                  U.S. Environmental Protection Agency (EPA)
              Office of Chemical Safety and Pollution Prevention
                          Response to Public Comments
                    Received on the Proposed Rule Entitled:
      "Revisions to EPA's Rule on Protections for Subjects in Human 
               Research Involving Pesticides" (RIN 2070-AJ76)
                                  02/06/2013
                                       
Public 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 the EPA's Rule on Protections for Subjects in Human Research Involving Pesticides that published on February 2, 2011 (76 FR 5735), in which the EPA proposed amending 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 the EPA.  All comments appear in their entirety in the public docket for this rulemaking, identified as EPA Docket ID No. EPA-HQ-OPP-2010-0785 and accessible at http://www.regulations.gov.
		EPA proposed several narrowly-targeted changes to regulatory text as a result of a settlement agreement and specifically requested comment on the proposed changes.   The Agency received 10 comments in response to the Notice of Proposed Rulemaking.  In the docket, documents identified with Document ID numbers ending in 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 discussion in Footnote 1, below).  
   II.       Comments on Issues within the Scope of the Proposed Amendments
      EPA has identified only two issues raised by commenters that are within the scope of the proposed amendments.  The first issue relates 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 relates 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 statistical power to detect appropriate effects.  The specific comments, and EPA's responses to those comments, are discussed below.
Document ID No.: 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 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).  
      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 the 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 continuing effect of its requirements, these requirements expired with FY 2006.  Accordingly, EPA is not citing the 2006 Appropriations Act as authority for the 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 gives 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 Appropriations 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 under 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 pesticides.  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.   
Document ID No.: 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:  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 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 involving 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, for example, by preventing researchers from studying whether repellent impregnated bed nets reduced the incidence of malaria in African villages.  
Document ID Nos.: 
   EPA-HQ-OPP-2010-0785-11 (Commenter: Agricultural Handler Exposure Task Force [AHETF])
   EPA-HQ-OPP-2010-0785-12 (Commenter: CropLife America [CLA])
   EPA-HQ-OPP-2010-0785-13 (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 (iii) 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 would 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 needed 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 data 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-OPP-2010-0785-11, pp. 15-16).
   CLA: "CLA notes and agrees 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-HQ-OPP-2010-0785-12, p. 6).
   AEATF: "AEATF 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 improving scientific validity or protection of human subjects." (EPA-HQ-OPP-2010-0785-13, p. 3).
	Further on the topic of "representative study populations" and "adequate statistical power", the commenters request that EPA "confirm that EPA does not expect any effect on the continued approval of the worker exposure studies" (AEATF, EPA-HQ-OPP-2010-0785-13, p. 5).
      Response:  As it has since its initial promulgation, the EPA will be guided in implementing the amended 2006 rule by the recommendations of the 2004 NAS Report.  Some of  the commenters may have misinterpreted the NAS recommendation to be required characteristics of all studies covered by this rule; rather, as further explained below, the NAS recommends that these concepts be considered in reviewing these studies.  As such, EPA disagrees with the assertion that the NAS recommendations on representative populations and statistical power are not applicable to exposure studies.    
      
      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 and used in EPA's science and ethics reviews of human research involving pesticides.   76 FR at 5737, 5741, 5749, 5751.  
      
      Under the 2006 rule as amended through this rulemaking, 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.  EPA does not believe the codification of the specific ethical and scientific factors derived from the 2004 NAS Report represents a material change in the way a particular pesticide study would have been reviewed. Thus, EPA believes that particular pesticides studies that have been approved under the 2006 rule, would also meet the standards reflected in this final rule.
      
      EPA notes that the NAS emphasized that EPA should focus on the "objectives of the study" in determining what is a representative population (NAS Report, p. 77).  Thus, representativeness is 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 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 exposures 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 their 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 and situations under which exposure occurs.  This approach meets the objectives of the study.        
      
      Similarly, statistical power considerations are also a relevant concept for both toxicology and exposure studies.  Statistical power evaluates 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 exposed and unexposed groups.  In some instances, exposed and unexposed 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 exposed and unexposed 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 exposed and unexposed 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 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 example, 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 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.
      
   I.       Comments on Issues Outside of the Scope of the Proposed Rulemaking
Document ID No.: EPA-HQ-OPP-2010-0785-07 (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."
      Response:  EPA's 2006 rule (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 rule.  
   2.    Comment:  "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 environmentally 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 involving conventionally grown foods." 
   
Response:  EPA's 2006 rule and the proposed amended version of the rule have a very clearly delineated scope.  The rule (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 ID No.: EPA-HQ-OPP-2010-0785-08 (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 ID No.: EPA-HQ-OPP-2010-0785-09 (Commenter: A. Sow)
4. Comment:  "My comment is that protecting 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 difference. 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"
      Response:  EPA's mission is to protect human health and the environment.  
Document ID No.: EPA-HQ-OPP-2010-0785-10 (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 pesticides with the intentions to see if they are safe or not makes absolutely no sense; doing this puts children in harm's way."
       Response:   EPA is proposing narrowly-targeted revisions to its 2006 rule for the protection of human subjects in research involving intentional exposure to pesticides.  General comments 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 ID Nos.: 
   EPA-HQ-OPP-2010-0785-11 (Commenter: AHETF)
   EPA-HQ-OPP-2010-0785-12 (Commenter: CLA)
   EPA-HQ-OPP-2010-0785-13 (Commenter: AEATF)
   EPA-HQ-OPP-2010-0785-14 (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 responses 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 covered by 40 CFR 26.  In the 2006 Appropriations Act, Congress intended to require EPA to promulgate a rule concerning "third-party intentional dosing human toxicity studies for pesticides."    EPA'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 study 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 additional worker protection has resulted from the additional HSRB oversight.
      Response: This topic is not within 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 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 level and/or timing of the worker's exposure.   The proposed rulemaking on which the Agency is currently accepting comment does not propose changes 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 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-promulgated provision by filing comments on the issue in a rulemaking that does not address the issue.
       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.
Document ID No.: EPA-HQ-OPP-2010-0785-11 (Commenter: AHETF)
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 should define "intentional exposure".  (p. 1).
      Response:   See response to Comment 6, pp. 7-8 of 14.                                                                            
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).
      Response:   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.  The 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. 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).     
      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 this 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 regulation 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.  Please see response to Comment 6, pp. 7-8 of 14.     
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 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).
      Response: It is not clear what public comments the commenter is suggesting would be reviewed by an expert panel, but the proposal of a "lessons learned" review has merit.  EPA will consider this option after the revised rule is promulgated. 
Document ID No.: EPA-HQ-OPP-2010-0785-12 (Commenter: CLA)
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. 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 responsive 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 response to Comment 6, pp. 7-8 of 14.                                                                                               
Document ID No.: EPA-HQ-OPP-2010-0785-13 (Commenter: AEATF) 
14. Comment:  The proposed amendments 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 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).
      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 moving from §26.1601(a) to 26.1603(d)).  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...."                                                                                            
Document ID No.: EPA-HQ-OPP-2010-0785-14 (Commenter: SC Johnson)
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 need for EPA's 2006 rule, Protections for Subjects in Human Research (40 CFR 26).  The current rulemaking does not reopen consideration of the 2006 rule generally, but rather makes certain narrowly-targeted revisions to a few specific provisions.  In the current rulemaking, EPA did not reconsider the underlying basis for the 2006 rule 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 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 toxicological 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 implementation 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).
      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 rule, please see response to Comment 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:  This comment is not responsive to the amendments under consideration in this rulemaking.   The HSRB's formation under the Federal Advisory Committee Act (FACA) is not an issue involved in this rulemaking, and, thus, comment on that decision is inappropriate here.   EPA is not commenting on whether the commenter's characterization of FDA's committee is accurate.                                                                                             
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 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 consistent with Executive Order 13563.       
Document ID No.: EPA-HQ-OPP-2010-0785-15 (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 unproductive, unethical and lacking in scientific integrity."  (p. 1).
      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 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 participate 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 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). 
      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 clearer.  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 2004 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 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."  Although this specific language is not being included in the final rule, EPA will be guided by the NAS recommendations in implementing the rule.                                                                                         
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 Human Studies Rule, will further strengthen EPA's process for reviewing these types of studies.    
Document ID No.: EPA-HQ-OPP-2010-0785-16 (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 final 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 rigorous 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.  In addition, 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.  
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 adding 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 reviews 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 amendment 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, through the proposed rule, of stronger, more specific scientific standards." (p. 7).
      Response:   As discussed in comment response #1 in this document, EPA believes there is no longer a legal obligation because section 201 of the Appropriations Act does not continue to impose any obligations on EPA.  For policy reasons, EPA has decided to include the specific text from the 2004 NAS Report in the final revisions with a few wording changes.  EPA believes that the revisions in the final rule are consistent with the recommendations in the 2004 NAS Report (entitled "Intentional Human Dosing Studies for EPA Regulatory Purposes") and EPA practice under the 2006 rule. That practice has been modeled primarily on EPA's practice under its Common Rule.  Sections 26.109, 26.111, 26.116, and 26.117 of EPA's Common Rule explicitly address most of the specific ethical considerations included in the amendments to the 2006 rule, including whether risks to subjects are minimized (compare §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 (compare §26.1603(c)(4) with existing §26.111(a)(3)); whether consent will be free and voluntary (compare §26.1603(c)(5) with existing §§26.116 and 26.117); whether an appropriately constituted IRB has reviewed the proposed research (compare §26.1603(c)(6) with §26.109); and whether the "special problems" of research involving vulnerable populations are taken into account (compare §26.1603(c)(7) and (8) with existing §26.111(a)(3)).  Other considerations are implicitly addressed.  
      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 §26.1603(c)(1)).  It would involve consideration of whether medical care is to be provided for injuries incurred in the proposed research (see §26.1603(c)(10)).  Section 26.111(b)'s requirement 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 only to individuals who are socioeconomically disadvantaged (see §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 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 included 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."
      
      Filename:
      RIN2070-AJ76_EO12866_HumanSubjectsRevisions_FRM_Response2Comments_2013-02-06redline.docx
