed research, whether there is a convincing 658 justification for selection of such a person, and whether measures taken to protect such human 659 subjects are adequate

. 660*** EO 12866 Draft

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Page 29 of 33 (9) Whether any proposed payments to subjects are consistent with the principles of 661 justice and respect for persons, and wheth er they are so high as to constitute undue inducement 662 or so low as to be attractive only to individuals who are socioeconomically disadvantaged

. 663 (10) Whether the sponsor or investigator would provide needed medical care for injuries 664 incurred in the propos ed research, without cost to the human subjects. 665 (d) With respect to any research or any class of research, the EPA Administrator may 666 recommend additional conditions which, in the judgment of the EPA Administrator, are 667 necessary for the protection of huma n subjects. 668
* * * * * 669 (h) EPA must provide the submitter of the proposal copies of the EPA and Human 670 Studies Review Board reviews. 671
1 7

. Amend newly redesignated § 26.1604 by revising paragraph (a) to read as follows: 672 § 26.1604 EPA review of completed human research. 673 (a) When considering, under any regulatory statute it administers, data from completed 674 research involving intentional exposure of humans to a pesticide, EPA must thoroughly review 675 the material submitted under § 26.1303, if any, and other a vailable, relevant information and 676 document its conclusions regarding the scientific and ethical conduct of the research. 677

***** 678
1 8

. Add §§ 26.1606 and 26.1607 to read as follows: 679 § 26.1606 Human Studies Review Board review of proposed human research. 680 In commenting on proposals for new research submitted to it by EPA, the Human Studies 681 Review Board must consider the scientific merits and ethical aspects of the proposed research, 682 including all elements listed in § 26.1603(b) and (c) and any additional co nditions recommended 683*** EO 12866 Draft

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Page 30 of 33 pursuant to § 26.1603(d). 684 § 26.1607 Human Studies Review Board review of completed human research. 685 In commenting on reports of completed research submitted to it by EPA, the Human 686 Studies Review Board must consider the scientific mer its and ethical aspects of the completed 687 research, and must apply the appropriate standards in s ubpart Q of this part. 688 19

. Revise the heading for subpart Q to read as follows: 689 Subpart Q

— Standards for Assessing Whether to Rely on the Results of Human Rese arch 690 in EPA Actions 691
2 0

. Revise §§ 26.1701

- 26.1705 to read as follows: 692 § 26.1701 To what does this subpart apply? 693 (a) For decisions under FIFRA (7 U.S.C

. 136

- 136y) or section 408 of FFDCA (21 U.S.C

. 694 346a), this subpart applies to research involving inte ntional exposure of human subjects to any 695 substance. 696 (b) For decisions under any regulatory statute administered by EPA other than those 697 statutes designated in paragraph (a) of this section, this subpart applies to research involving 698 intentional exposure of human subjects to a pesticide. 699 § 26.1702 Definitions. 700 The definitions in § 26.1102 and § 26.1202 apply to this subpart as well. 701 § 26.1703 Prohibitions applying to all research subject to this subpart. 702 (a) Prohibition of reliance on scientifically inv alid research

. EPA must not rely on data 703 from research subject to this subpart unless EPA determines that the data are relevant to a 704 scientific or policy question important for EPA decision

- making, that the data were derived in a 705 manner that makes them sc ientifically valid and reliable, and that it is appropriate to use the data 706*** EO 12866 Draft

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Page 31 of 33 for the purpose proposed by EPA

. In making such determinations, EPA must consider: 707 (1) Whether the research was designed and conducted in accordance with appropriate 708 scientific s tandards and practices prevailing at the time the research was conducted

. 709 (2) The extent to which the research subjects are representative of the populations for the 710 end point or endpoints in question. 711 (3) The statistical power of the data to support the scientific conclusion EPA in tends to 712 draw from the data. 713 (4) In a study that reports only a No Observed Effect Level (NOEL) or a No Observed 714 Adverse Effect Level (NOAEL), whether a dose level in the study gave rise to a biological 715 effect, thereby demonstr ating that the study had adequate sensitivity to detect an effect of 716 interest. 717 (b) Prohibition of reliance on research subject to this subpart involving intentional 718 exposure of human subjects who are pregnant women (and therefore their fetuses), nursing 719

w omen, or children

. Except as provided in § 26.1706, EPA must not rely on data from any 720 research subject to this subpart involving intentional exposure of any human subject who is a 721 pregnant woman (and therefore her fetus), a nursing woman, or a child. 722 § 26.1704 Prohibition of reliance on unethical human research with non
- pregnant, non 723 nursing adults which is not subject to § 26.1705. 724 (a) This section applies to research subject to this subpart that is not subject to § 26.1705. 725 (b) Except as provided in § 26.1706, EPA must not rely on data from any research subject 726 to this section if there is clear and convincing evidence that: 727 (1) The conduct of the research was fundamentally unethical (e.g., the research was 728 intended to seriou sly harm participants or failed to obtain informed consent) ; or 729*** EO 12866 Draft

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Page 32 of 33 (2) The conduct of the research was deficient relative to the ethical standards prevailing 730 at the time the research was conducted in a way that placed participants at increased risk of harm 731 (based on knowledge available at the time the study was conducted) or impaired their informed 732
consent

. 733 (c) This prohibition is in addition to the prohibitions in § 26.1703. 734 § 26.1705 Prohibition of reliance on unethical human research with non
- pregnan t, non 735 nursing adults initiated after April 7 , 2006, and subject to subparts A through L of this 736 part or codification of the Common Rule by another Federal department or agency . 737 (a) This section applies to research subject to this subpart, that: 738 (1) Was initiated after April 7 , 2006

. 739 (2) Was subject, at the time it was conducted, either to subparts A through L of this part 740 or to another codification of the Federal Policy for the Protection of Human Subjects, generally 741 referred to as the “Common Rule

. ” 742 (b) Except as provided in § 26.1706, EPA must not rely on data from any research subject 743 to this section unless EPA determines that the research was conducted in substantial compliance 744 with either: 745 (1) All applicable provisions of subparts A through L of this part or codification of the 746 Common Rule by another Federal department or agency ; or 747 (2) If the research was conducted outside the United States, with procedures at least as 748 protective of subjects as those in subparts A through L of this part or codif ication of the 749 Common Rule by another Federal department or agency

. 750 (c) Except as provided in § 26.1706, EPA must not rely on data from any research subject 751 to this section unless EPA determines that the research was conducted in substantial compliance 752*** EO 12866 Draft

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Page 33 of 33 wi th either: 753 (1) A proposal that was found to be acceptable under § 26.1603(c), and no amendments 754 to or deviations from that proposal placed participants at increased risk of harm (based on 755 knowledge available at the time the study was conducted) or impaire d their informed consent

. If 756 EPA discovers that the submitter of the proposal materially misrepresented or knowingly omitted 757 information that would have altered the outcome of EPA’s evaluation of the proposal under § 758 26.1603(c), EPA must not rely on that data. 759 (2) A proposal that would have been found to be acceptable under § 26.1603(c), if it had 760 been subject to review under that section, and no amendments to or deviations from that proposal 761 placed participants at increased risk of harm (based on knowled ge available at the time the study 762 was conducted) or impaired their informed consent. 763 (d) This prohibition is in addition to the prohibitions in § 26.1703. 764
21

. In paragraph (d) of § 26.1706 , remove the phrase “publishes” and add in its place 765 “has publi shed

. ” 766 [FR Doc

. ??

– ????? Filed ??

– ??

– ??; 8:45 am] 767*** EO 12866 Draft

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Page 1 of 15 EO 128 66_HumanSubjectsRevisions_ RIN 2070

- AJ76_FRM_RtC_2011

- 09

- 15 .doc x

EPA R esponse to Public Comment s Action : Proposed Rule; Revisions to EPA’s Rule on Protections for Subjects in Human Research Involving Pesticides (Tier 3; SAN 5448; RIN 2070
- AJ76) Comment Period : 2/ 2 /2011
- 4/4/2011
I. Summary This document addresses comments received in response to the Notice of Proposed Rulemaking for Revisions to EPA’s Rule on Protections for Subje cts in Human Research Involving Pesticides , published o n February 2, 2011 (76 FR 5735)

. EPA is proposing amending the portions of its rules for the protection of human subjects of research applying to third parties who conduct or support research with pesticides involving intentional exposure of human subjects and to persons who submit the results of human research with pesticides to EPA. All comments appear in their entirety in the public docket for this rulemaking, identified as “ EPA

HQ

- OPP

- 2010

- 0785 ” and accessible at www.regulations.gov

. EPA proposed several narrowly

- targeted changes to regulatory text as a result of a settlement agreement and specifically requested com ment on the proposed changes. The Agency received 10 comments in response to the N otice of P roposed Rulemaking

. 1 In the d ocket , Documents 1 through 6 are supporting documents for the rulemaking . Documents 7

- 16 are public comments. Documents 17

- 55 are the 28 attachments to NRDC ’s comment ( see discuss ion in Footnote 1 , below )

. II. Comments on Issues within the Scope of the Proposed Rulemaking EPA has identified only two issues raised by commenters that are within the sc ope of the proposed rulemaking. The first issue relate s to the proposed expansion of the rule to cover human testing with pesticides submitted to EPA under any regulatory statute it administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA. The second issue relate s to propos ed revisions to § 26.1603(b)(2)(ii ) and ( iii ) and § 26.1703(a)(2 ) and ( 3) to require EPA to consider whether proposed and completed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. The specific comments, and EPA’s responses to those comments, are discussed below.

1 One comment from the Natural Resources Defense Council included 28 attachments. Although these attachments were posted to the docket as individual comments, they are actually supporting documents for NRDC’s comments on this proposed rulemaking. The 28 documents also appear in other EPA dockets, but NRDC resubmitted them because they wanted all of the documents located in a single docket.*** EO 12866 Draft

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Page 2 of 15 Document # EPA
- HQ
- OPP
- 2010
- 0785
- 14 (Commenter: SC Johnson)
1. Comment: The 2006 Appropriations Act does not require or authorize EPA to issue a rule tha t applies to studies performed outside of the FFDCA/FIFRA context. “EPA’s proposed revision exceeds the Agency’s statutory authority by attempting to regulate human testing under statutes beyond FIFRA and FFDCA. We therefore urge EPA not to adopt this pro posed revision to the Rule.” (p 10). Response: EPA’s authority for this proposed revision to the rule can be found in the 2006 Appropriations Act and in FIFRA. Section 201 of the 2006 Appropriations Act gives EPA the authority to issue a rule covering research involving the intentional dosing toxicity studies for pesticides. The 2006 Appropriations Act does not expressly limit EPA’s authority to studies conducted with pesticides that are intended to be submitted under only FIFRA and the FFDCA. FIFRA p rovides additional authority to issue rules covering the use of both unregistered and registered pesticides, regardless of whether that research is conducted for submission under FIFRA. Section 3(a) of FIFRA permits 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”. Section 25(a) authorizes EPA to “prescribe regulations to carry out the provisions of [FIFRA].” EPA has determined that this rule ensures that registered and unregistered pesticides are not used in a manner that would cause unreasonable adverse effects on the environment, including humans. Document # EPA
- HQ
- OPP
- 2010
- 0785
- 16 (Commenter: Natural Resources Defense Council [NRDC])
2. Comment: While the expanded scope of the proposed rule “would narrow the loophole created by the ‘intention’ [to submit to EPA] standard, we would prefer that the loophole be closed by including a clear ban on the conduct of any intentional dosing toxicity study on pregnant women or children. Section 201 [of the 2006 Appropriations Act] requires such a ban...” (p 6) Response: Notwithstanding the authority provided in the 2006 Appropriations Act and in FIFRA, EPA does not believe that the 2 006 Appropriations Act compels the broad ban advocated by NRDC. The human studies that Congress was primarily concerned about during the debates leading up to the passage of the 2006 Appropriations Act were those that involved intentional testing of pestic ides on human subjects and EPA’s consideration or reliance on those studies. EPA was prohibited from relying on any human studies until it issued a rule in accordance with the requirements of the 2006 Appropriations Act. This context implies that a reaso nable interpretation of what Congress was requiring EPA to do was to issue a rule covering human studies involving exposure to pesticides when those studies were submitted to EPA. Nothing in the legislative history indicates that Congress intended EPA’s r ule to apply to studies that were outside of EPA’s purview. As mentioned above, EPA has authority, and believes it is reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides that are submitted to EPA under other laws that it administers. This rule covers studies that are within EPA’s*** EO 12866 Draft

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Page 3 of 15 purview. However, to expand the 2006 rule to impose prohibitions or conditions on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies involvi ng unregistered pesticides that are conducted outside the United States) is clearly outside EPA’s authority. Moreover, such a prohibition, if enforceable, could have the unintended effect of prohibiting valuable research. Document # EPA
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- 11 (Commenter : Agricultural Handler Exposure Task Force [AHETF])
Document # EPA
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- 12 (Commenter: CropLife America [CLA]) Document # EPA
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- 13 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF])
3. Comment: The AHETF, CLA , and AEATF cite concerns with the proposed new regulatory text at § 26.1603(b)(2)(ii ) and ( iiii) that would require EPA to consider whether the proposed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. AEATF, AHETF, and CLA are similarly concerned with the proposed new regulatory text at § 26.1703(a)(2 ) and ( 3) that wo uld require EPA to consider these factors in determining whether to rely on completed research . The commenters’ argue that while these factors are pertinent to clinical studies they have little or no relevance to exposure studies. The specific comments from each commenter are quoted below.
AHETF : “Another problem area for the proposed amendments to the Rule concerns issues that require case

- by

- case consideration of the EPA and HSRB. In these situations, the proposed Rule cannot address the specificity n eeded for a given proposed study because of the contextual information and interpretation required. Specifically, the proposed amendments (see Exhibit A, Subpart K, Section 26.1703), present an itemized list regarding EPA ‟ s consideration of reliance on dat a from research involving “intentional exposure” of human subjects... These criteria require interpretation by subject matter experts on a case

by

- case basis and ... more specific definition of the terms “representative” and “statistical power” are necessary because these are protocol/study design

- specific aspects...Further, these criteria are more appropriate for clinical studies and do not translate directly to occupational exposure studies...” (EPA

- HQ

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- 11, p 15

- 16)
CLA : “CLA notes and agrees that t hese considerations play an important role in some human testing and we argue that subject matter experts need to provide input on a case

- by

- case basis. The study design aspects require specific considerations to be made by EPA (and the HSRB, as well as ot her federal advisors, i.e., the EPA FIFRA Scientific Advisory Panel). However, there appears to be unnecessary complexity added to the evaluation of occupational exposure studies. Many of these criteria are more appropriate for clinical studies and do not translate directly to occupational exposure studies whose purpose is to develop observational exposure data.” (EPA

- HQ

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- 12, p 6)
AEATF : “AEATF is concerned, however, that proposed changes to 40 CFR Part 26, requiring representative study popul ations and ‘ adequate statistical power ’ are inapposite to*** EO 12866 Draft

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Page 4 of 15 the types of exposure research being conducted by AEATF and others, are too ambiguous to offer clarity and predictability to study sponsors and investigators, and impose unwarranted burdens in study sponsors and investigators without improving scientific validity or protection of human subjects.” (EPA

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- 13, p 3)

. Further on the topic of “representative study populations” and “adequate statistical power”, the commenters request that EP A “confirm that EPA does not expect any effect on the continued approval of the worker exposure studies” (AEATF, EPA

- HQ

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- 13, p 5). Response: As discussed in the preamble to the proposed rule, this language is a combination of recommendations 3

- 1(b) and 5

- 1(c) from the 2004 Report by the National Research Council of the National Academies of Science (NAS) titled Intentional Human Dosing Studies for EPA Regulatory Purposes (hereafter, NAS Report). EPA disagrees with the assertion that the criteria on representative populations and statistical power are not applicable to exposure studies. Although the NAS recommendations on which these criteria are based were drafted with a n eye toward toxicological testing, the scientific concepts embodied have broad applicability to scientific testing. Further, the language used by EPA in this rule is generic in nature and not limited to toxicological testing. Terms such as “effect” or “ endpoint,” when used without a modifier, can refer to any result to be examined in a scientific study. Thus, EPA believes the criteria are potentially applicable to all types of intentional exposure human studies covered by this rule. Nonetheless, EPA does not believe that adoption of these criteria will impose additional burdens on sponsors of the type of exposure studies referenced by the commenters. Even though the NAS’ recommendations about representative study populations and adeq uate statistical power were not specifically articulated in EPA’s 2006 Final Rule (40 CFR 26), EPA has applied the principles underlying these recommendations, as well as the general NAS directive that studies should be designed and conducted in accordance with appropriate scientific standards and practices, in its consideration of human research since the promulgation of the rule in 2006. Thus, EPA does not anticipate any effect from adding these NAS recommendations to the 2006 rule on the Agency’s consid eration of ongoing or future worker occupational exposure studies, except that EPA’s consideration of these issues will be even more transparent. As EPA repeatedly noted in the preamble to the proposed rule, the proposed amendments essentially codify the scope and approach used under the 2006 rule in EPA’s science and ethics reviews of human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this comment response, EPA further clarifies the applicability of the criteria a t issue to exposure studies. The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is relevant to any scientific endeavor in which less than the full population is examined or tested and for which valid extrapolation to a l arger population is desired. EPA does not agree that the language could be construed as not applying to exposure studies, given that the representativeness of the sample is a relevant consideration in evaluating, for proposed and completed research, whe ther the observed effects of the completed study would predict the responses of a larger population.*** EO 12866 Draft

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Page 5 of 15 In evaluating what is a representative population for a study, the NAS emphasized that EPA should focus on the “objectives of the study” (NAS Report, p . 77). For a study intended to measure worker exposure, representation of the general workforce would be evaluated with respect to, among other characteristics, types of equipment used, the monitored subjects’ work experience, and work situations that coul d be defined by factors such as geographic location or crop. The exposure studies to date have been representative of the workforce studied in this manner. As discussed below, EPA considers explicit adoption of the representative population criterion as a codification of existing practice and does not believe that adoption of this criterion will impose any additional burden on sponsors of exposure studies. The commenters appear to be concerned that the representative population consideration will require that a study use a fully statistically random sample imposing additional burdens on sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular method for demonstrating representativeness; rather, the rule only requires that EPA, in determining the scientific validity and reliability of proposed and completed studies, “consider” representativeness. Moreover, as noted above, the NAS Report stressed that representativeness was a study

- specific determination based on the ob jectives of the study. For exposure studies, a fully statistically random sample may neither be feasible nor, in some cases, desirable. Alternate sampling strategies can produce a sample which represents a broader range of conditions than would be prese nt in a random sample of similar limited size and thus may produce results that reasonably approximate real world exposures with respect to the overall magnitude and “spread.” For example, the Agricultural Handler Exposure Task Force (AHETF) and the Antim icrobial Exposure Assessment Task Force II (AEATF

- II) are using a “purposive diversity selection” sampling procedure in their exposure research. This procedure attempts to produce a sample which incorporates some random elements (where feasible); the resu lting sample can be more useful from a regulatory perspective in that it more likely represents the range of conditions and situations under which exposure occurs. This approach meets the objectives of the study and is consistent with the representative p opulation consideration requirement. The Agency recognizes that random sampling, in many cases, may be considered to be the “gold

- standard” for demonstrating representativeness in a statistical sense. Nonetheless, for the reasons stated above, the use of alternate sampling strategies can, under certain circumstances, produce a sample which is sufficiently representative given the study objectives. The statistical power consideration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is also a relevant con cept for both toxicology and exposure studies. Statistical power evaluates how accurately a study can measure the effect being studied. For example, a toxicity study typically evaluates whether a chemical causes an effect by comparing the responses of the treated and untreated groups. In some instances , treated and untreated groups will not show different (statistically significant) responses, even though the chemical actually does cause the effect. The statistical “power” of a toxicological study can be thought of as the ability of the study to detect a difference between treated and untreated groups given that a difference of a defined magnitude does exist. Statistical power can be an important concept in evaluating the design of toxicity studies since it helps in ascertaining the degree to which the study will be able to find a significant difference*** EO 12866 Draft

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Page 6 of 15 between treated and untreated groups , when a difference of defined magnitude does indeed exist. Obviously, for completed toxicological studies, the statis tical power of the study is an irrelevant consideration if the study found a statistically significant relationship between exposure and an effect. Conversely, when a completed toxicity study finds no such relationship, evaluating the statistical power of the study design becomes relevant because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of the result. As to exposure studies, statistical power could have applicability to an exposure study design if, for examp le, that study attempted to evaluate the relationship between dermal or inhalation exposure and an exposure variable. The statistical power of such an exposure study would also be a consideration if that study was interpreted as showing that there is no r elationship between the tested variables. EPA has required various statistical analyses of exposure studies under the 2006 rule other than statistical power analyses. For example, EPA has relied upon standard regression analyses and calculation of su mmary statistics (e.g. means and percentiles) in evaluating the merit of worker exposure studies. EPA expects that those or similar analyses will, in all probability, suffice going forward under the requirement in the revised rule that researchers have a general obligation to ensure that their research is “designed and conducted in accordance with appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 26.1703(a) (EPA must determine that “data were derived in a manne r that makes them scientifically valid and reliable”). Therefore, EPA does not believe that the revised rule will impose any additional burden on sponsors of exposure studies with regard to statistical analyses generally. Finally, even if either or both o f these criteria turn out to be inapplicable to some studies covered by the rule, that fact should not result in a significant burden for either EPA, the HSRB, or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 26.1703, if in rev iewing a study, EPA or the HSRB determines that either or both of the criteria are not applicable to that particular study, a notation by EPA or the HSRB of the reason for such determination would constitute appropriate consideration of the criteria in acc ordance with the rule. Similarly, for a person submitting a study design or a completed study to EPA and the HSRB for review, an explanation of why certain criteria are inapplicable to the study submitted may satisfy the rule’s requirements.

III. Comments on Issues Outside of the Scope of the Proposed Rulemaking Document # EPA
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- 07 ( Commenter: Anonymous ) 1. Comment: “ It is plausible that several of the current or future

- use pesticides might exert trans

- generational epigenetic effects that have not been studied yet. Families of applicators may be at highest risk for these kinds of effects. It is hard to imagine a scientifically valid study of these effects that would not require inclusion of children (but these children need not be exposed). A finer distinction should be made in the regulation between assent of children to participate in studies where they will be exposed to a pesticide, and assent of children to participate in studies where someone else will be exposed to a pesticide.”*** EO 12866 Draft

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Page 7 of 15 Response: EPA’s 2006 r ule (currently, and as it is proposed to be amended) covers intentional exposure studies, not epidemiological or observational studies. The type of study that the commenter has described (studying pesticide applicator families) would likely be epidemiological or observational and would not be covered by the rule. If, however, a protocol proposed intentional exposure research involving families with children or pregnant women, that research would not be permitted under EPA’s 2006 r ule. 2. Commen t: “On another note, the phrasing of this proposed regulation is very broad and I worry could have a negative impact on research intended to intervene against the childhood obesity and diabetes epidemics, which disproportionately affect socially and envir onmentally disadvantaged communities. Is consumption of a conventional apple in an obesity study considered an intentional exposure to pesticide? EPA should clarify in its final regulation that this statute does not limit assent of minors for studies invol ving conventionally grown foods.” Response: EPA’s 2006 r ule and the proposed amended version of the r ule have a very clearly delineated scope. The r ule (currently, and as it is proposed to be amended) applies to intentional exposure studies intended for submission to EPA. It does not apply to dietary studies even if those studies involve consumption of a food item containing a pesticide residue, because such a study would not be considered an intentional exposure study. Document # EPA
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- 08 ( Commenter: Chris (no surname provided) ) 3. Comment: Commenter objects “to the requirement and reliance on animal research that continue to be present in research procedures required by the EPA.” Response: Comments concerning research with animals are beyond the scope of these revisions. Document # EPA
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- 09 ( Commenter: A. Sow )
4. Comment : “ My comment is that p rotecting the environment will be great for our safety and our wellbeing. I am confident that by improving this regulation we will save the world. People will feel much healthier and have a longer life expectancy. We should educate people how not to use things that harm the environment and fine those who do not respect it. There are many social issues that are harming our environment right now and we can fix them if we all pitch in and do our part, we can change things all around us and in the world and make a differen ce. As Theodore Roosevelt said “ To waste and destroy our natural re sources, to skin and exhaust the land instead of using it so as to increase its usefulness, will result in undermining in the days of our children the very prosperity which we ought by right to hand down to them. ” EPA's main role would be to protect and improve the environment. By doing so EPA will make sure that businesses and industries understand their environment responsibilities, enabling them to comply with legislation and good practice and to realize the great economic benefits for a good environme ntal practice ”*** EO 12866 Draft

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Page 8 of 15 Response: EPA’s mission is to protect human health and the environment. Document # EPA
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- 10 ( Commenter: Anonymous ) 5. Comment: “ Human testing is never a safe or smart way to decide whether or not a product is safe. In the p redicament that pesticides or other products that were being tested on human was unsafe; human beings being used as test subject would suffer unjustly. Products such as pesticides need to be made and created with all knowledge of being safe for use and tes ted on animals and not humans. There needs to be defined regulations on new products and how to go about make them safe for everyone. Exposing children to new pesticides with the intentions to see if they are safe or not makes absolutely no sense; doing t his puts children in harm’s way. ” Response: EPA is proposing narrowly

- targeted revision s to its rules for the protection of human subjects in research involving intentional exposure to pesticides

. General c omments on the scientific merit of conducting pesticide research with human subjects are beyond the scope of the proposed rulemaking . However, consistent with the commenter’s concern for children, the proposed rule does strengthen the provisions in EPA’s 2006 rule ensuring that children are not used as test subjects in research involving intentional exposure to pesticides. Comments with Common Focus Document # EPA
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- 11 (Commenter: Agricultural Handler Exposure Task Force [AHETF] ) Document # EPA
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- 2010
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- 12 (Commenter: Crop Life America [CLA] ) Document # EPA
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- 2010
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- 13 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF]) Document # EPA
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- 14 (Commenter: SC Johnson)
Documents

- 11,

- 12,

- 13 and

- 14 , from the AHETF, CLA , AEATF, and SC Johnson, are similar in content , so their major points and EPA’s resp onses to those points are discussed together.
6. Comment: EPA should reconsider its interpretation of the definition of research involving intentional exposure of a human subject. Studies monitoring the occupational exposure of workers while they mix , load, and/or apply registered pesticide products in a manner that is consistent with normal work activities should not be considered intentional exposure studies. All four commenters present essentially the same arguments in favor of this change to the rule:
• Occupational exposure studies were not intended to be cov ered by 40 CFR 26. In the 2006 Appropriations Act, Congress intended to require EPA to promulgate a r ule concerning “ third

- party intentional dosing human toxicity studies for pesticides. ” EPA’s current practice of considering occupational exposure stud ies that alter a*** EO 12866 Draft

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Page 9 of 15 worker ’s exposure to be intentional exposure studies goes beyond the legal mandate required by the 2006 Appropriations Act.
• A s tud y measuring a worker’s exposure during normal agricultural activities is not the same as a human toxicity study.
• EPA needs better occupational exposure data. Considering these studies to be intentional exposure studies requiring Human Studies Review Board (HSRB) review has caused delays and greater expense.
• Very little addi tional worker protection has resulted from the additional HSRB oversight. Response: This topic is not withi n the scope of the current rulemaking. The 2006 rule provides the definition for “research involving intentional exposure of a human subject” : § 26.1102(i) Research involving intentional exposure of a human subject means a study of a substance in which the exposure to the substance experienced by a human subject participating in the study would not have occurred but for the human subject's particip ation in the study. Since promulgation of the rule in 2006, EPA has interpreted this definition, consistent with its discussion in the preamble to the final rule (71 FR 6138) , as covering scripted worker exposure studies because the scripting alters the le vel and/or timing of the worker’s exposure. The proposed rulemaking on which the Agency is currently accepting comment does not propose change s to the definition of “research involving intentional exposure of a human subject ” in section 26.1102(i)

. Further , the Agency has not invited comment on its application of that definition , or, in any other way, indicated it intended to reconsider the scope of research covered by this definition . Accordingly, no response to this comment is warranted. The prop osed changes to the 2006 rule do not reopen the question of the applicability of the rule to worker exposure studies and the commenters cannot reopen consideration of that previously

- promulgated provision by filing comments on the issue in a rulemaking tha t does not address the issue. Document # EPA
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- 1 1 (Commenter: Richard Collier, Agricultural Handler Exposure Task Force)
7. Comment : “[T] he AHETF supports EPA’s ongoing efforts to ensure protection of the health and safety of human subjects participating in research studies. However, the occupational exposure monitoring studies conducted by AHETF should not be subject to this regulatory program. The Final Rule went far beyond the legal mandate required by the Appropriations Act of 2006 which concerned “third party intentional dosing human toxicity studies for pesticides”. The Rule also is at odds with the 2004 NRC report as to how intentional human dosing should be defined. ” Classifying studies that monitor exposure to individuals who would be exposed in the course of their normal activities in the same manner as studies that measure the toxic effects of pesticides in human subjects is disingenuous. Therefore, the proposed amendments are neither adequate nor appropriate to clarify how EPA shoul d define “intentional exposure”. (p

. 1)*** EO 12866 Draft

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Page 10 of 15 Response : See response to Comment 6 , p p . 7

- 8 of 1 4

. 8. Comment: “ EPA's anticipated revision of its Human Subjects Rule presents an opportunity for the Agency to clarify the definition of “research involving intentional exposure of a human subject.” (p

. 7)
R esponse : EPA did not take the opportunity presented by the proposed revisions to the Human Research Rule to reconsider, or invite reconsideration of, the definition of “research involving intentional exposure of a human subject.” Having not taken that opportunity in the proposed rule, it would be inappropriate to address the issue here.
9. Comment: “ EPA claims to need the data in a timely fashion in order to make accurate, data

based decisions on the safety of pesticide use. T he current impact of these delays will be that a program consisting of 33 study types that should have been completed by 2011 is now probably an additional 10 years from completion.” (p. 12) Response: EPA agrees that the occupational exposure data currently being generated by the AHETF is useful for risk assessment purposes. However, the requirement for HSRB review of this type of human study was not raised in the proposed rule, and, thus, it would be inappropriate to address the issue here. 10. Com ment: The HSRB has changed the underlying objectives of the AHETF program “...from a diversity capturing approach toward more of a population sampling approach. Instead of allowing the selection of workers and other monitoring unit (MU) conditions that will achieve the original diversity objectives, AHETF was forced to modify its approach by adopting the overly extensive recruitment plan that ensures that virtually every worker in a selected monitoring area has the potential of being monitored.” (p

. 15) Response: Comments on particular HSRB recommendations that are not relevant to the proposed changes to 40 CFR 26 are beyond the scope of this rulemaking and it would be inappropriate to comment on them in the context of th is rulemaking.
11. Comment: EPA says that they want to reduce regulatory burden, but there is no evidence of that desire in the revision to the rule. These revisions implement by regula tion what EPA was already doing. Response : The burden

- reducing steps sought by this commenter relate to matters not addressed by this rulemaking. As such, it would be inappropriate to comment on them in the context of the rulemaking.
12. Comment: “ AHETF recommends that EPA consider utilizing an expert panel to review public comments, regarding the “lessons learned” from the EPA and HSRB process and options for continued improvements. Such a forum could address various aspects of the process involved in vetting occupatio nal exposure studies which have substantive impact on time and cost. These include: 1) determining the documentation necessary for proposed research (using examples); 2) the format of the documentation needed for efficient electronic submission and subsequ ent review; and 3) ways to optimize and expedite the process (web*** EO 12866 Draft

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Page 11 of 15 based meetings; internet and intranet sites that could facilitate review by EPA and the HSRB). ” (p

. 16) Response: It is not clear what public comments the commenter is suggesting would be reviewed by an expert panel , b ut th e proposal of a “lessons learned” review has merit. EPA will consider this option after the revised rule is promulgated. Document # EPA
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- 12 (Commenter: Wendelyn Jones, Crop Life America)
13. Comment: Occupational monitoring studies, as is the case with all human studies, must meet at least four stringent conditions: 1. The knowledge gained from the study is expected to promote human health. 2. The knowledge cannot be reasonably obtained by other means

. 3. The study is not expected to cause serious or irreversible harm to the subjects. 4. Appropriate safeguards are in place to minimize harm to the subjects. All AHETF occupational exposure studies are in compliance with the EPA approved label involving a pplication rates, methods of application, and crops treated. Therefore, such design and study conduct is observational in nature. This type of study is in distinct contrast to clinical investigations involving intentional dosing of human subjects to study toxicity. ” (p

. 7) Response : This comment is not responsi ve to the proposed rulemaking. EPA agrees that these four conditions , among others, are necessary for occupational exposure monitoring studies to be considered ethical , and that these are not clinical investigations involving intentional dosing to study toxicity. To the extent the commenter is arguing that this distinction means occupational exposure studies should not be covered by the Human Research Rule, please see the re sponse to Comment 6 , pp. 7

- 8 of 1 4

. Document # EPA
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- 13 (Commenter: Has Shah, American Chemistry Council, for the Antimicrobial Exposure Assessment Task Force II)
14. C omment: The p roposed a mendments also authorize the EPA Administrator to "recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for the protection of human subjects." Proposed 40 CFR 26.1603(d). This provision does not provide any boundaries for such conditions and therefore does not provide sufficient opportunity for stakeholders to comment. Such a pro vision does not provide adequate certainty or predictability to study sponsors or investigators and therefore should not be adopted in a final rule. (p

. 5) Response: The language “ recommend additional conditions which, in the judgment of the EPA Administr ator, are necessary for t he protection of human subjects” i s already present in 40 CFR part 26, at § 26.1601(a). The Agency is re - ordering the text (the language is moving from § 26.1601(a) to 26.1603(d)). But there will not be any change s in the meaning or application of this provision . As a result , this comment is not*** EO 12866 Draft

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Page 12 of 15 responsive to the current rulemaking. In simply re

- ordering the text of the rule with regard to this language, EPA did reconsider the need for this language or invite reco nsideration by commenters. Document # EPA
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- 14 (Commenter: Charles Boyd, SC Johnson & Co . )
15. Comment: “Continuing to impose these burdens simply cannot be justified where there is already an adequate review process in place. The Common Rule and comparable consensus standards apply regardless of the type of human subjects ’ research being conducted....” (p

. 2) Response : This comment questions the ne ed for EPA’s 2006 r ule , Protections for Subjects in Human Research (40 CFR 26) . Th e current rulemaking does not reopen consideration of the 2006 r ule generally , but rather makes certain narrowly

- targeted revisions to a few specific provisions. In th e current rulemaking , EPA did not reconsider the underlying basis for the 2006 r ule and comments raising such issues are beyond the scope of this rulemaking.
16. Comment: “The burdens of the HSRB process disproportionately impact personal insect repellent p roducts. New products using existing active ingredient personal insect repellents are taking over two years to get through the HSRB process, even though these are well characterized active ingredients with complete and fully understood toxicological profi les, decades of consumer use, and very low incidence of adverse effects. The impact on new actives is also problematic. We understand that no new insect repellent active ingredients have gone through the HSRB review process since the implementation of t he 2006 Rule. We believe the burdens and uncertainties involved with the HSRB review process are directly impeding the development of new repellent products

. ” (p

. 6) Response: This comment is not responsive to the current proposed rulemaking. To the extent this comment is implying that human studies involving personal insect repellents should not be covered by the r ule, please see response to C omment 6 , pp. 7

- 8 of 14

. 17. Comment: HSRB should be more like FDA’s advisory committees which are not FACA committees and do not have to have public meetings. “... the ‘openness’ requirements of FACA have created significant obstacles for registrants. In studies of repellent products, much of the information submitted for HSRB review is proprietary and confidential.... Notwithstanding the importance of maintaining the confidentiality of information , it has been extremely difficult to obtain adequate assurance that proprietary information will be protected from disclosure by the HSRB.” (p

. 7) Response: T his comment is not responsive to the amendments under consideration in this rulemaking. The HSRB’s formation under the Federal Advisory Committee Act is not an issue involved in this rulemaking, and, thus, comment on that decision is inappropriate here. Similar comments were made on the 2006 Rule , to which the Agency responded,

“ Specifically, (1) FACA committees are required to be unbiased and independent. (2) The HSRB is not simply an “ethics committee”; it will provide formal external peer*** EO 12866 Draft

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Page 13 of 15 review of both scientific and ethical aspects of human research; as such it will be entirely consistent with other FACA committees established by EPA. (3) The FDA review process does not involve an independent review committee as required by the Appropriat ions Act. (4) The NAS recommended an HSRB, and noted that there were various models elsewhere in the government. The FDA model was identified as one extreme, in that neither the proceedings nor the reports of the internal committee were public. At the othe r extreme the NAS committee noted the NIH recombinant DNA oversight committee, which does all its business in the public eye. (5) EPA acknowledges that different procedures apply to EPA research and to covered third

party research, but notes as well that t his has been true for many years, and that under this final rule, for the first time the substantive standards for approving and conducting first

- second

- and third

- party research will be the same. (6) EPA agrees that regulatory ethics review for pesticide s should be independent, apolitical, and consistent with the Common Rule. (7) EPA does not agree that consistency with FDA is more important than compliance with the Appropriations Act. An internal review group, such as FDA’s, would not satisfy the clear r equirements of that Act.

... FACA committees are able to protect confidential business information. There are established procedures for this, and none need to be defined in this rule. ” ( Docket ID EPA

- HQ

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- 2003

- 0132

- 0656 , p p. 266

- 267)
18. Comment: Executive Order #13563 requires federal agencies to review the necessity and effectiveness of existing regulations and consider principles to use the best and “least burdenso me” tools for achieving regulatory ends. It also r equires inter

- agency coordination to simplify and harmonize redundant or inconsistent regulations. Response: EPA is continuing to carefully consider all existing regulations under Executive Order 13563

. The revisions to EPA’s 2006 rule proposed in this action are not part of that effort. Document # EPA
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- 15 (Nichelle Harriott, Beyond Pesticides)
19. Comment: “ [C] onducting experiments on human subjects, intentionally exposing them to chemicals that can cause both short and long term adverse effects is un productive, unethical and lacking in scientific integrity. ” (p

. 1) Response: Comments regarding the validity of any rese arch with human subjects are beyond the scope of this rulemaking. Similar comments were made on EPA’s 2006 Human Research Rule , to which the Agency responded, “ Nevertheless , the Agency believes that there is still a place in its regulatory decision

- making for scientifically sound, ethically conducted human research.” ( Docket ID EPA

- HQ

- OPP

- 2003

- 0132

- 0656 , p . 143)
20. Comment : Beyond Pesticides is concerned that paying subjects to p articipate in studies will lead to coercion based on financial compensation. “The agency must seriously address the issue of remuneration so as to protect those who may be recruited to becoming a subject for human dosing studies . The agency must also define what constitutes payments as being considered too high or too low. Nevertheless low

- income and other financially*** EO 12866 Draft

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Page 14 of 15 disadvantaged populations will be disproportionately affected, especially since payment for research participati on can be perceived as a potential income source among participants

. Thus, financial remuneration for participating in human studies should be reconsidered, and be done on a strictly voluntary basis with non monetary incentives.” (p

. 3) Response: EPA specifically sought comment on whether the exact language regarding remuneration from NAS Recommendation 5

- 3 or EPA’s proposed language (slightly re

worded from NAS Recommendation 5

- 3 ) is clear er . The commenter is not addressing that issue, but is instead objecting to the overall notion of remuneration , arguing that financial remuneration is not appropriate for human subjects in pesticide studies . EPA continues to agree with the NAS report that remuneration is appropriate to provide an incentive f or participation and to reimburse subjects for the time and inconvenience of participating in such research. The question of what amount of remuneration is appropriate is more difficult , but EPA agrees with the NAS benchmarks that such payments should be neither “so high as to constitute undue inducement” nor “so low as to be attractive only to individuals who are socioeconomically disadvantaged.” EPA has explicitly added these factors in the proposed rule to ensure that they are consider ed in evaluating the appropriateness of payments to study subjects.
21. Comment: “It is inevitable that although this proposal theoretically sets a higher standard for the review of human studies, EPA’s lax oversight and review process would lead to the unconditional approval of many questionable human studies.” (p

. 3 ) Response: EPA has engaged in a rigorous scientific and ethical review of all intentional exposure human studies submitted for consideration under FIFRA and the FFDCA. Since the promulgation of the 2006 rule, this review has involved consultation with science and ethics experts on the Human Studies Review Board about all intentional exposure studies . The present rulemaking , which proposes narrowly

- targeted changes to the EPA’s 2006 H uman S tudies R ule, will further strengthen EPA’s process for reviewing these types of studies. Document # EPA
- HQ
- OPP
- 2010
- 0785
- 16 (Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC))
22. Comment: “The proposed rule would amend the 2006 final rule to partially or fully address many of the 2006 final rule ’ s deficiencies, including inconsistencies with Section 201, and would reduce the likelihood that unethical or unscientific research being conducted and/or relied upon by EPA.” (p

. 6) Response: The Agency is pleased that NRDC supports the proposed changes to the rule, although EPA does not concede that the 2006 fina l rule contained any deficiencies that compelled the proposed changes to that rule. EPA also disagrees that there is a likelihood, in the absence of the proposed changes, that EPA would rely on unethical or unscientific human research. EPA performs rigor ous scientific and ethical reviews and submits those reviews to, and consults with , the Human Studies Review Board before determining whether to approve intentional exposure human study protocols or to rely on completed research in regulatory decisions

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Page 15 of 15 23. Comment: “ The issue of significantly deficient is adequately addressed by deleting the word “significantly”, as recommended by the Human Studies Review Board (HSRB) (FR at 5750)... We are satisfied with this amendment to delete the word.” (p

. 6) Response: The Agency is pleased that NRDC is satisfied with the proposed change , although EPA notes that this change was not recommended by the HSRB as suggested by NRDC

. EPA notes that in addition to deleting the word “significantly” from §26.1704, the Agency is a dd ing language that explicitly characterizes the kinds of deficiencies that would make a study unacceptable. The language is based on the HSRB’s application of the standard of §26.1704 in its review s since 2006

. 24. Comment: “ The issue of consent by a surrogate is addressed by EPA ’ s proposal to delete all references permitting consent by a subject ’s legal representative (FR at 5745). We are satisfied with this a mendment to delete the reference.” (p

. 7) Response: The Agency is pleased that NRDC is satisfied with the proposed change.
25. Comment: “ The proposed rule would also add substantive standards for assessing scientific validity. While EPA may believe that such standards are unnecessary, because it had discretion under the 2006 final rule to reject studies it considered unscientific, there is a substantial policy and legal need for incorporating such standards into the rule....We support EPA ’ s incorporation, t hrough the proposed rule, of stronger, more specific scientific standards.” (p 7) Response: The Agency is pleased that NRDC supports this proposed change.

## Attachment # B
– Review Period: 11/07/11
– 06/08/12

(2) Documentation of any substantive changes that were made to the draft document that was submitted to OIRA/OMB for review, when compared with what completed review, using

... (a) A copy of the draft document submitted, with redline and strikeout to show all the substantive changes that were made during the review. 02/08/201311P

- 1492 EO 12866_Human Subjects Revisions_RIN 2070

- AJ76 _FRM_2011

- 09

- 15 .doc x BILLING CODE 6560

– 50

– P

ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 26 [ EPA

– HQ

– OPP

– 20 10

– 0785 ; FRL

– XXXX

– X 9325
- 5 ] RIN 2070

– AJ76 Protections for Subjects in Human Research Involving Pesticides AGENCY: Environmental Protection Agency (EPA). ACTION: Final rule. SUMMARY: EPA is finalizing narrowly

- tailored amendments to the portions of its rules for the protection of human subjects of research apply ing to third parties who conduct or support

resear ch with pesticides involving intentional exposure of human subjects and to person s who submit the results of human research with pesticides to EPA

. The amendments broaden the applicability of the rules to cover human testing with pesticides submitted to E PA under any regulatory statute it administers

. They also disallow participation in third

- party pesticide studies by subjects who cannot consent for themselves

. Finally , the amendments identify specific considerations to be addressed in EPA require science and ethics reviews of proposed and completed human research with pesticides , drawn from the recommendations of the National Academy of Sciences (NAS)

. . The amendments make no changes to the current Federal Policy for the Protection of Human Subjects (the " Common Rule "), which governs research with human subjects conducte d or EPA’s codification of the Common Rule. supported by EPA and many other Federal departments and agencies, DATES : This rule is effective on [ insert date 60 days after date of publication ] in the Federal*** EO 12866 Draft

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Page of Register ]

. ADDRESSES: EPA has established a The docket for this action is available at http://www.regulations.gov under docket identification (ID) number EPA

– HQ

– OPP

– 20 10

– 0785

. All documents in the docket are listed in the docket index available at

. Although listed in the index, some information is not publicly available, e.g., CBI or other information whose disclosure is restricted by statute

. Certain other material, such as copyrighted material, is not placed on the Internet and will be publicly available only in hard copy form

. Publicly available docket materials are available either in the electronic docket at , , or, if only available in hard copy, at the OPP Regulatory Public Docket in Rm

. S

– 4400, One Potomac Yard (South Bldg.),
2777 S

. Crystal Dr., Arlington, VA

. The the EPA Docket Center (EPA/DC), located in EPA West, Room 3334, 1301 Constitution Ave. NW., Washington, DC 20460

. The EPA/DC hours of operation of this Docket Facility are from 8:30 a.m

. to 4 p.m., Monday through Friday, excluding legal holidays

. The Docket Facilit y telephone number of the EPA/DC Public Reading Room is (202) 566

- 1744, and for the OPP Docket it is (703) 305

- 5805. For more information about the docket and instructions about visiting the EPA/DC, go to http://www.epa.gov/dockets/

. FOR FURTHER INFORMATION CONTACT: Kelly Sherman , Immediate Office of the Director (7501P) , Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460

– 0001; telephone number: (703) 305

- 8401; fax number: (703) 308

- 4776; e

- mail address: sherman.kelly @epa.gov

. SUPPLEMENTARY INFORMATION:
I. Does this Action Apply to Me? Executive Summary
A. Does this Action Apply to Me? You may be potentially affected by this action if you conduct human research on substances regulated by EPA. Potentially affected entities may include, but are not limited to ,*** EO 12866 Draft

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Page of entities that conduct or sponsor research involving that may be submitted to E PA and which involves intentional exposure of human subjects that may be submitted to EPA.

. The following list of North American Industrial Classification System (NAICS) codes is not intended to be exhaustive, but rather provide s a guide to help readers determine whether this document might apply to them. Although EPA has in the past received such third

- party research from pesticide registrants, other entities could submit such information to EPA.

• Pesticide and other Agricultural Chemical Manufacturing (NAICS code 325320) who sponsor or conduct human research with pesticides

.

• Other entities (NAICS code 541710) that sponsor or conduct human research with pesticides, and Institutional Review Boards who review human research with pesticides to ensure it meets applicable st andards of ethical conduct. This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this a ction. Other types of entities not listed in this unit could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether this action might apply to certain entitie s. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT

. I I . General Information
A B

. What Action is the Agency Taking ? The amendm ents contained in this final rule change the 2006 rule, published in the Federal Register 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 CFR p art 26, in the following substantive respects:*** EO 12866 Draft

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Page of • By broadening the applicability of 40 CFR part 26, subparts K, L, M, and Q , so these subparts would apply not only to research submitted to or considered by EPA under the pesticide laws, but also to research involving 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 regulatory statute it adm inisters.

• By incorporating the definition of “pesticide” 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 o n behalf of a subject in research invo lving intentional exposure to a pesticide by a subject’s “legally authorized representative.”

• By incorporating into 40 CFR part 26, subparts P and Q , factors to be considered by an explicit requirement that EPA and the Human Studies Review Board ( HSRB ) ) , in their review of propo sed and completed human research, derived from must consider the recommendations of
NAS in its 2004 R eport to EPA , ethical aspects and from scientific validity and reliability of research under the Nuremberg Code requirements of the Common Rule as codified in 40 CFR part 26, Subpart A. The “Common Rule” is the name generally used to ref er to the Federal Policy for the Protection of Human Subjects, which governs research with human subjects conducted or supported by EPA and many other Federal departments and agencies. EPA's codification of the Common Rule appears as subpart A in 40 CFR pa rt 26

. B C

. What is the Agency's Authority for Taking this Action? The Sections 3(a) and 25(a) of FIFRA provide the legal authority for the se amendments to the 2006 rule on human research

. D. What are the Incremental Costs and Benefits of this Action?*** EO 12866 Draft

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Page of The incremental costs of these amendments both to industry and to EPA are expected to be negligible. EPA has not, therefore, prepared a new economic analysis for this rulemaking. Because no research has been identified that is outside the scope of the 20 06 rule but that would be within the scope of these 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 renewal of the Informatio n Collection Request (ICR) for the existing regulation at 40 CFR part 26. The recent estimates included in the ICR are summarized in Unit is set forth in detail in the preamble to th e proposed rule. 76 FR 5735, 5736

- 5755 (February 2, 2011)

. In brief, the authority for these amendments is provided V.B

. and a copy of the ICR is available in the docket.
I I . Background As required by section 201 of the Department of the Interior, Environment, and Related Agencies Appropriations Act, 2006, Public Law 109

- 54 (2006 Appropriations Act) , and sections 3(a)( and 25(a) of FIFRA

. II I . Background As required by section 201 of the 2006 Appropriations Act, EPA promulg at ed a rule in
2006 establishing a set of protections for people participating as subjects in third

- party human research with pesticides

. in 40 CFR part 26

. (In this context “third

- party” research is research neither conducted (“first

- party”) nor supported (“second

- party”) by EPA or another Common Rule Federal department or agency.) The 2006 rule prohibits EPA from relying on third

- party research on pesticides involving intentional exposure of children or of pregnant or nursing

women , unless relying on the data is crucial to a decision that would impose a more stringent regulatory restriction that would improve prot ection of public health than could be justified*** EO 12866 Draft

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Page of without relying on the data

. It further forbids EPA itself to conduct or support any research involving intentional exposure of pregnant or nursing women or of children to any substance

. In early 2006 , the Natural Resources Defense Council, Inc., Pesticide Action Network North American, Pineros y Campesinos Unido Del Noroeste, Physicians for Social Responsibility

- San Francisco, Farm Labor Organizing Committee, ALF

- CIO, and Migrant Clinicians Network pet itioned for review of the 2006 rule in the United States Court of Appeals for the Second Circuit (Second Circuit Court of Appeals)

. ( NRDC v . EPA , No

. 06

- 0820

- ag (2d Cir

. ))

. The Petitioners argued that the 2006 r ule violated the 200 6 Appropriations Act be cause it d id not bar all pesticide research with pregnant women and children , w as inconsistent with the
2004 NAS Report , Report by the National Research Council of the National Academies of Science (NAS) titled Intentional Human Dosing Studies for EPA Regulatory Purpo ses (hereafter,
2004 NAS Report ) , and w as inconsistent with the Nuremburg Code

. After briefing and argument , but before a decision was rendered by the Second Circuit Court of Appeals , EPA and P etitioners entered a settlement agreement in which EPA agree d to conduct notice

- and

- comment rulemaking on the issue of whether the 2006 r ule should be amended

. EPA also agree d to propose, at a minimum, amendments to the 2006 rule that were substantially consistent with language negotiated between the parties and a ttached to the settlement agreement as Exhibit A

. This agreement , including Exhibit A , is available in the docket for this action as described under ADDRESSES

. The settlement agreement make s clear that EPA retain ed full discretion concerning what amendme nts wer e proposed, and what, if any , amendments are finalized. Consistent with the settlement agreement, on January 18, 2011, EPA Administrator Lisa Jackson signed a notice of proposed rulemaking for proposed amendments to the 2006 rule . The proposed ame ndments were substantially consistent with the regulatory language negotiated with*** EO 12866 Draft

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Page of Petitioners. The notice of proposed rule making was published in the Federal Register on of February 2, 2011.
I II . The Final Rule EPA is finalizing the proposed changes to the scope and consent provisions of the 2006 rule as proposed

. EPA has decided to modify the form in which EPA articulates the requirement for consideration of ethical and scientific factors when reviewing propose d and completed human research . Specifically, instead of codifying selected individual recommendations from the 2004 NAS Report as the specific ethical and scientific factors to be considered in reviewing proposed and completed human research (i.e., propos ed sections 26.1603 and 26.170 3 ) , s ee 76 FR 5735, 5745

- 5749 , February 2, 2011 , EPA has included broader language requiring EPA and the Human Studies Review Board to “consider the ethical aspects and scientific validity and reliability of the proposed resea rch under the requirements of the Common R ule as codified in 40 CFR part 26, Subpart A, except as modified in 40 CFR 26.1116 and 26.1117 .” See 40 CFR
26.1603 as promulgated in this final rule (review of proposed research)

. As indicated in the following discussion , EPA considers that the substituted language regarding the Common Rule either explicitly or implicitly addresses the individual 2004 NAS recommendations originally proposed for inclusion. As such, EPA’s revised approach maximizes consistency a cross the Federal Government with regard to requirements pertaining to the review of human studies and allow s EPA to continue to consider the individual recommendations of the 2004 NAS Report in its review of human research involving pesticides. This appro ach is consistent with existing Agency practice and goals of section 201 of the 2006 Appropriations Act. EPA’s decision not to include the specific text from the 2004 NAS report in the final revisions i s driven by t wo factors. First, on July 26, 2011, after issuance of the proposed rule, the Department of Health and Human Services (HHS) , in coordination with the Office of Science*** EO 12866 Draft

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Page of and Technology Policy (OSTP) , issued an advance notice of proposed rulemaking concerning modernization of the Common Rule whi ch governs research with human subjects conducted or supported by EPA and many other Federal departments and agencies

. ( 76 FR 44512 , July 26 , 2011). HHS and OSTP sought comment on “how to better protect human subjects who are involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators.” Id. HHS and OSTP identified seven areas of concern regarding the Common Rule. Most relevant to EPA’s proposed amendments to the 2006 rule , was a concern with “t he multiple, differing regulatory requirements that can apply to a single research study . . . .” These requirements, according to HHS and OSTP, “have been criticized as complex, inconsistent, and lacking in clarity,” and can result in “unwarranted variab ility across institutions and their [Institutional Review Boards] in how the requirements are interpreted and implemented .” (76 FR at 45514.) HHS and OSTP stressed the importance of clarifying and harmonizing human subject protections across the federal government and sought comment on the means by which this could be accomplished. (76 FR at 44528.) EPA believes that including the specific NAS

- derived considerations in the 2006 rule, which otherwise closely mirrors the Common Rule, will make the federal government’s goal of harmonization of rules governing human research more difficult. A second fa ctor influencing EPA’s decision is that EPA did receive several comments noting that as to some of the NAS

- derived considerations, it was unclear as to how these specific criteria would apply to human exposure, as opposed to human toxicity, studies. EPA b elieves these types of issues can be more appropriately addressed through a guidance document rather than through rule text. Despite the decision not to include the NAS

- derived factors for consideration in the final rule, the rule will be consistent with the recommendations in the 2004 NAS Report and EPA*** EO 12866 Draft

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Page of practice under the 2006 rule. Sections 26.109, 26.111, 26.116, and 26.117 of EPA’s Common Rule explicitly address most of the specific ethical considerations proposed for inclusion in the 2006 rule includ ing whether risks to subjects are minimized (compare proposed §26.1603(c)(2) with existing §26.111(a)(2)); whether risks are reasonable in comparison to benefits (compare §26.1603(c)(3) with §26.111(a)(2)); whether subject selection would be equitable (com pare §26.1603(c)(4) with existing §26.111(a)(3) ) ; whether consent will be free and voluntary (compare proposed §26.1603(c)(5) with existing §§26.116 and 26.117); whether an appropriately constituted IR B has reviewed the proposed research (compare proposed §26.1603(c)(6) with §26.109); and whether the “special problems” of research involving vulnerable populations are taken into account (compare proposed §26.1603(c)(7) and (8) with existing §26.111(a)(3)). Other proposed considerations are implicitly addres sed. The Common Rule’s requirement to “minimize risks” in section 26.111(a)(1) necessitates consideration of whether adequate animal data is available to assess potential risks to subjects (see proposed §26.1603(c)(1 )). It would involve consideration of whether medical care is to be provided for injuries incurred in the proposed research (see proposed §26.1603(c)(10)). Section 26.111(b)’s requirement that additional safeguards be in place to protect against undue influence of “economically” disadvantage d persons ensures that consideration of whether any proposed payments are so high as to constitute undue inducement or so low as to be attractive only to individuals who are socioeconomically disadvantaged (see proposed §26.1603(c)(9)). Although scientifi c considerations are not addressed in similar detail in the Common Rule requirements, nonetheless, the requirement to consider scientific validity and reliability and the Common Rule’s emphasis on the need for “sound research design” in section 26.111(a)(1 ) and the need to take “the importance of the knowledge that may reasonably be expected to result” from the study into
account , mandate that EPA focus on considerations addressing scientific validity such as those*** EO 12866 Draft

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Page of proposed for inclusion in sections 26.1603 and 26.1703. At a minimum, NAS Recommendations 3

- 1, 4

- 1, 5

- 1, 5

- 2, 5

- 3, and 5

- 5 are critical to proper consideration of the Common Rule’s ethical requirements and its requirement for “sound research design .”
I V. Public Comments on the Notice of Propose d Rulemaking
A. Summary This unit discusses, in general terms, the public comments on the proposed rulemaking and EPA’s responses to those comments. For additional details, please refer to the docket for this action ( EPA

– HQ

– OPP

– 20 10

– 0785 ) . The docket includes all of the comments submitted to EPA on this action, as well as a separate document that provides EPA’s detailed responses to the
comments. EPA received a total of 10 public comments on the proposed rulemaking during the 60

- day comment period. Comments we re submitted by four individual citizens and six different entities

– the Agricultural Handler Exposure Task Force, the American Chemistry Council (on behalf of the Antimicrobial Exposure Assessment Task Force II), Beyond Pesticides, CropLife America, Natu ral Resources Defense Council, and SC Johnson & Son, Inc. The docket ( under Docket ID No. EPA

– HQ

– OPP

– 20 10

– 0785) includes all of the comments submitted to EPA on th e proposed rule, as well as EPA’s Response to Comments document, which provides detailed
resp onses to all comments received.
B. A. Comments within on Proposal to Expand Scope to Include Research Submitted to EPA Under Any Regulatory Statute EPA Administers Two comments addressed the proposed changes to the scope of the proposed rulemaking 2006 rule. One commenter stated that the 2006 Appropriations Act did not permit an expansion of scope beyond pesticide studies performed in the FIFRA and FFDCA context , and another argued that the 2006 Appropriations Act required that the scope of the rule be further*** EO 12866 Draft

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Page of expanded beyond stu dies submitted, or intended for submission, to EPA

. EPA has identified only two issues raised by the commenters that are within the scope of the proposed rulemaking. T he first issue relate s to the proposed expansion of the scope of the rule to cover human testing with pesticides submitted to EPA under any regulatory statute it administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA.
O ne commenter argued that EPA was without authority to expand the scope of the rule and another requested that the scope be even broader. The second issue relate s to new regulatory text
at § 26.1603(b)(2)(ii and iii) and § 26.1703(a)(2 and 3) which would require EPA to consider whether proposed and completed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. Several commenters addressed this issue.
1. Comments abou t p roposed s cope c hanges
Comment: SC Johnson & Son commented that the proposed scope expansion exceeds EPA’s statutory authority

. Response: EPA’s authority for this proposed revision to the rule can be found in the Appropriations Act and in FIFRA. Section 201 of the Appropriations Act gives EPA the authority to issue a rule covering research involving the intentional dosing toxicity studies for pesticides. The Appropriations Act does not expressly limit EPA’s authority to studies conducted with pesticides that are intended to be submitted under only FIFRA and the FFDCA. FIFRA provides additional authority to issue rules covering the use of both unregistered and registered pesticides, regardless of whether that research is conducted for submission under FIFRA. Section 3(a) of FIFRA permits EPA to regulate the distribution, sale, or use of any unregistered pesticide in any State “[t]o the ext ent necessary to prevent unreasonable adv erse effects on the environment

. ” Section 25(a) authorizes EPA to “prescribe regulations to carry out*** EO 12866 Draft

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Page of the provisions of [FIFRA].” EPA has determined that this rule ensures that registered pesticides are not used i n a manner that would cause unreasonable adverse effects on the environment, including humans.
Comment: Natural Resources Defense Council commented that the scope should be further expanded, asserting that Section 201 of the 2006 Appropriations Act req uires a “clear ban on intentional dosing toxicity stud[ies] on pregnant women or children

. ” Natural Resources Defense Council believes the “intent to submit” requirement in the scope provisions creates a loophole that could allow third parties to conduct i ntentional dosing toxicity studies with pregnant women or children. Response: Notwithstanding the authority provided in the 2006 Appropriations Act and in FIFRA, EPA does not believe that the 2006 Appropriations Act compels the broad ban advocated by NR DC. The human studies that Congress was primarily concerned about during the debates leading up to the passage of the 2006 Appropriations Act were those that involved intentional testing of pesticides on human subjects and EPA’s consideration or reliance o n those studies. EPA was prohibited from relying on any human studies until it issued a rule in accordance with the requirements of the 2006 Appropriations Act. This context implies that a reasonable interpretation of what Congress was requiring EPA to d o was to issue a rule covering human studies involving exposure to pesticides when those studies were submitted to EPA. Nothing in the legislative history indicates that Congress intended EPA’s rule to apply to studies that were outside of EPA’s purview. As mentioned above, EPA has authority, and believes it is reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides that are submitted to EPA under other laws that it administers. This rule covers studies that are within EPA’s purview. However, to expand the 2006 rule to impose prohibitions or conditions on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies*** EO 12866 Draft

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Page of involving unregistered pesticides that are conducted outside the Un ited States) is clearly outside EPA’s authority. Moreover, such a prohibition, if enforceable, could have the unintended effect of prohibiting valuable research.
2. Comments about revised rule language on representative subjects and statistical analysis
Co mment: The American Chemistry Council (for the Antimicrobial Exposure Assessment Task Force II), the Agricultural Handler Exposure Task Force, and CropLife America commented on the new regulatory text at §26.1603(b)(2)(ii and iii) which would require EPA After considering these comments, EPA has decided to finalize the rule text relating to scope as it was proposed, i.e., expanding the scope to cover research involving intentional exposure of human subje cts to pesticides where that research is submitted, or intended to be submitted, to EPA under any regulatory statute that EPA administers. As noted in
E PA’s Response to Comments document , EPA no longer regards the 2006 Appropriations Act as authority for this rule . Therefore, EPA believes it is unnecessary to address whether the 2006 Appropriation Act either requires or does not allow EPA to establish a different scope for this rule

. Nevertheless, EPA regards FIFRA as providing adequate legal authority for the scope of research covered by this final rule. FIFRA sections 3(a) and 25(a) provide EPA with authority to regulate pesticides, including research involving intentional exposure of a human subject to a substance, when the substance is being tested as a “pesticide.” That includes research intended for submission to EPA, whether under FIFRA, FFDCA or any of EPA’s other regulatory authorities. EPA believes it makes sense to apply the same standards to all human studies involving pesticides submitted t o EPA. On the other hand, EPA believes that it is not in the public interest to extend the prohibition against research involving intentional exposure of*** EO 12866 Draft

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Page of children or pregnant women to pesticides beyond the scope delineated in the proposed rule because suc h a prohibition, if enforceable, could have the unintended effect of prohibiting valuable research.

. B. Comments on I nclusion of NAS

- D erived C onsiderations Two commenters questioned whether new regulatory text proposed at §26.1603(b)(2)(ii and iii) would change the ways in which EPA has been reviewing proposed studies to measure exposures experienced by people who mix, load, or apply pesticides. As proposed , EPA would have been required to consider whether the proposed research includes representat ive study populations for the endpoint in question and has adequate statistical power to detect appropriate effects , and the new . These commenters expressed the same concern regarding the proposed regulatory text at §26.1703(a)(2 and 3 ) ) , which would require EPA to con sider these factors in determining whether to rely on the research . The American Chemistry Council argues that these criteria are “inapposite to the types of exposure research being conducted by AEATF and others...” The Agricultural Handler Exposure Task Force and CropLife America claim that the criteria are “more appropriate for clinical studies and do not translate directly to occupational exposure studies...” All three commenters sought clarification on how the criteria would apply to exposure stu dies. They expressed concern that adding these criteria to the rule would impose additional burdens on sponsors of exposure studies. Specifically, they asked that EPA confirm that it does not expect any effect from the adoption of these criteria on the continued approval of the worker exposure studies. Response: As discussed in the preamble to the proposed rule, this language is a combination of recommendations 3

- 1(b) and 5

- 1(c) from the 2004 Report by the National Research Council of the National Ac ademies of Science (NAS) titled Intentional Human Dosing Studies for EPA Regulatory Purposes (hereafter, NAS Report). EPA disagrees with the assertion*** EO 12866 Draft

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Page of that the criteria on representative populations and statistical power are not applicable to exposure
stu dies. Although the NAS recommendations on which these criteria are based were drafted with an eye toward toxicological testing, the scientific concepts embodied have broad applicability to scientific testing. Further, the language used by EPA in this rul e is generic in nature and not limited to toxicological testing. Terms such as “effect” or “endpoint,” when used without a modifier, can refer to any result to be examined in a scientific study. Thus, EPA believes the criteria are potentially applicable to all types of intentional exposure human studies covered by this rule. Nonetheless, EPA does not believe that adoption of these criteria will impose additional burdens on sponsors of the type of exposure studies referenced by the commenters. Even thou gh the NAS’ recommendations about representative study populations and adequate statistical power were not specifically articulated in EPA’s 2006 Final Rule (40 CFR 26), EPA has applied the principles underlying these recommendations, as well as the genera l NAS directive that studies should be designed and conducted in accordance with appropriate scientific standards and practices, in its consideration of human research since the promulgation of the rule in 2006. Thus, EPA does not anticipate any effect fr om adding these NAS recommendations to the 2006 rule on the Agency’s consideration of ongoing or future worker occupational exposure studies, except that EPA’s consideration of these issues will be even more transparent. As EPA repeatedly noted in the pre amble to the proposed rule, the proposed amendments essentially codify the scope and approach used under the 2006 rule in EPA’s science and ethics reviews of human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this comment response, EPA further clarifies the applicability of the criteria at issue to exposure studies. The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is*** EO 12866 Draft

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Page of relevant to any scientific endeavor in which less than the full population is examined or tested and for which valid extrapolation to a larger population is desired. EPA does not agree that the language could be construed as not applying to exposure studies, given that the representativeness of the sample is a rele vant consideration in evaluating, for proposed and completed research, whether the observed effects of the completed study would predict the responses of a larger population. In evaluating what is a representative population for a study, the NAS emphasi zed that EPA should focus on the “objectives of the study” (NAS Report, p. 77). For a study intended to measure worker exposure, representation of the general workforce would be evaluated with respect to, among other characteristics, types of equipment use d, the monitored subjects’ work experience, and work situations that could be defined by factors such as geographic location or crop. The exposure studies to date have been representative of the workforce studied in this manner. As discussed below, EPA c onsiders explicit adoption of the representative population criterion as a codification of existing practice and does not believe that adoption of this criterion will impose any additional burden on sponsors of exposure studies. The commenters appear to be concerned that the representative population consideration will require that a study use a fully statistically random sample imposing additional burdens on sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular meth od for demonstrating representativeness; rather, the rule only requires that EPA, in determining the scientific validity and reliability of proposed and completed studies, “consider” representativeness. Moreover, as noted above, the NAS Report stressed th at representativeness was a study

- specific determination based on the objectives of the study. For exposure studies, a fully statistically random sample may neither be feasible nor, in some cases, desirable. Alternate sampling strategies can produce a s ample which represents a broader range of conditions than*** EO 12866 Draft

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Page of would be present in a random sample of similar limited size and thus may produce results that reasonably approximate real world exposures with respect to the overall magnitude and “spread.”
For exa mple, the Agricultural Handler Exposure Task Force (AHETF) and the Antimicrobial Exposure Assessment Task Force II (AEATF

- II) are using a “purposive diversity selection” sampling procedure in their exposure research. This procedure attempts to produce a s ample which incorporates some random elements (where feasible); the resulting sample can be more useful from a regulatory perspective in that it more likely represents the range of conditions and situations under which exposure occurs. This approach meets the objectives of the study and is consistent with the representative population consideration requirement. The Agency recognizes that random sampling, in many cases, may be considered to be the “gold

- standard” for demonstrating representativeness in a s tatistical sense. Nonetheless, for the reasons stated above, the use of alternate sampling strategies can, under certain circumstances, produce a sample which is sufficiently representative given the study objectives. The statistical power conside ration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is also a relevant concept for both toxicology and exposure studies. Statistical power evaluates how accurately a study can measure the effect being studied. For example, a toxicity study typically evaluate s whether a chemical causes an effect by comparing the responses of the treated and untreated groups. In some instances , treated and untreated groups will not show different (statistically significant) responses, even though the chemical actually does cau se the effect. The statistical “power” of a toxicological study can be thought of as the ability of the study to detect a difference between treated and untreated groups given that a difference of a defined magnitude does exist. Statistical power can b e an important concept in evaluating the design of toxicity studies since it helps in ascertaining the degree to which the study will be able to find a significant difference between treated and untreated groups , when a difference of defined*** EO 12866 Draft

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Page of magnitude does indeed exist. Obviously, for completed toxicological studies, the statistical power of the study is an irrelevant consideration if the study found a statistically significant relationship between exposure and an effect. Conversely, when a completed toxi city study finds no such relationship, evaluating the statistical power of the study design becomes relevant because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of the result. As to exposure studies, statistica l power could have applicability to an exposure study design if, for example, that study attempted to evaluate the relationship between dermal or inhalation exposure and an exposure variable. The statistical power of such an exposure study would also be a consideration if that study was interpreted as showing that there is no relationship between the tested variables. EPA has required various statistical analyses of exposure studies under the 2006 rule other than statistical power analyses. For exampl e, EPA has relied upon standard regression analyses and calculation of summary statistics (e.g. means and percentiles) in evaluating the merit of worker exposure studies. EPA expects that those or similar analyses will, in all probability, suffice going forward under the requirement in the revised rule that researchers have a general obligation to ensure that their research is “designed and conducted in accordance with appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 26.1703(a) (EPA must determine that “data were derived in a manner that makes them scientifically valid and reliable”). Therefore, EPA does not believe that the revised rule will impose any additional burden on sponsors of exposure studies with re gard to statistical analyses generally. Finally, even if either or both of these criteria turn out to be inapplicable to some studies covered by the rule, that fact should not result in a significant burden for either EPA, the HSRB, or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 26.1703, if in*** EO 12866 Draft

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Page of reviewing a study, EPA or the HSRB determines that either or both of the criteria are not applicable to that particular study, a notation by EPA or the HSRB of the reason for such determ ination would constitute appropriate consideration of the criteria in accordance with the rule. Similarly, for a person submitting a study design or a completed study to EPA and the HSRB for review, an explanation of why certain criteria are inapplicable to the study submitted may satisfy the rule’s requirements.
B. Comments outside of the scope of the proposed rulemaking As explained previously , EPA has decided not to final ize the proposed text detailing specific scientific and ethical aspects of proposed and completed research

– including the text
propos ed at §26.1603(b)(2)(ii and iii) and at §26.1703(a)(2 and 3)

– that EPA and the HSRB would have been required to consider. Although not finalizing the proposed text makes the comments moot, EPA notes that, under the 2006 rule as amended through this rulem aking, EPA does not intend to change the way in which it reviews exposure research with respect to the inclusion of representative populations or the statistical power of the study although EPA will consider whether further guidance on this issue is needed

. C. Other Comments, Including Comments on Narrowing the Scope of the 2006 Rule to Include Only Intentional Dosing Studies The remainder of the public comments addressed issues beyond the scope of the proposed rulemaking. These comments included argumen ts that the burden of the requirements of the 2006 rule (as opposed to any burden connected to this rulemaking) are unjustified, and assertions that EPA ’s i nterpretation in the 2006 rule of t he language “research involving intentional exposure of a human subject” from the 2006 Appropriations act was incorrect. EPA’s interpretation in the 2006 rule of the language “research involving intentional exposure of a human s ubject” incorrectly expanded the scope of the rule beyond that required in the 2006*** EO 12866 Draft

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Page of Appropriations Act, which addressed only “intentional dosing human toxicity studies.” The commenters are referring to section 26.1101(a) of the 2006 rule, which defines th e scope of the rule as applying to “all research initiated after April 7, 2006 involving intentional exposure of a human subject ...” As EPA explained in the preamble to the proposal for the 2006 rule, this scope was intended to capture “all intentional dos ing human studies intended for submission to EPA under the pesticide laws”, i.e., studies involving intentional dosing to measure a toxic effect and studies involving intentional dosing to measure other scientific endpoints , like exposure. 70
FR 53838 at 53845 (September 12, 2005). Additional discussion in the preambles to the proposed and final rules further explains what studies EPA intended to be included within the scope of the 2006 rule. 70 FR at 53845

- 47; 71 FR 6138, 6146, 6149

- 50 (February 6, 2006 ). Because these comments were directed at a prior rulemaking and EPA has not reopened these issues for reconsideration in this rulemaking, they are beyond the scope of this rulemaking and no response to them is appropriate at this time. EPA’s Response to Comments document, available in the docket for this action, explains in more detail why these comments are outside the scope of the c urrent rulemaking , and no response to them is required to finalize this rule. Nonethe less, EPA appreciates the concerns expressed by the commenters with regard to the burdens imposed by the 2006 rule and recognizes that there may be value in considering further amend ments to the 2006 rule in a way that reduces the burdens on investigators , e.g., by limiting the types of research that are subject to particular requirements of the rule

. V . Final Rule As noted above, I V . Conclusion

EPA received relatively few comments on the proposed rule, and most many of the comments received did not even address the amendments in the proposal. For the reasons noted above previously , the comments that did address the proposal do not , for the most part, merit any*** EO 12866 Draft

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Page of change to the amendments, as proposed. As explained in the preamble to the proposed rule, EPA proposed these amendments because they further Accordingly, with the excep tion of the 2006 rule ’ s goal of ensuring that EPA does not rely on research involving in tentional
exposure inclusion of human subjects to pesticides that is not ethically conducted or that is not scientifically sound the NAS

- derived considerations in proposed sections 26.1603 and they are consistent with the language and purposes of the 2006 Appropriations Act. Many of the amendments are codifications of the manner in which EPA and HSRB have interpreted and implemented the 2006 rule. For these reasons 26.1703 , EPA is finalizing the rule in the same form as proposed in 7 6 FR 5735, 5736

- 57 55 (February 2, 2011) . A detailed explanation of for the reasons stated herein and in the preamble to the proposed rule. Given the amendments is provided reasons discussed i n the preamble of Unit I II. , EPA is not including the proposed rule. NAS

- derived considerations and substituting more general language requiring consideration of ethical and scientific requirements in the Common Rule in reviewing proposed and final human research. This approac h allows EPA to continue to review such research consistent with the 2004 NAS Report recommendations while not interfering with HHS’ and OSTP’s initiative to harmonize the federal government’s standards on human research.
V I V . Statutory and Executive Ord er Reviews
A. Executive Order 12866: Regulatory Planning and Review and Executive Order 13563: I

mproving Regulation and Regulatory Review Under Executive Order 12866 (58 FR 51735, October 4, 1993), this action is a “significant regulatory action , ” because OMB the Office of Management and Budget (OMB) determined that it would raise novel legal or policy issues arising out of legal mandates, the President’s priorities, or the principles set forth in the Executive Order. Accordingly, EPA submitted this ac tion to the Office of Management and Budget ( OMB ) for review under*** EO 12866 Draft

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Page of Executive Order s 12866 and 13563 (76 FR 3821, January 21, 2011). A ny changes made in response to OMB recommendations have been documented in the docket for this rulemaking as required by the Executive Order. The incremental costs of these amendments both to industry and to EPA are expected to be negligible. EPA has not, therefore, prepared a new economic analysis for this rulemaking. Because no research has been identified that is outside the scope of the 20 06 rule but that would be within the scope of these 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 renewal of the Informatio n 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 i n the docket

. B

. Paperwork Redu ction Act (PRA) This action does not impose any new information collection burden that would require additional review or approval by OMB . However, the Office of Management and Budget ( OMB ) has previously approved the information collection requirements contained in the existing regulations a t 40 CFR part 26 under the provisions of the Paperwork Reduction Act ( PRA ) , , 44 U.S.C. 3501 et. seq
. . , and has assigned OMB Control No

. 2070

- 0169 (EPA ICR No

. 2195)

. The OMB control numbers for EPA’s regulations in 40 CFR are listed in 40 CFR part 9. 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 require about 598 hours per study at a cost of $45,927 per study, for a total estimated annual burden for affected entities of 20,332 hours at an estimated cost of $1,561,518

. In addition, EPA estimated annual submission of 20 repo rts of*** EO 12866 Draft

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Page 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 total estimate of the annual respondent burden and cost was the sum of these two estimates, or 2,572 hours/$1,579,098

. These paperwork burden and cost estimates include activities related to initial rule familiarization, as well as activities that researchers would have to perform even without the Agency’s rulemaking in this area, such as developing a protocol and mainta ining 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 su bmissions was estimated to be 44 hours/$3,158 per study, or 880 hours/$63,160 per year

. The total estimate of the annual burden on EPA was the sum of these two estimates, or 6,932 hours/$636,000 per year. In no year since promulgation of the 2006 rule have more than 7 protocols been submitted to EPA by industry; the average annual rate 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 an d 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 suggest an upward trend, and nothing in these amendments is believed likely to lead to a significant change in the ra te of protocol and study submissions. An agency may not conduct or sponsor, and 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. Regulatory Flexibility Act (RFA) The Regulatory Flexibility Act RFA , 5 U.S.C. 601 et seq
. , generally requires an Agency to prepare a regulatory flexibility analysis of any rule subject to n otice and comment ru lemaking*** EO 12866 Draft

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Page of requirements under the Administrative Procedure Act or any other statute unless the agency certifies that the rule will not have a significant economic impact on a substantial number of small entities. Small entities include s mall businesses, small organizations and small governmental jurisdictions

. For purposes of assessing the impacts of today’s rule on small entities, small entity is defined as: ( 1 ) a small business as defined by the Small Business Administration’s (SBA) regulations at 13 CFR 121.201 , which is based on either the maximum number of employees or on the sales for small bus inesses in each industry sector, as defined by a 6

- digit NAICS code, and for this rule is p esticide and other agricultural chemical manufac turers (NAICS code 325320) who sponsor or conduct human research with pesticides, or other entities (NAICS code 541710) that sponsor or conduct human research with pesticides, and Institutional Review Boards who review human research with pesticides to ens ure it meets applicable standards of ethical conduct; ( 2 ) a small governmental jurisdiction that is a government of a city, county, town, school district or special district with a population of less than 50,000 ; or ( 3 ) a small organization that is any n ot

- for

- profit enterprise which is independently owned and operated and is not dominant in its field

. After considering the economic impacts of this final rule on small entities, I certify that this action will not have a significant adverse economic impact on a substantial number of small entities. Because no small entities have been identified that are directly regulated by these amendments, EPA has not attempted to reduce the impact of this final rule on small entities

. Public c omments were explicitly invited on all aspects of the proposal and its impacts on small entities , but no such comments were received

. D

. Unfunded Mandate s Reform Act (UMRA) Title II of UMRA, 2 U.S.C. 1531

- 1538, establishes requirements for Federal agencies to*** EO 12866 Draft

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Page of assess the effects of their regulatory actions on State, local, and tribal governments and the private sector. This rule does not contain a Federal ma ndate 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. Thus, this rule is not subject to the requirements of sections 202 or 205 of
UMRA. This rule is also not subject to the requirements of section 203 of UMRA, because it contains no regulatory requirements that might significa ntly or uniquely affect small governments. These amendments are unlikely to affect State, local, and tribal governments at all, and are likely to affect the private sector only trivially

. E

. Executive Order 13132 ( : Federalism ) This action does not have federalis m implications . It because i t will not have substantial direct effects on the States, on the relationship between the national government and the States, or on the distribution of power and responsibilities among the various levels of government, as

s pecified in Executive Order 13132 (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 human subjects, and refines the standards fo r EPA oversight of and reliance on such research

. Thus, Executive Order 13132 does not apply to this action. In the spirit of Executive Order 1313 2, and consistent with EPA policy to promote communications between EPA and State and local governments, EPA specifically requested
comment s on th e proposed action from State and local officials. EPA did not receive any such
comments.
F

. Executive Order 13175 : Consultation and Coordination with Indian Tribal Governments This action does not have tribal implications as specified in Executive Order 13175 (65 FR 67249, November 9, 2000)

. This action would will not have substantial direct effects on Indian Tribes, will not significantly or uniquely affect the communities of Indian Tribal*** EO 12866 Draft

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Page of governments, and does not involve or impo se any requirements that affect Indian Tribes

. Thus , Executive Order 13175 does not apply to this action

. G

. Executive Order 13045: Protection of Children from Environmental Health Risks and Safety Risks EPA interprets EO Executive Order 13045 (62 FR 19885, April 23, 1997), as applying only to those regulatory actions that concern health or safety risks, such that the analysis required under section 5

- 501 of the Order has the potential to influence the regulation

. This action is not subj ect to EO Executive Order 13045, because it does not establish an environmental standard intended to mitigate health or safety risks, nor 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 exposure of human subjects, and prohibits the conduct of or EPA reliance on any such research involving subjects who are children, or pregnant or nursing

women . These provisions would not be affected by the amendments.
H

. Executive Order 13211: Actions Concerning Regulations That Significantly Affect E nergy Supply, Distribution , or Use This action is not a “significant regulatory action” as defined in Executive Order 13211 (66 FR 28355, May 22, 2001), because it is not likely to have a significant adverse e ffect on the supply, distribution, or use of energy.
I

. National Technology Transfer and Advancement Act (NTTAA) Section 12(d) of the National Technology Transfer and Advancement Act of 1995 ( “ NTAA ” ), Public Law No. 104

- 113, 12(d) ( NT T AA , 15 U.S.C. 272 note ) , directs EPA to use voluntary consensus st andards in its regulatory activities unless to do so would be inconsistent with applicable law or otherwise impractical. Voluntary consensus standards are technical standards (e.g., materials specifications, test methods, sampling procedures, and business*** EO 12866 Draft

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Page of practices) that are developed or adopted by voluntary consensus standards bodies. NTTAA directs EPA to provide Congress, through OMB, explanations when the Agency decides not to use available and applicable voluntary consensus standards. T his action doe s not involve any technical standards . Therefore, EPA did not consider the use of any voluntary consensus standards.
J

. E xecutive O rder 12898: Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations Executive Order (EO) 12898 ( 59 FR 7629, February 16, 1994) establishes federal executive policy on environmental justice. Its main provision directs federal agencies, to the greatest extent practicable and permitted by law, to make environmental justice part of their

m ission by identifying and addressing, as appropriate, disproportionately high and adverse human health or environmental effects of their programs, policies, and activities on minority populations and low

- income populations in the United States. EPA has de termined that t his final rule will not have disproportionately high and adverse human health or environmental effects on minority or low

- income populations, because it does not affect the level of protection provided to human health or the environment. Th is rule does not entail special considerations o f environmental justice related issues. The strengthened protections for human subjects participating in covered research established in the 2006 rule will not be altered by these amendments

. VI. Congre ssional Review Act The Congressional Review Act, 5 U.S.C. 801 et seq
. , as added by the Small Business Regulatory Fairness Act of 1996, generally provides that before a rule may take ef fect, the

a gency promulgating the rule must submit a rule report , which includes a copy of the rule, to each House of the Congress and the Comptroller General of the United States. Pursuant to t he*** EO 12866 Draft

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Page of Congressional Review Act, 5 U.S.C. 801 et seq
. , EPA will submit a report containing this rule and other required information to the U.S. Senate, the U.S. House of Representatives, and the Comptroller General of the United States prior to publication of the rule in the Federal Register

. A Major rule cannot take effect until 60 days after it is published in the Federal Register

. This action is a n ot a “major rule” as defined by 5 U.S.C. 804(2). List of Subjects in 40 CFR P art 26 Environmental protection, Administrative practice and procedures, Human r esearch, Pesticides and pests. Dated:

_________________

____________________________________ Administrator.*** EO 12866 Draft

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Page of Therefore, 40 CFR chapter I will 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. 531; and 42 U.S.C

. 300v

– 1(b).
2

. Amend § 26.1101 as follows:

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

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

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

. § 26.1101 To what does this subpart apply? (a) Except as provided in paragraph (c) of this section, this subpart 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 research, 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 Rodenticide 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

researc h for later inspection by EPA under FIFRA (7 U.S.C

. 1 36

- 136y) or section 408 of
FFDCA (21 U.S.C

. 346a); or (2) A pesticide if, at any time prior to initiating such research, any person who conducted or supported such research intended either to submit res ults of the research to EPA for consideration in connection with any action that may be performed 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 th e research for later inspection by EPA under any regulatory*** EO 12866 Draft

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Page of statute administered by EPA other than those statutes desi gnated in paragraph (a)(1) of this section

. (b) For purposes of determining a person’s intent under paragraph (a) of this section , EPA ma y consider any available and relevant information

. EPA 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 me mber of a class of people who, or whose products or activities, are regulated by EPA and, at the time the research was initiated, the results of such research would be relevant to EPA’s exercise of its regulatory authority with respect to that class of peo ple, products, or activities.
* * * * * (d) The Administrator retains final judgment as to whether a particular activity is covered by this subpart.
* * * * * 3

. In § 26.1102 , r evise paragraph s (a) and (c) to read as follows: § 26.1102 Definitions. (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) Pesticide means any substance or mixture of substances meeting the definiti on in 7
U.S.C

. 136(u) [Federal Insecticide, Fungicide , and Rodenticide Act , section 2(u)]

. § 26.11 11 [AMENDED] 4

. In § 26.1111 r emove from paragraph (a)(4) the phrase “or the subject’s legally*** EO 12866 Draft

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Page of authorized representative”

. 5

. In § 26.1116 revis e the introductory text of th e section to read as follows: § 26.1116 General requirements for informed consent. No investigator may involve a human being as a subject in research covered by this subpart unless the investigator has obtained the legally e ffective informed consent of the subject

. An investigator must seek such consent only under circumstances that provide the prospective subject sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion o r undue influence

. The information that is given to the subject must be in language understandable to the subject

. No informed consent, whether oral or written, may include any exculpatory language through which the subject is made to waive or appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence.
6

. Revise § 26.1117 to read as follows: § 26.1117 Documentation of informed consent. (a) Informed consent must be documented by the use of a written consent form approved by the IRB and signed by the subject

. A copy shall be given to the subject. (b) The consent form may be either of the following: (1) A written consent document that emb odies the elements of informed consent required by § 26.1116

. This form may be read to the subject, but in any event, the investigator must give the subject adequate opportunity to read it before it is signed; or (2) A short form written consent document stating that the elements of informed consent required by § 26.1116 have been presented orally to the subject

. When this method is used, there
must be a witness to the oral presentation

. Also, the IRB shall approve a written summary of what is to be said to the subject

. Only the short form itself is to be signed by the subject

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Page of H owever, the witness must sign both the short form and a copy of the summary, and the person actually obtaining consent must sign a copy of the summary

. A copy of the summary must be given to the subject, in addition to a copy of the short form.
7

. Revise the heading for subpart L to read as follows: Subpart L

— Prohibition of Third
- Party Research Involving Intentional Exposure to a Pesticide of Human Subjects W ho are Children or Pregnant or Nursing Women
8

. Revise § 26.1201 to read as follows: § 26.1201 To what does this subpart apply? This s ubpart 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 human research for consideration in connection with an action th at 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 performed by EPA under any regulatory
statute administered by EPA. § 26.1 3 02 [AMENDED] 1 0

. In § 26.1302 remov e the word “shall

. ” § 26.1 5 02 [AMENDED] 1 1

. Amend § 26.1502 as follows:

a . In the first sentence of p aragraph (a) remove the period after the phrase “during an*** EO 12866 Draft

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Page of inspection” and add in its place a comma; and b

. In the second sentence of paragraph (a) remove the phrase “The A gency” and add in its place “EPA.” c. In the last sentence of the introductory text of paragraph (b) remove the phrase “The
A gency ” and add in its place “EPA.” § 26.1 5 0 5 [AMENDED] 1 2

. In § 26.1505 remove from the last sentence , the phrase “§ 26.1502(c)” and add in its place “§ 26.1502(b)(4).” § 26.1 5 0 7 [AMENDED] 1 3

. In § 26.1507 re mov e from the last sentence, the phrase “The A gency” and add in its place “EPA”. § 26.1 6 0 1
- 26. 1603 [REDESIGNATED] 1 4

. Amend s ubpart P of this part by redesignating §§ 26.1601 through 26.1603 as §§ 26.1603 through 26.1605.

1 5

. 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 the fina l 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. § 26.1602 Definitions. The definitions in § 26.1102 apply to this subpart as well.*** EO 12866 Draft

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Page of 1 6

. Amend newly redesignat ed § 26.1603 as follows:

a . Remove p aragraphs (a) and (e). b

. Redesignate paragraphs (b) thr ough (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 m ust review all proposals for new human research submitted under § 26.1125 in a timely manner. (b) In reviewing proposals for new human research submitted under § 26.1125, the EPA Administrator must consider and make determinations regarding the proposed research, including: the ethical aspects and scientific validity and reliability of the proposed research under the requirements of the Common Rule as codified in 40 CFR Part 26, Subpart A, except as modified in 40 CFR § § 26.1116 and 26.1117

. (1) Whether the research would be likely to produce data that address an important scientific or policy question that cannot be reso lved on the basis of animal data or human observational research. (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 populat ions for the endpoint in question

. (iii) Have adequate statistical power 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*** EO 12866 Draft

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Page of Administrator must consider and make determinations regarding ethical aspects of the proposed research , including: (1) Whether adequate information is available from prior animal studies or from other sources to assess the potential risks to subjects in the proposed research

. (2) Whether the research proposal adequately identifies anticipated risks to hum an subjects and their likelihood of occurrence, minimizes identified risks to human subjects, and identifies likely benefits of the research and their distribution

. (3) Whether the proposed research presents an acceptable balance of risks and benefits

. I n making this determination for research intended to reduce the interspecies uncertainty factor in a pesticide risk assessment, the Administrator must consider Recommendation 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 Purposes: Scientific and Ethical Issues .” (4) Whether subject selection will be equitable

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

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

. (7) If any person from a vulnerable population may become a subject in the proposed research, whether there is a convincing justification for sele ction of such a person, and whether measures taken to protect such human subjects are adequate

. (8) If any person with a condition 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 such a person, and whether measures taken to protect such human subjects are adequate

. (9) Whether any proposed payments to subjects are consistent with the principles of*** EO 12866 Draft

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Page of justice and respect for persons, and wheth er they are so high as to constitute undue inducement or so low as to be attractive only to individuals who are socioeconomically disadvantaged

. (10) Whether the sponsor or investigator would provide needed medical care for injuries incurred in the propos ed research, without cost to the human subjects. (d ( c ) With respect to any research or any class of research subject to this subpart , the EPA Administrator may recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for the protection of human subjects.
* * * * * (h) EPA must provide the submitter of the proposal copies of the EPA and Human Studies Review Board reviews.
1 7

. Amend newly redesignated § 26.1604 by revising paragraph (a) to read as follows: § 26.1604 EPA review of completed human research. (a) When considering, under any regulatory statute it administers, data from completed research involving intentional exposure of humans to a pesticide, EPA must thoroughly review the material submitted under § 26.1303, if any, and other available, relevant information and document its conclusions regarding the scientific and ethical conduct of the research.

*****
1 8

. 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 must consider the scientific merits and ethical aspects of the proposed research, including all elements listed required in § 26.1603(b) and (c) and any additional conditio ns recommended pursuant to § 26.1603( d c ). § 26.1607 Human Studies Review Board review of completed human research.*** EO 12866 Draft

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Page of In commenting on reports of completed research submitted to it by EPA, the Human Studies Review Board must consider the scientific merits an d ethical aspects of the completed research, and must apply the appropriate standards in s ubpart Q of this part. 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
i n EPA Actions
2 0

. 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 intentiona l exposure of human subjects to any substance. (b) For decisions under any regulatory statute administered by EPA other than those statutes designated in paragraph (a) of this section, this subpart applies to research involving intentional exposure of hum an subjects to a pesticide. § 26.1702 Definitions. The definitions in § 26.1102 and § 26.1202 apply to this subpart as well. § 26.1703 Prohibitions applying to all research subject to this subpart. (a) Prohibition of reliance on scientifically invalid r esearch

. EPA 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 important for EPA decision

- making, that the data were derived in a manner that makes them scientif ically valid and reliable, and that it is appropriate to use the data for the purpose proposed by EPA

. In making such determinations, EPA must consider: (1) Whether the research was designed and conducted in accordance with appropriate scientific s tandards and practices prevailing at the time the research was conducted

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Page of (2) The extent to which the research subjects are representative of the populations for the end point or endpoints in question. (3) The statistical power of the data to support the scientific conclusion EPA in tends to draw from the data. (4) In a study that reports only a No Observed Effect Level (NOEL) or a No Observed Adverse Effect Level (NOAEL), whether a dose level in the study gave rise to a biological effect, thereby demonstr ating that the study had adequate sensitivity to detect an effect of interest. (b) Prohibition of reliance on research subject to this subpart involving intentional exposure of human subjects who are pregnant women (and therefore their fetuses), nursing women, or children

. Except as provided in § 26.1706, EPA must not rely on data from any research subject to this subpart involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nurs ing woman, or a child. § 26.1704 Prohibition of reliance on unethical human research with non
- pregnant, non nursing 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 § 26.170 6, EPA must not rely on data from any research subject to this section if there is clear and convincing evidence that: (1) 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 (2) The conduct of the research was deficient 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

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Page of (c) This prohibition is in addition to the prohibitions in § 26.1703. § 26.1705 Prohibition of reliance on unethical human research with non
- pregnant, non nursing adults initiated a fter April 7 , 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 research subject to this subpart, that: (1) Was initiated after April 7 , 2006

. (2) Was subject, at the time it was conducted, either to subparts A through L of this part or to another codification of the Federal Policy for the Protection of Human Subjects, generally referred to as the “Common Rule

. ” (b) Except as provided in § 26.1706, EPA must not rely on data from any research subject to this section unless EPA determines that the research was conducted in substantial compliance with either: (1) All applicable provisions of subparts A through L of this part or codification of the Common Rule by another Federal department or agency ; or (2) If the research was conducted outside the United States, with procedures at least as protective of subjects as those in subparts A through L of this part or codif ication of the Common Rule by another Federal department or agency

. (c) Except as provided in § 26.1706, EPA must not rely on data from any research subject to this section unless EPA determines that the research was conducted in substantial compliance wi th either: (1) A proposal that was found to be acceptable under § 26.1603(c), and no amendments 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 impaire d their informed consent

. If EPA discovers that the submitter of the proposal materially misrepresented or knowingly omitted*** EO 12866 Draft

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Page of information that would have altered the outcome of EPA’s evaluation of the proposal under § 26.1603(c), EPA 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 amendments to or deviations from that proposal placed participants at increased risk of harm (based on knowled ge available at the time the study was conducted) or impaired their informed consent. (d) This prohibition is in addition to the prohibitions in § 26.1703.
21

. In paragraph (d) of § 26.1706 , remove the phrase “publishes” and add in its place “has publi shed

. ” [FR Doc

. ??

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– ??

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Page 1 of 20 EO12866_HumanSubjectsRevisions_RIN2070
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EO 12866 Review Draft
– As revised by EPA on 6/6/2012; 6:23 pm
. 

### EPA R esponse to Public Comment s on the Action : Proposed Rule; Revisions to EPA’s Rule on Protections for Subjects in Human Research Involving Pesticides (Tier 3; SAN 5448; ( RIN 2070
- AJ76) Comment Period : 2/ 2 /2011
- 4/4/2011 Docket ID No.: EPA

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I. Summary This document addresses comments received in response to the Notice of Proposed Rulemaking for Revisions to EPA’s Rule on Protections for Subje cts in Human Research Involving Pesticides , which published o n February 2, 2011 (76 FR 5735)

. EPA is proposing amending propos ed to amend the portions of its 2006 rules for the protection of human subjects of research applying to third parties who conduct or support research with pesticides involving intentional exposure of human subjects and to persons who submit the results of human research with pesticides to EPA. All comments appear in their entirety in the public docket for this rulemaking is accessible at http://www.regulations.gov , identified as “ EPA

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. EPA proposed several narrowly

- targeted changes to regulatory text as a result of a settlement agreement and specifically requested com ment on the proposed changes. The Agency received 10 comments in response to the N otice of P roposed Rulemaking

. 1 In As listed i n the index for Docket ID No. EPA

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- 000 1 through 6

- 000 6 are supporting documents for the rulemakin g . Documents 7

- 16 identified by document ID Nos. that end in

- 000 7 through

- 00 16 are public comments. Documents 17

- 55 identified by document ID Nos. that end in

- 00 17 through

- 00 55 are the 28 attachments to NRDC ’s submitted with the comment identified by the document ID No. that end s in

- 00 16 ( see discuss ion in Footnote 1 , below )

. II. Comments on Issues within the Scope of the Proposed Rulemaking EPA has identified only two significant issues raised by commenters that are within the sc ope of the proposed rulemaking. The first issue relate s to the proposed expansion of the rule to

1 One The comment from the Natural Resources Defense Council (NRDC) included 28 attachments. Although these attachments were are posted to the docket as individual comments, they are actually supporting the documents for NRDC’s provided by NRDC in support of their comments on this proposed rulem aking. The 28 documents also appear in other EPA dockets, but NRDC resubmitted them because they wanted all of the documents located in a single docket as part of their comments on this proposed rulemaking

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Page 2 of 20 cover human testing with pesticides submitted to EPA under any regulatory statute it administers, rather than just studies submitted to or considered by EPA under FIFRA or FFDCA. The second issue relate s to proposed revisions to § 26.1603(b)(2)(ii ) and ( iii ) and § 26.1703(a)(2 ) and ( 3) to require EPA to consider whether proposed and completed research includes representative study populations for the endpoint in question and has adequate stat istical power to detect appropriate effects. The specific comments, and EPA’s responses to those comments, are discussed below.

Document # EPA
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- 14 (Commenter: SC Johnson) 1. Comment: T he 2006 Appropriations Act does not require or authorize EPA to issue a rule that applies to studies performed outside of the FFDCA / FIFRA context

. “ “ Nothing in the Appropriations Act language required or authorized EPA to issue a rule that applies to studies performed outside of the FIFRA/FFDCA context. Thus, the Appropriations Act does not expand EPA’s rulemaking authority under FIFRA or the FFDCA such that EPA can issue a rule that regulates studies performed for submission under other statutes. EPA’s proposed revision exceeds the Agency’s statutory authority by attempting to regulate human testing under statutes beyond FIFRA and FFDCA. We therefore urge EPA not to adopt this proposed revision to the Rule.” (p 10).
See Document No. EPA

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- 00 14 Response: EPA’s authority for this proposed revision to the rule can be found in the 2006 Appropriations Act and in FIFRA. Section 201 of the 2006 Appropriations Act gives EPA the authority to issue a rule covering research involving the intentional dosing toxicity studies for pesticides. The 2006 Appropriations Act does not expressly limit EPA’s authority to studies conducted with pesticides that are intended to be submitted under only FIFRA and the FFDCA. FIFRA p rovides additional authority to issue rules covering the use of both unregistered and registered pesticides, regardless of whether that research is conducted for submission under FIFRA. Section 3(a) of FIFRA permits 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”. Section 25(a) authorizes EPA to “prescribe regulations to carry out the provisions of [FIFRA].” EPA has determined that this rule ensures that registered and unregistered pesticides are not used in a manner that would cause unreasonable adverse effects on the environment, including humans. Document # EPA
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- 16 (Commenter: Natural Resources Defense Council [NRDC]) (Commenter: SC Johnson).
EPA Response: EPA originally promulgated this rule under the authority of the 2006 Appropriations Act and FIFRA. Although the proposal cites the 2006 Appropriations Act as authority for th e proposed rule, it has been determined that section 201 of the 2006 Appropriations Act does not continue to impose any requirements on EPA. “ A federal appropriations act applies only for the fiscal year in which it is passed, unless it expressly provides otherwise .” Building & Constr. Trades Dep't v. Martin , 961 F.2d 269 (D.C. Cir.), cert. denied , 506 U.S. 915 (1992). Because section 201 contains no language providing for the*** EO 12866 Draft

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Page 3 of 20 continuing effect of its requirements, these requirements expired with FY 2006. Accordin gly, EPA is not citing the 2006 Appropriations Act as authority for th e final rule. Because the 2006 Appropriations Act is no longer in effect, this expansion of the scope of the 2006 rule is being promulgated on the authority of FIFRA alone. FIFRA give s EPA broad authority to regulate the sale, distribution, and use of pesticides . This authority encompasses regulation of the sale, distribution, and use of pesticides in human testing. The commenter is wrong to suggest that EPA interpreted the 2006 Appro priations Act as expanding its authority under FIFRA. The commenter is also incorrect to argue that EPA is asserting the authority under FIFRA to regulate testing under other EPA regulatory statutes. EPA is not in this rule generally regulating testing u nder all of its regulatory statutes; rather, it is regulating the use of pesticides in human testing, regardless of under what EPA regulatory regime that testing is done. FIFRA authority easily extends to cover such a sale, distribution, and use of pestic ides. EPA believes this expansion of the scope of the 2006 rule is warranted to assure that research involving intentional exposure of human subjects to pesticides will be treated in a similar manner under all of EPA’s regulatory statutes. 2. Comment: W hi le the expanded scope of the proposed rule “would narrow the loophole created by the ‘intention’ [to submit to EPA] standard, we would prefer that the loophole be closed by including a clear ban on the conduct of any intentional dosing toxicity study on pr egnant women or children. Section 201 [of the 2006 Appropriations Act] requires such a ban...” (p 6 ) )

. See Document No. EPA

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- 0016 Response: Notwithstanding the authority provided in the 2006 Appropriations Act and in FIFRA, EPA does not believe that the 2 006 Appropriations Act compels the broad ban advocated by NRDC. The human studies that Congress was primarily concerned about during the debates leading up to the passage of the 2006 Appropriations Act were those that involved intentional testing of pestic ides on human subjects and EPA’s consideration or reliance on those studies. EPA was prohibited from relying on any human studies until it issued a rule in accordance with the requirements of the 2006 Appropriations Act. This context implies that a reaso nable interpretation of what Congress was requiring EPA to do was to issue a rule covering human studies involving exposure to pesticides when those studies were submitted to EPA. Nothing in the legislative history indicates that Congress intended EPA’s r ule to apply to studies that were outside of EPA’s purview. (Commenter: Natural Resources Defense Council [NRDC]) 2

. EPA Response: Because NRDC’s argument is based on a statutory provision no longer in force (i.e., section 201 of the Appropriations Act), it is without merit

. As mentioned above, EPA has authority, and believes it is reasonable, to issue a rule that expands coverage of the 2006 rule to studies involving pesticides that are submitted to EPA under other laws that it administers. This rule covers studies that are within EPA’s purview. However, to expa nd the 2006 rule to impose prohibitions or conditions on the conduct of studies involving pesticides to which EPA would have no nexus (e.g., studies involving unregistered pesticides that are conducted outside the United States) is clearly outside EPA’s au thority. Moreover, such a prohibition, if enforceable, could have the unintended effect of prohibiting valuable research

. , for example, by preventing researchers from studying whether repellent impregnated bed nets reduced the incidence of malaria in Afric an villages.

2 See footnote 1, and use docket index to access individual attachments to this comment.*** EO 12866 Draft

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Page 4 of 20 Document # EPA
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- 11 (Commenter : Agricultural Handler Exposure Task Force [AHETF])
Document # EPA
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- 12 (Commenter: CropLife America [CLA]) Document # EPA
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- 13 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF]) 3. Comment: The AHETF, CLA , and AEATF cite concerns with the proposed new regulatory text at § 26.1603(b)(2)(ii ) and ( iiii) that would require EPA to consider whether the proposed research includes representative study populations for the endpoint in question and has adequate statistical power to detect appropriate effects. AEATF, AHETF, and CLA are similarly concerned with the proposed new regulatory text at § 26.1703(a)(2 ) and ( 3) that wo uld require EPA to consider these factors in determining whether to rely on completed research . The commenters’ argue that while these factors are pertinent to clinical studies they have little or no relevance to exposure studies. The specific comments from each commenter are quoted below.
See c omments: Document No. EPA

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- 0011 (Commenter: Agricultural Handler Exposure Task Force [AHETF]) ; Document N o. EPA

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- 0012 (Commenter: CropLife America [CLA]) ; Document No. EPA

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- 0013 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF])

. AHETF : “Another problem area for the propos ed amendments to the Rule concerns issues that require case

- by

- case consideration of the EPA and HSRB. In these situations, the proposed Rule cannot address the specificity needed for a given proposed study because of the contextual information and interpr etation required. Specifically, the proposed amendments (see Exhibit A, Subpart K, Section 26.1703), present an itemized list regarding EPA ‟ s consideration of reliance on data from research involving “intentional exposure” of human subjects... These criteri a require interpretation by subject matter experts on a case

by

- case basis and ... more specific definition of the terms “representative” and “statistical power” are necessary because these are protocol/study design

- specific aspects...Further, these criteria a re more appropriate for clinical studies and do not translate directly to occupational exposure studies...” ( EPA

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- 0011 (EPA

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CLA : “CLA notes and ag rees that these considerations play an important role in some human testing and we argue that subject matter experts need to provide input on a case

- by

- case basis. The study design aspects require specific considerations to be made by EPA (and the HSRB, as well as other federal advisors, i.e., the EPA FIFRA Scientific Advisory Panel). However, there appears to be unnecessary complexity added to the evaluation of occupational exposure studies. Many of these criteria are more appropriate for clinical studies and do not translate directly to occupational exposure studies whose purpose is to develop observational exposure data.” ( EPA

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Page 5 of 20 AEATF : “AE ATF is concerned, however, that proposed changes to 40 CFR Part 26, requiring representative study populations and ‘ adequate statistical power ’ are inapposite to the types of exposure research being conducted by AEATF and others, are too ambiguous to offer clarity and predictability to study sponsors and investigators, and impose unwarranted burdens in study sponsors and investigators without imp roving scientific validity or protection of human subjects.” ( EPA

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- 13, , p 3)

. Further on the topic of “representative study populations” and “adequ ate statistical power”, the commenters request that EPA “confirm that EPA does not expect any effect on the continued approval of the worker exposure studies” ( EPA

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- 13, , p 5).
EPA Response: As discussed in the preamble This comment is moot to the extent it refers to the NAS

- derived considerations included in proposed rule, this sections 26.1603 and 26.1703 because EPA has removed that specific language is a combination of recommendations 3

- 1(b) and 5

- 1(c) from the 2004 Report final rule. However, the co mments remain relevant because EPA will be guided in implementing the amended 2006 rule (as it has since its initial promulgation) by the National Research Council of the National Academies of Science (NAS) titled Intentional Human Dosing Studies for EPA Regulatory Purposes (hereafter, recommendations of the NAS Report ). EPA . Accordingly, EPA believes a detailed response to these comments is appropriate.
EPA disagrees with the assertion that the criteria NAS recommendations on representative populations and statistical power are not applicable to exposure studies. Although the NAS recommendations on which these criteria are based were drafted with an eye toward toxicological testing, the scientifi c concepts embodied have broad applicability to scientific testing. Further, the language used by EPA in this rule is generic in nature and not limited to toxicological testing. Terms such as “effect” or “ endpoint,” when used without a modifier, can refer to any result to be examined in a scientific study. Thus, EPA believes the criteria are potentially applicable to all types of intentional exposure human studies covered by this rule. Nonetheless, EPA does not believe that adoption of these criteria will impose additional burdens on sponsors of the type of exposure studies referenced by the commenters. Even though the NAS’ recommendations about representative study populations and adequate statistical power were not specifically articulated in EPA’s 2006 Final Rule (40 CFR 26), EPA has applied the principles underlying these recommendations, as well as the general NAS directive that studies should be designed and conducted in accordance with appropriate scientific standards and practices, in its consideration of human research since the promulgation of the rule in 2006

. Thus, EPA does not anticipate any effect from adding these NAS recommendations to the 2006 rule on the Agency’s consid eration of ongoing or future worker occupational exposure studies, except that EPA’s consideration of these issues will be even more transparent. As EPA repeatedly noted in the preamble to the proposed rule, the proposed amendments essentially codify the scope and approach used under the 2006 rule and used in EPA’s science and ethics reviews of human research involving pesticides. 76 FR at 5737, 5741, 5749, 5751. In the remainder of this comment response, EPA further clarifies the applicability of the criteria a t issue to exposure studies.*** EO 12866 Draft

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Page 6 of 20 The representative population consideration at §26.1603(b)(2)(ii) and §26.1703(a)(2) is relevant to any scientific endeavor in which less than the full population is examined or tested and for which valid extrapolation to a l arger population is desired. EPA does not agree notes that the language could be construed as not applying to exposure studies, given that the representativeness of the sample is a relevant consideration in evaluating, for proposed and completed research, whe ther the observed effects of the completed study would predict the responses of a larger population. In evaluating what is a representative population for a study, the NAS emphasized that EPA should focus on the “objectives of the study” in determini ng what is a representative population (NAS Report, p. 77). For a study intended to measure worker exposure, representation of the general workforce would be evaluated with respect to, among other characteristics, types of equipment used, the monitored subjects’ work experience, and work situations that coul d be defined by factors such as geographic location or crop. The exposure studies to date have been representative of the workforce studied in this manner. As discussed below, EPA considers explicit adoption of the representative population criterion as a codification of existing practice and does not believe that adoption of this criterion will impose any additional burden on sponsors of exposure studies. The commenters appear to be concerned that the representative population consideration will require that a study use a fully statistically random sample imposing additional burdens on sponsors of exposure studies. EPA disagrees. The rule language does not mandate a particular method for demonstrating representativeness; rather, the rule only requires that EPA, in determining the scientific validity and reliability of proposed and completed studies, “consider” representativeness. Moreover, as noted above, the NAS Report stressed that representativeness was Thus, representativeness i s a study

- specific determination based on the objectives of the study. For exposure studies, a fully statistically random sample may neither be feasible nor, in some c ases, desirable. Alternate sampling strategies can produce a sample which represents a broader range of conditions than would be present in a random sample of similar limited size and thus may produce results that reasonably approximate real world exposur es with respect to the overall magnitude and “spread.” For example, the Agricultural Handler Exposure Task Force (AHETF) and the Antimicrobial Exposure Assessment Task Force II (AEATF

- II) are using a “purposive diversity selection” sampling procedure in t heir exposure research. This procedure attempts to produce a sample which incorporates some random elements (where feasible); the resulting sample can be more useful from a regulatory perspective in that it more likely represents the range of conditions a nd situations under which exposure occurs. This approach meets the objectives of the study and is consistent with the representative p opulation consideration requirement. The Agency recognizes that random sampling, in many cases, may be considered to be the “gold

- standard” for demonstrating representativeness in a statistical sense. Nonetheless, for the reasons stated above, the use of alternate sampling strategies can, under certain circumstances, produce a sample which is sufficiently representative given the study objectives This approach meets the objectives of the study

. The Similarly, statistical power consideration at §26.1603(b)(2)(iii) and §26.1703(a)(3) is consideration s are also a relevant concept for both toxicology and exposure studies. Statistical power evaluates how accurately the extent to which a study design can measure the effect being studied. For example, a toxicity study typically evaluates whether a chemical causes an effect by comparing the responses of the treated exposed and untreated un exposed groups. In some*** EO 12866 Draft

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Page 7 of 2 0 instances , treated expos ed and untreated un expos ed gr oups will not show different (statistically significant) responses, even though the chemical actually does cause the effect. The statistical “power” of a toxicological study can be thought of as the ability of the study to detect a difference between treated expos ed and untreated un expos ed groups given that a difference of a defined magnitude does exist. Statistical power can be an important concept in evaluating the design of toxicity studies since it helps in ascertaining the degree to which the study will be able to find a significant difference between treated expos ed and untreated un expos ed groups , when a difference of defined magnitude does indeed exist. Obviously, for completed toxicological studies, the statistical power of the study is an irrelevant consideration if the study found a statistically significant relationship between exposure and an effect. Conversely, when a completed toxicity study finds no such relationship, evaluating the statistical power of the study design becomes relevant because, if statistical power is lacking, there is, by definition, low confidence in the accuracy of the result. As to exposure studies, statistical power could have applicability to an exposure study design if, for example, that study attempted to evaluate the relationship between dermal or inha lation exposure and an exposure variable. The statistical power of such an exposure study would also be a consideration if that study was interpreted as showing that there is no relationship between the tested variables. EPA has required various stati stical analyses of exposure studies under the 2006 rule other than statistical power analyses. For example, EPA has relied upon standard regression analyses and calculation of summary statistics (e.g. means and percentiles) in evaluating the merit of work er exposure studies. EPA expects that those or similar analyses will, in all probability, suffice going forward under the requirement in the revised rule that researchers have a general obligation to ensure that their research is “designed and conducted in accordance with appropriate scientific standards and practices . . . .” 40 CFR 26.1703(a)(1); see also 40 CFR 26.1703(a) ( EPA must determine that “data were derived in a manner that makes them scientifically valid and reliable ”). ”. 40 CFR 26.1703(a) . Therefore, EPA does not believe that the revised rule will impose any additional burden on sponsors of exposure studies with regard to statistical analyses generally. Finally, even if either or both o f these criteria turn out to be inapplicable to some studies covered by the rule, that fact should not result in a significant burden for either EPA, the HSRB, or the study sponsor. Similar to any of the other criteria in §§ 26.1603 and 26.1703, if in rev iewing a study, EPA or the HSRB determines that either or both of the criteria are not applicable to that particular study, a notation by EPA or the HSRB of the reason for such determination would constitute appropriate consideration of the criteria in acc ordance with the rule. Similarly, for a person submitting a study design or a completed study to EPA and the HSRB for review, an explanation of why certain criteria are inapplicable to the study submitted may satisfy the rule’s requirements.

III. Comments on Issues Outside of the Scope of the Proposed Rulemaking

Document # EPA
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- 07 ( Commenter: Anonymous ) 1. Comment: “ It is plausible that several of the current or future

- use pesticides might exert trans

- generational epigenetic effects that have not been studied yet. Families of applicators may be at highest risk for these kinds of effects. It is ha rd to imagine a scientifically valid*** EO 12866 Draft

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Page 8 of 20 study of these effects that would not require inclusion of children (but these children need not be exposed). A finer distinction should be made in the regulation between assent of children to participate in studies wh ere they will be exposed to a pesticide, and assent of children to participate in studies where someone else will be exposed to a pesticide.”
See Document No. EPA

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- 0007 (Commenter: Anonymous).
EPA Response: EPA’s 2006 r ule (currently, and as it is proposed to be amended) covers intentional exposure studies, not epidemiological or observational studies. The type of study that the commenter has described (studying pesticide applicator families) would likely be epidemiolog ical or observational and would not be covered by the rule. If, however, a protocol proposed intentional exposure research involving families with children or pregnant women, that research would not be permitted under EPA’s 2006 r ule. 2. Comment: “On anot her note, the phrasing of this proposed regulation is very broad and I worry could have a negative impact on research intended to intervene against the childhood obesity and diabetes epidemics, which disproportionately affect socially and environmentally d isadvantaged communities. Is consumption of a conventional apple in an obesity study considered an intentional exposure to pesticide? EPA should clarify in its final regulation that this statute does not limit assent of minors for studies involving convent ionally grown foods.”
See Document No. EPA

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- 0007 (Commenter: Anonymous).
EPA Response: EPA’s 2006 r ule and the proposed amended version of the r ule have a very clearly delineated scope. The r ule (currently, and as it is proposed to be amended) applies to intentional exposure studies intended for submission to EPA. It does not apply to dietary studies even if those studies involve consumption of a food item containing a pesticide residue, because such a study would not be considered an intentional exposure study. Document # EPA
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- 07 85
- 08 ( Commenter: Chris (no surname provided) ) 3. Comment: Commenter objects “to the requirement and reliance on animal research that continue to be present in research procedures required by the EPA.”
See Document No. EPA

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- 08 (Commenter: Chris (no surname provided))

. EPA Response: Comments concerning research with animals are beyond the scope of these revisions. Document # EPA
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- 09 ( Commenter: A. Sow ) 4. Comment : “ My comment is that p rotecting the environment will be great for our safety and our wellbeing. I am confident that by improving this regulation we will save the world. People will feel much healthier and have a longer life expectancy. We should e ducate people how not to use things that harm the environment and fine those who do not respect it. There are many social issues that are harming our environment right now and we can fix them if we all pitch in and do our part, we can change things all aro und us and in the world and make a*** EO 12866 Draft

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Page 9 of 20 differen ce. As Theodore Roosevelt said “ To waste and destroy our natural resources, to skin and exhaust the land instead of using it so as to increase its usefulness, will result in undermining in the days of our children the very prosperity which we ought by right to hand down to them. ” EPA's main role would be to protect and improve the environment. By doing so EPA will make sure that businesses and industries understand their environment responsibilities, enabling them to comply with legislation and good practice and to realize the great economic benefits for a good environmental practice ”
See Document No. EPA

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- 000 9 (Commenter: A. Sow).
EPA Response: EPA’s mission is to protect human health and the environment. Document # EPA
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- 10 ( Commenter: Anonymous ) 5. Comment: “ Human testing is never a safe or smart way to decide whether or not a product is safe. In the predicament that pesticides or other products that were being tested on human was unsafe; human beings being used as test subject would suffer unjustly. Products such as pesticides need to be made and created with all knowledge of being safe for use and tested on animals and not humans. There needs to be defined regulations on new products and how to go about make them safe for everyone. Exposing children to new p esticides with the intentions to see if they are safe or not makes absolutely no sense; doing this puts children in harm’s way. ”
See Document No. EPA

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- 0010 (Commenter: Anonymous)

. EPA Response: EPA is proposing narrowly

- targeted revision s to its rules for the protection of human subjects in research involving intentional exposure to pesticides

. General c omments on the scientific merit of conducting pesticide research with human subjects are beyond the scope of the proposed rulemaking . However, consistent with the commenter’s concern for children, the proposed rule does strengthen the provisions in EPA’s 2006 rule ensuring that children are not used as test subjects in research involving intentional exposure to pesticides. Comments with Common Focus Document # EPA
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- 11 (Commenter: Agricultural Handler Exposure Task Force [AHETF] ) Document # EPA
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- 12 (Commenter: Crop Life America [CLA] ) Document # EPA
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- 13 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF]) Document # EPA
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- 14 (Commenter: SC Johnson)
Documents

- 11,

- 12,

- 13 and

- 14 , from the AHETF, CLA , AEATF, and SC Johnson, are similar in content , so their major points and EPA’s resp onses to those points are discussed together.*** EO 12866 Draft

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Page 10 of 20 6. Comment: EPA should reconsider its interpretation of the definition of research involving intentional exposure of a human subject. Studies monitoring the occupational exposure of workers while they mix , load, and/or apply registered pesticide products in a manner that is consistent with normal work activities should not be considered intentional exposure studies. All four commenters present essentially the same arguments in favor of this change to the rule:
• Occupational exposure studies were not intended to be covered by 40 CFR 26. In the 2006 Appropriations Act, Congress intended to require EPA to promulgate a r ule concerning “ third

- party intentional dosing human toxicity studies for pesticides. ” E PA’s current practice of considering occupational exposure studies that alter a worker ’s exposure to be intentional exposure studies goes beyond the legal mandate required by the 2006 Appropriations Act.
• A s tud y measuring a worker’s exposure during normal agricultural activities is not the same as a human toxicity study.
• EPA needs better occupational exposure data. Considering these studies to be intentional exposure studies requiring Human Studies Review Board (HSRB) review has caused delays and g reater expense.
• Very little additional worker protection has resulted from the additional HSRB oversight. Since the se major points of the following commenters are similar in content, and EPA’s responses to those points are discussed together : See Documen t No. EPA

- HQ

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- 0011 (Commenter: Agricultural Handler Exposure Task Force [AHETF]) ; Document No. EPA

- HQ

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- 2010

- 0785

- 0012 (Commenter: CropLife America [CLA]) ; Document No. EPA

- HQ

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- 2010

- 0785

- 0013 (Commenter: American Chemistry Council/Antimicrobial Exposure Assessment Task Force II [AEATF]) ; Document No. EPA

- HQ

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- 0014 (Co mmenter: SC Johnson)

. EPA Response: This topic is not withi n the scope of the current rulemaking. The 2006 rule provides the definition for “research involving intentional exposure of a human subject” : § 26.1102(i) Research involving intentional exposure of a human subject means a study of a substance in which the exposure to the substance experienced by a human subject participating in the study would not have occurred but for the human subject's participation in t he study. Since promulgation of the rule in 2006, EPA has interpreted this definition, consistent with its discussion in the preamble to the final rule (71 FR 6138) , as covering scripted worker exposure studies because the scripting alters the level and/or timing of the worker’s exposure. The proposed rulemaking on which the Agency is currently accepting comment does not propose change s to the definition of “research involving intentional exposure of a human subject ” in section 26.1 102(i) . Further , the Agency has not invited comment on its application of that definition , or, in any other way, indicated it intended to reconsider the scope of research covered by this definition . Accordingly, no response to this comment is warranted. The proposed changes to the 2006 rule do not reopen the question of the applicability of the rule to worker exposure studies and the commenters cannot reopen consideration of that previously

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Page 11 of 20 promulgated provision by filing comments on the issue in a rulem aking that does not address the issue. Document # EPA
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- 1 1 (Commenter: Richard Collier, Agricultural Handler Exposure Task Force) Nonetheless, EPA appreciates the concerns expressed by the commenters with regard to the burdens imposed by the 2006 rule and recognizes that there may be value in further amending the rule in a way that reduces the regulatory burdens on investigators , e.g., by limiting the types of research that are subject to particular requirements of the rule

. 7. Comment : “[T] he AHETF supports EPA’s ongoing efforts to ensure protection of the health and safety of human subjects participating in research studies. However, the occupational exposure monitoring studies conducted by AHETF should not be subject to this regulatory program. The Final Rule went far beyond the legal mandate required by the Appropriations Act of 2006 which concerned “third party intentional dosing human toxicity studies for pesticides”. The Rule also is at odds with the 2004 NRC report as to how intentional human dosing should be defined. ” Classifying studies that monitor exposure to individuals who would b e exposed in the course of their normal activities in the same manner as studies that measure the toxic effects of pesticides in human subjects is disingenuous. Therefore, the proposed amendments are neither adequate nor appropriate to clarify how EPA shou ld define “intentional exposure”. (p

. 1 ) )

. See Document No. EPA

- HQ

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- 2010

- 0785

- 0011 (Commenter: Richard Collier, Agricultural Handler Exposure Task Force)

. EPA Response : See the EPA response to C c omment # 6 , p p . 7

- 8 of 1 4 in this unit

. 8. Comment: “ EPA's anticipated revision of its Human Subjects Rule presents an opportunity for the Agency to clarify the definition of “research involving intentional exposure of a human subject.” (p

. 7)
See Document No. EPA

- HQ

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- 2010

- 0785

- 0011 (Commenter: Richard Collier, Agricultural Handler Exposure Task Force)

. EPA R esponse : EPA did not take the opportunity presented by the pro posed revisions to the Human Research Rule to reconsider, or invite reconsideration of, the definition of “research involving intentional exposure of a human subject.” Having not taken that opportunity in the proposed rule, it would be inappropriate to ad dress the issue here. 9. Comment: “ EPA claims to need the data in a timely fashion in order to make accurate, data

- based decisions on the safety of pesticide use. The current impact of these delays will be that a program consisting of 33 study types that should have been completed by 2011 is n ow probably an additional 10 years from completion.” (p. 12 ) )

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Page 12 of 20 See Document No. EPA

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- 0011 (Commenter: Richard Collier, Agricultural Handler Exposure T ask Force)

. EPA Response: EPA agrees that the occupational exposure data currently being generated by the AHETF is useful for risk assessment purposes. However, the requirement for HSRB review of this type of human study was not raised in the proposed rule, and, thus, it would be inappropriate to address the issue here. 10. Comment: The HSRB has changed the underlying objectives of the AHETF program “...from a diversity capturing approach toward more of a population sampling approach. Instead of allowing the selection of workers and other monitoring unit (MU) conditions that will achieve the original diversity objectives, AHETF was forced to modify its approach by adopting the overly extensive recruitment plan that ensures that virtually every worker in a selected monitoring area has the potential of being monitored.” (p

. 15 ) )

. See Document No. EPA

- HQ

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- 2010

- 0785

- 0011 (Commenter: Richard Collier, Agricultural Handle r Exposure Task Force)

. EPA Response: Comments on particular HSRB recommendations that are not relevant to the proposed changes to 40 CFR 26 are beyond the scope of this rulemaking and it would be inappropriate to comment on them in the context of th is rulemaking. 11. Comment: EPA says that they want to reduce regulatory burden, but there is no evidence of that desire in the revision to the rule. These revisions implem ent by regula tion what EPA was already doing.
See Document No. EPA

- HQ

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- 2010

- 0785

- 0011 (Commenter: Richard Collier, Agricultural Handler Exposure Task Force)

. EPA Response : The burden

- reducing steps sought by this commenter relate to matters not addressed by this rulemaking. As such, it would be inappropriate to comment on them in the context of the rulemaking. P lease see t he EPA response to comment #6 in this unit

. 12. Comment: “ AHETF recommends that EPA consider utilizing an expert panel to review public comments, regarding the “lessons learned” from the EPA and HSRB process and options for continued improvements. Such a forum could address various aspects o f the process involved in vetting occupational exposure studies which have substantive impact on time and cost. These include: 1) determining the documentation necessary for proposed research (using examples); 2) the format of the documentation needed for efficient electronic submission and subsequent review; and 3) ways to optimize and expedite the process (web based meetings; internet and intranet sites that could facilitate review by EPA and the HSRB). ” (p

. 16 ) )

. See Document No. EPA

- HQ

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- 2010

- 0785

- 0011 (Commenter: Richard Collier, Agricultural Handler Exposure Task Force)

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Page 13 of 20 EPA Response: It is not clear what public comments the commenter is s uggesting would be reviewed by an expert panel , b ut th e proposal of a “lessons learned” review has merit. EPA will consider this option after the revised rule is promulgated. Document # EPA
- HQ
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- 0785
- 12 (Commenter: Wendelyn Jones, Crop Life America) 13. Comment: Occupational monitoring studies, as is the case with all human studies, must meet at least four stringent conditions: 1. The knowledge gained from the study is expected to promote human health. 2. The knowledge cannot be reasonably obtained by other means. 3. The study is not expected to cause serious or irreversible harm to the subjects. 4. Appropriate safeguards are in place to minimize harm to the subjects. All AHETF occupational exposure studies are in compliance with the EPA approved label involving application rates, methods of application, and crops treated. Th erefore, such design and study conduct is observational in nature. This type of study is in distinct contrast to clinical investigations involving intentional dosing of human subjects to study toxicity. ” (p

. 7 ) )

. See Document No. EPA

- HQ

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- 2010

- 0785

- 0012 (Commenter: Wendelyn Jones, Crop Life America)

. EPA Response : This comment is not responsi ve to the proposed rulemaking. EPA agrees that these four conditions , among others, are necessary for occupational exposure monitoring studies to be considered ethical , and that these are not clinical investigations involving intentional dosing to study toxicity. To the extent the comm enter is arguing that this distinction means occupational exposure studies should not be covered by the Human Research Rule, please see the EPA response to C c omment # 6 , pp. 7

- 8 of 1 4 in this unit

. Document # EPA
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- 13 (Commenter: Has Shah, American Chemistry Council, for the Antimicrobial Exposure Assessment Task Force II) 1. C omment: The p roposed a mendments also authorize the EPA Administrator to "recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for the protection of human subjects." Proposed 40 CFR 26.1603(d). This provision does not provide any boundaries for such conditions and therefore does not provide sufficient opportunity for stakeholders to comment. Such a pro vision does not provide adequate certainty or predictability to study sponsors or investigators and therefore should not be adopted in a final rule. (p

. 5) Response: The language “ recommend additional conditions which, in the judgment of the EPA Administr ator, are necessary for t he protection of human subjects” i s already present in 40 CFR part 26, at § 26.1601(a). The Agency is re

- ordering the text (the language is mo ving from § 26.1601(a) to 26.1603(d)). But there will not be any change s in the meaning or application of this provision . As a result , this comment is not responsive to the current rulemaking. In simply re

- ordering the text of the rule with*** EO 12866 Draft

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Page 14 of 20 regard to this language, EPA did reconsider the need for this language or invite reco nsideration by commenters. Document # EPA
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- 14 (Commenter: Charles Boyd, SC Johnson & Co . ) 14. Comment: “Continuing to impose these burdens simply cannot be justified where there is already an adequate review process in place. The Common Rule and comparable consensus standards apply regardless of the type of human subjects ’ research being conducted....” (p

. 2 ) )

. See Document No. EPA

- HQ

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- 2010

- 0785

- 0014 (Commenter: Charles Boyd, SC Johnson & Co.)

. EPA Response : This comment questions the need for EPA’s 2006 r ule , Protections for Subjects in Human Research (40 CFR 26) . Th e current rulemaking does not reopen consideration of the 2006 r ule generally , but rather makes certain narrowly

- targeted revisions to a few specific provisi ons. In th e current rulemaking , EPA did not reconsider the underlying basis for the 2006 r ule and comments raising such issues are beyond the scope of this rulemaking. 15. Comment: “The burdens of the HSRB process disproportionately impact personal insect repellent products. New products using existing active ingredient personal insect repellents are taking over two years to get through the HSRB process, even though these are well characterized active ingredients with complete and fully understood toxicolo gical profiles, decades of consumer use, and very low incidence of adverse effects. The impact on new actives is also problematic. We understand that no new insect repellent active ingredients have gone through the HSRB review process since the implemen tation of the 2006 Rule. We believe the burdens and uncertainties involved with the HSRB review process are directly impeding the development of new repellent products

. ” (p

. 6 ) )

. See Document No. EPA

- HQ

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- 2010

- 0785

- 0014 (Commenter: Charles Boyd, SC Johnson & Co.)

. EPA Response: This comment is not responsive to the current proposed rulemaking. To the extent this comment is implying that human studies involving personal insect repellents should not be covered by the r ule, please see the EPA response to C c omment # 6 , pp. 7

- 8 of 14 in this unit

. 16. Comment: HSRB should be more like FDA’s advisory committees which are not FACA committees and do not have to have public meetings. “... the ‘openness’ requirements of FACA have created significant obstacles for registrants. In studies of repellent products, much of the information submitted for HSRB review is propr ietary and confidential.... Notwithstanding the importance of maintaining the confidentiality of information , it has been extremely difficult to obtain adequate assurance that proprietary information will be protected from disclosure by the HSRB.” (p

. 7 ) )

. S ee Document No. EPA

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- 2010

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- 0014 (Commenter: Charles Boyd, SC Johnson & Co.)

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Page 15 of 20 EPA Response: This comment is not responsive to the amendments under consideration in this rulemaking. The HSRB’s formation under the Federal Advisory Committee Act is not an issue involved in this rulemaking, and, thus, comment on that decision is inappropriate here

. Similar comments were made on the 2006 Rule , to which the Agency responded , :

“ Specifically, (1) FACA committees are required to be unbiased and independent. (2) The HSRB is not simply an “ethics committee”; it will provide formal external peer review of both scientific and ethical aspects of human research; as such it will be entire ly consistent with other FACA committees established by EPA. (3) The FDA review process does not involve an independent review committee as required by the Appropriations Act. (4) The NAS recommended an HSRB, and noted that there were various models elsewh ere in the government. The FDA model was identified as one extreme, in that neither the proceedings nor the reports of the internal committee were public. At the other extreme the NAS committee noted the NIH recombinant DNA oversight committee, which does all its business in the public eye. (5) EPA acknowledges that different procedures apply to EPA research and to covered third

- party research, but notes as well that this has been true for many years, and that under this final rule, for the first time the s ubstantive standards for approving and conducting first

- second

- and third

party research will be the same. (6) EPA agrees that regulatory ethics review for pesticides should be independent, apolitical, and consistent with the Common Rule. (7) EPA does not agree that consistency with FDA is more important than compliance with the Appropriations Act. An internal review group, such as FDA’s, would not satisfy the clear requirements of that Act.

... FACA committees are able to protect confidential business inform ation. There are established procedures for this, and none need to be defined in this rule. ” ( Doc k um e n t ID No. EPA

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- 0132

- 0656 EPA

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2003

- 0132

- 0656 , , p p. 266

- 267) 1. Comment: Exec utive Order #13563 requires federal agencies to review the necessity and effectiveness of existing regulations and consider principles to use the best and “least burdensome” tools for achieving regulatory ends. It also requires inter

- agency coordination to simplify and harmonize redundant or inconsistent regulations. Response: EPA is continuing to carefully consider all existing regulations under Executive Order 13563

. The revisions to EPA’s 2006 rule proposed in this action are not part of that effort

. Document # EPA
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- 15 (Nichelle Harriott, Beyond Pesticides) 17. Comment: “ [C] onducting experiments on human subjects, intentionally exposing them to chemicals that can cause both short and long term adverse effects is un productive, unethical and lacking in scientific integrity. ” (p

. 1 ) )

. See Document No. EPA

- HQ

- OPP

- 2010

- 0785

- 0015 (Nichelle Harriott, Beyond Pesticides)

. EPA Response: Comments regarding the validity of any research with human subjects are beyond the scope of this rulemaking. Similar comments were made on EPA’s 2006 Human Research Rule , to which the Agency responded, “ Nevertheless , the Agency believes that there is stil l a place in its regulatory decision

- making for scientifically sound, ethically conducted human*** EO 12866 Draft

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Page 16 of 20 research.” ( Doc k um e n t ID No. EPA

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- 0656 EPA

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- 0656 , , p . 143 ) )

. 18. Comment : Beyond Pesticides is concerned that paying subjects to participate in studies will lead to coercion based on financial compensation. “The agency must seriously address the iss ue of remuneration so as to protect those who may be recruited to becoming a subject for human dosing studies . The agency must also define what constitutes payments as being considered too high or too low. Nevertheless low

- income and other financially disadvantaged populations will be disproportionately affected, especially since payment for research participation can be perceived as a potential income source among participants

. Thus, financial remuneration for participating in human studies should be reconsidered, and be done on a strictly voluntary basis with non monetary incentives.” (p

. 3 ) )

. See Document No. EPA

- HQ

- OPP

- 2010

- 0785

- 0015 (Nichelle Harriott, Beyond Pesticides)

. EPA Response: EPA specifically sought comment on whether the exact language regarding remuneration from NAS Recommendation 5

- 3 or EPA’s proposed language (slightly re

- worded from NAS Recommendation 5

- 3 ) is clear er . The commenter is not addressing that issue, but is instead objecting to the overall notion of remuneration , arguing that financial remuneration is not appropriate for human subjects in pesticide studies . EPA continues to agree with the NAS report that remuneration is appropriate to provide an incentive for participation and to reimburse subjects for the time and inconvenience of participating in such research. The question of what amount of remuneration is appropriate is more difficult , but EPA agrees with the NAS be nchmarks that such payments should be neither “so high as to constitute undue inducement” nor “so low as to be attractive only to individuals who are socioeconomically disadvantaged.” EPA has explicitly added these factors Although this specific language is not being included in the final rule , EPA will be guided by the NAS recommendations in implementing the rule.
IV. Other Comments 1. Comment: The proposed rule amendments also authorize the EPA Administrator to ensure that they "recommend additional conditions which, in the judgment of the EPA Administrator, are consider ed in evaluating the appropriateness of payments necessary for the protection of human subjects." Proposed 40 CFR 26.1603(d). This provision does not provide any boundaries for such conditions and therefore does not pro vide sufficient opportunity for stakeholders to comment. Such a provision does not provide adequate certainty or predictability to study sponsors or investigators and therefore should not be adopted in a final rule. (p. 5).
Document No. EPA

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- 0013 (Commenter: Has Shah, American Chemistry Council, for the Antimicrobial Exposure Assessment Task Force II). EPA Response: The language “recommend additional conditions which, in the judgment of the EPA Administrator, are necessary for the protection of human subjects” is already present in 40 CFR part 26, at § 26.1601(a). The Agency is re

- ordering the text (the language is mo ving from § 26.1601(a) to 26.1603(d)). subjects. In addition, EPA is clarifying in the final rule that § 26.1603(d) is applicable only to “any research or class of research that is subject to this subpart....”*** EO 12866 Draft

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Page 17 of 20 2. Comment: “It is inevitable that although this proposal theoretically sets a higher standard for the review of human studies, EPA’s lax oversight and review process would lead to the unconditional approval of many question able human studies.” (p. 3 ) ).
See Document No. EPA

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- 0015 (Nichelle Harriott, Beyond Pesticides).
EPA Response: EPA has engaged in a rigorous scientific and ethical review of all intentional exposure human studies submitted for consideration under FIFRA and the FFDCA. Since the promulgation of the 2006 rule, this review has involved consultation with science and ethics experts on the Human Stud ies Review Board about all intentional exposure studies. The present rulemaking, which proposes narrowly

- targeted changes to the EPA’s 2006 Human Studies Rule, will further strengthen EPA’s process for reviewing these types of studies. 3. Comment: Exec utive Order #13563 requires federal agencies to review the necessity and effectiveness of existing regulations and consider principles to use the best and “least burdensome” tools for achieving regulatory ends. It also requires inter

- agency coordination to simplify and harmonize redundant or inconsistent regulations.
See Document # EPA
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- 2010
- 0785
- 16 No. EPA

- HQ

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- 2010

- 0785

- 0014 (Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC)) Charles Boyd, SC Johnson & Co.). EPA Response: EPA is continuing to carefully consider all existing regulations under Executive Order 13563. The revisions to EPA’s 2006 rule proposed in this action are not part of that effort

. V. Comments Substantially Agreeing with the Proposed Rulemaking 1. Comment: “The proposed rule would amend the 2006 final rule to partially or fully address many of the 2006 final rule ’ s deficiencies, including inconsistencies with Section 201, and would reduce the likelihood that unethical or unscientific research being conducted and/or relied upon by EPA.” (p

. 6 ) )

. See Document No. EPA

- HQ

- OPP

- 2010

- 0785

- 0016 (Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC))

. EPA Response: The Agency is pleased that NRDC supports the proposed changes to the rule, although EPA does not concede that the 2006 final rule contained any deficiencies that compel led the proposed changes to that rule. EPA also disagrees that there is a likelihood, in the absence of the proposed changes, that EPA would rely on unethical or unscientific human research. EPA performs rigorous scientific and ethical reviews and submit s those reviews to, and consults with , the Human Studies Review Board before determining whether to approve intentional exposure human study protocols or to rely on completed research in regulatory decisions

. As noted in comment response #1, it has been determined that section 201 of the 2006 Appropriations Act does not continue to impose any requirements on EPA.*** EO 12866 Draft

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Page 18 of 20 2. Comment: “ The issue of significantly deficient is adequately addressed by deleting the word “significantly”, as recommended by the Human Studies Review Board (HSRB) (FR at 5750)... We are satisfied with this amendment to delete the word.” (p

. 6 ) )

. See Document No. EPA

- HQ

- OPP

- 2010

- 0785

- 0016 (Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC)).
EPA Response: The Agency is pleased that NRDC is satisfied with the proposed change , although EPA notes that this change was not recommended by the HSRB as suggested by NRDC

. EPA note s that in addition to deleting the word “significantly” from §26.1704, the Agency is add ing language that explicitly characterizes the kinds of deficiencies that would make a study unacceptable. The language is based on the HSRB’s application of the stand ard of §26.1704 in its review s since 2006

. 3. Comment: “ The issue of consent by a surrogate is addressed by EPA ’ s proposal to delete all references permitting consent by a subject ’s legal representative (FR at 5745). We are satisfied with this amendment to delete the reference.” (p

. 7 ) )

. See Document No. EPA

- HQ

- OPP

- 2010

- 078 5

- 0016 (Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC)).
EPA Response: The Agency is pleased that NRDC is satisfied with the proposed change. 4. Comment: “ The proposed rule would also add substantive standards for assessing scientific validity. While EPA may believe that such standards are unnecessary, because it had discretion under the 2006 final rule to reject studies it considered unscientific, there is a substantial policy and legal need for incorporating such standards into the ru le....We support EPA ’ s incorporation, through the proposed rule, of stronger, more specific scientific standards.” (p 7 ) )

. See Document No. EPA

- HQ

- OPP

- 2010

- 0785

- 0016 Response: The Agency is pleased that NRDC supports this proposed change. (Commenter: Jennifer Sass, Natural Resources Defense Council (NRDC)).
EPA Response: As discussed in comment response #1, it has been determined that there is no longer a legal obligation to include the NAS

- derived recommendations because section 201 of the Appropriations Act does not continue to impose any obligations on EPA . For policy reasons, EPA has decided to modify the form in which EPA articulates the requirement for consideration of ethical and scientific factors when rev iewing proposed and completed human research. Specifically, instead of codifying selected individual recommendations from the 2004 NAS Report as the specific ethical and scientific factors to be considered in reviewing proposed and completed human research (i.e., proposed sections 26.1603 and 26.1703), see 76 FR 5735, 5745

- 5749, February 2, 2011, EPA has included broader language requiring EPA and the Human Studies Review Board to “consider the ethical aspects and scientific validity and reliability of the proposed research under the requirements of the Common Rule as codified in 40 CFR part 26, Subpart A, except as modified in 40 CFR 26.1116 and 26.1117.” See 40 CFR 26.1603 as promulgated in this final rule (review of proposed research). As indicated in t he following discussion, EPA considers that the substituted language regarding the Common Rule either*** EO 12866 Draft

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Page 19 of 20 explicitly or implicitly addresses the individual 2004 NAS recommendations originally proposed for inclusion. As such, EPA’s revised approach maximizes consistency across the Federal Government with regard to requirements pertaining to the review of human studies and allows EPA to continue to consider the individual recommendations of the 2004 NAS Report in its review of human research involving pesticide s. This approach is consistent with existing Agency practice and goals of section 201 of the 2006 Appropriations Act. EPA’s decision not to include the specific text from the 2004 NAS report in the final revisions is driven by two factors. First, on July 26, 2011, after issuance of the proposed rule, the Department of Health and Human Services (HHS), in coordination with the Office of Science and Technology Policy (OSTP), issued an advance notice of proposed rulemaking concerning modernization of the Commo n Rule which governs research with human subjects conducted or supported by EPA and many other Federal departments and agencies. (76 FR 44512, July 26, 2011). HHS and OSTP sought comment on “how to better protect human subjects who are involved in resear ch, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators.” Id. HHS and OSTP identified seven areas of concern regarding the Common Rule. Most relevant to EPA’s proposed amendments to the 2006 rule, was a conce rn with “the multiple, differing regulatory requirements that can apply to a single research study . . . .” These requirements, according to HHS and OSTP, “have been criticized as complex, inconsistent, and lacking in clarity,” and can result in “unwarran ted variability across institutions and their [Institutional Review Boards] in how the requirements are interpreted and implemented.” (76 FR at 45514.) HHS and OSTP stressed the importance of clarifying and harmonizing human subject protections across t he federal government and sought comment on the means by which this could be accomplished. (76 FR at 44528.) EPA believes that including the specific NAS

- derived considerations in the 2006 rule, which otherwise closely mirrors the Common Rule, will make the federal government’s goal of harmonization of rules governing human research more difficult. A second factor influencing EPA’s decision is that EPA did receive several comments noting that as to some of the NAS

- derived considerations, it was unclear as to how these specific criteria would apply to human exposure, as opposed to human toxicity, studies. EPA believes these types of issues can be more appropriately addressed through a guidance document rather than through rule text. Despite the decision not to include the NAS

- derived factors for consideration in the final rule, the rule will be consistent with the recommendations in the 2004 NAS Report and EPA practice under the 2006 rule. Sections 26.109, 26.111, 26.116, and 26.117 of EPA’s Common Rule e xplicitly address most of the specific ethical considerations proposed for inclusion in the 2006 rule including whether risks to subjects are minimized (compare proposed §26.1603(c)(2) with existing §26.111(a)(2)); whether risks are reasonable in compariso n to benefits (compare §26.1603(c)(3) with §26.111(a)(2)); whether subject selection would be equitable (compare §26.1603(c)(4) with existing §26.111(a)(3)); whether consent will be free and voluntary (compare proposed §26.1603(c)(5) with existing §§26.116 and 26.117); whether an appropriately constituted IRB has reviewed the proposed research (compare proposed §26.1603(c)(6) with §26.109); and whether the “special problems” of research involving vulnerable populations are taken into account (compare propos ed §26.1603(c)(7) and (8) with existing §26.111(a)(3)). Other proposed considerations are implicitly addressed. The Common Rule’s requirement to “minimize risks” in section 26.111(a)(1) necessitates consideration of whether adequate animal*** EO 12866 Draft

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Page 20 of 20 data is avail able to assess potential risks to subjects (see proposed §26.1603(c)(1)). It would involve consideration of whether medical care is to be provided for injuries incurred in the proposed research (see proposed §26.1603(c)(10)). Section 26.111(b)’s requirem ent that additional safeguards be in place to protect against undue influence of “economically” disadvantaged persons ensures that consideration of whether any proposed payments are so high as to constitute undue inducement or so low as to be attractive on ly to individuals who are socioeconomically disadvantaged (see proposed §26.1603(c)(9)). Although scientific considerations are not addressed in similar detail in the Common Rule requirements, nonetheless, the requirement to consider scientific validity a nd reliability and the Common Rule’s emphasis on the need for “sound research design” in section 26.111(a)(1) and the need to take “the importance of the knowledge that may reasonably be expected to result” from the study into account, mandate that EPA foc us on considerations addressing scientific validity such as those proposed for inclusion in sections 26.1603 and 26.1703. At a minimum, NAS Recommendations 3

- 1, 4

- 1, 5

- 1, 5

- 2, 5

- 3, and 5

- 5 are critical to proper consideration of the Common Rule’s ethical requirements and its requirement for “sound research design.”