71 FR 24 pgs. 6138-6176 - Protections for Subjects in Human Research
Type: RULEVolume: 71Number: 24Pages: 6138 - 6176
Docket number: [EPA-HQ-OPP-2003-0132;FRL-7759-8]
FR document: [FR Doc. 06-1045 Filed 2-3-06; 8:45am]
Agency: Environmental Protection Agency
Official PDF Version: PDF Version
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 9 and 26
[EPA-HQ-OPP-2003-0132;FRL-7759-8]
RIN 2070-AD57
Protections for Subjects in Human Research
AGENCY:
Environmental Protection Agency(EPA).
ACTION:
Final rule.
SUMMARY:
With this final rule, EPA bansresearch for pesticides involving intentional exposure of humansubjects, when the subjects are pregnant women or children. Therule further strengthens existing protections for subjects inresearch conducted or supported by EPA, by prohibiting suchresearch if it would involve intentional exposure of humansubjects who are pregnant women or children. The rule alsoextends new protections to adult subjects in research forpesticides conducted by others who intend to submit the researchto EPA, when it involves intentional exposure of human subjectswho are non-pregnant adults, and creates a new, independent HumanStudies Review Board to advise the Agency on the ethical andscientific issues arising in such research. This final rulefocuses on third-party intentional dosing human studies forpesticides and sets the stage for further Agency actions. Inaddition, in order to display the OMB control number for theinformation collection requirements contained in this final rule,EPA is amending the table of OMB approval numbers for EPAregulations that appears in 40 CFR part 9.
DATES:
This rule is effective on April 7, 2006.
ADDRESSES:
EPA has established a docket for thisaction under docket identification (ID) numberEPA-HQ-OPP-2003-0132. All documents inthe docket are listed in the index for the docket. Althoughlisted in the docket index, some information is not publiclyavailable, i.e., Confidential Business Information (CBI) orother information whose disclosure is restricted by statute.Certain other material, such as copyrighted material, is notavailable through the electronic docket and will be publiclyavailable only in hard copy form. Publicly available docketmaterials are available either electronically at http://www.regulations.gov or in hard copy at thePublic Information and Records Integrity Branch (PIRIB), Rm. 119,Crystal Mall #2, 1801 S. Bell St., Arlington, VA. This DocketFacility is open from 8:30 a.m. to 4 p.m., Monday through Friday,excluding legal holidays. The Docket telephone number is (703)305-5805.
FOR FURTHER INFORMATION CONTACT:
William L. Jordan, Mailcode 7501C, Office of PesticidePrograms, Environmental Protection Agency, 1200 PennsylvaniaAve., NW.,Washington, DC 20460; telephone number: (703) 305-1049; faxnumber: (703) 308-4776; e-mail address: jordan.william@epa.gov .
SUPPLEMENTARY INFORMATION:
I. General Information
A. What Does this Final Rule Do?
With this final rule EPA significantly strengthens and expandsthe protections for subjects of "third-party" humanresearch (i.e., research that is not conducted or supported byEPA) by: (1) Prohibiting new research involving intentionalexposure of pregnant women or children, intended for submissionto EPA under the pesticide laws; (2) extending the provisions ofthe Federal Policy for the Protection of Human Subjects ofResearch (the "Common Rule") to other human researchinvolving intentional exposure of non-pregnant adults, intendedfor submission to EPA under the pesticide laws; (3) requiringsubmission to EPA of protocols and related information aboutcovered human research before it is initiated; and (4)establishing an independent Human Studies Review Board to reviewboth proposals for new research and reports of covered humanresearch on which EPA proposes to rely under the pesticidelaws.
The final rule also: (1) Categorically prohibits any EPAresearch involving intentional exposure of human subjects who arepregnant women or children to pesticides or any substances; and(2) adapts regulations of the Department of Health and HumanServices providing additional protections beyond those of theCommon Rule to pregnant women and children as subjects in EPAobservational research-i.e., research which does notinvolve intentional exposure to any substance. (Researchconducted by EPA is referred to as "first-party"research, and "second-party" research refers toresearch supported by EPA but performed by others.)
Finally, this rule forbids EPA to rely, in its actions underthe pesticide laws, on intentional-exposure human research thateither involves pregnant women or children or is otherwiseconsidered unethical, except in narrowly defined circumstances.For example, if children were at risk from unsafe exposure to asubstance, the Agency would be permitted to rely on otherwiseunacceptable research to justify setting a more restrictivestandard to protect them.
B. Legal Authority
EPA is promulgating this final rule to effectuate the expressmandate of the United States Congress as set forth in section 201of the Department of the Interior, Environment, and RelatedAgencies Appropriations Act, 2006, Public Law No. 109-54(Appropriations Act), which provides appropriated funds for EPAand other federal departments and agencies. In addition, today'sfinal rule is authorized under provisions of the followingstatutes that EPA administers: Section 3(a) of the FederalInsecticide, Fungicide, and Rodenticide Act (FIFRA), whichauthorizes the Administrator to regulate the distribution, sale,or use of any unregistered pesticide in any State "[t]o theextent necessary to prevent unreasonable adverse effects on theenvironment" (defined at FIFRA section 2(bb), in pertinentpart, as "any unreasonable risk to man or the environment,taking into account the economic, social, and environmental costsand benefits of the use of any pesticide"); section 25(a)of FIFRA, which authorizes the Administrator to "prescriberegulations to carry out the purposes of [FIFRA]," andsection 408(e)(1)(C) of the Federal Food, Drug, and Cosmetic Act(FFDCA), which authorizes the Administrator to issue a regulationestablishing "general procedures and requirements toimplement [Section 408]." In addition, EPA's expansion ofits human subject protection regulations to include additionalsubparts supplementing EPA's codification of the Common Ruleregarding first- and second-party research are authorizedpursuant to 5 U.S.C. 301 and 42 U.S.C. 300v-1(b).
C. Does this Action Apply to Me?
You may be potentially affected by this action if you conducthuman research on substances regulated by EPA. Potentiallyaffected entities may include, but are not limited to, entitiesthat conduct or sponsor research involving intentional exposureof human subjects that may be submitted to EPA under FIFRA orFFDCA. Although EPA has in the past received such third-partyresearch from pesticide registrants, other entities could submitsuch information to EPA.
• Pesticide and other Agricultural ChemicalManufacturing (NAICS code 325320).
This listing is not intended to be exhaustive, but ratherprovides a guide regarding entities likely to be affected by thisaction. Other types of entities not listed in this unit couldalso be affected. The North American Industrial ClassificationSystem (NAICS) code has been provided to assist you and others indetermining whether this action might apply to certain entities.To determine whether you or your business may be affected by thisaction, you should carefully examine the applicability provisionsof 40 CFR part 26. If you have any questions regarding theapplicability of this action to a particular entity, consult theperson listed under FOR FURTHER INFORMATIONCONTACT .
D. How Can I Access Electronic Copies of this Document andOther Related Information?
You may access an electronic copy of this FederalRegister document and the associated electronic docket at http://www.regulations.gov , or you may access this Federal Register document electronically through theEPA Internet under the " FederalRegister " listings at http://www.epa.gov/fedrgstr/ . A frequently updatedelectronic version of the Code of Federal Regulations (CFR) isavailable at http://www.gpoaccess.gov/ecfr/ .
II. Background
A. Summary of EPA Goals for this Final Rule
EPA's most important statutory responsibility is to protectpublic health and the environment by regulating air and waterpollutants, pesticides, hazardous wastes, industrial chemicals,and other environmental substances. To meet this responsibilitythe Agency considers a wide range of information about eachsubstance, including its potential to cause harm-i.e., itstoxicity-and how and at what levels people may be exposedto it-i.e., their exposure. By linking information abouttoxicity with estimates of exposure, EPA can estimate the risk asubstance poses to exposed populations, and then decide whetherand how best to regulate releases of the substance into theenvironment.
EPA believes that in general it can best protect public healthby considering all available, relevant, scientifically soundinformation, including information developed through researchwith human subjects. But at the same time, EPA wants to takeaction to ensure that research conducted by EPA or for EPA,submitted to EPA, and relied on by EPA-especially researchwith human subjects-has been conducted ethically.
B. The Role of Human Research in EPA Risk Assessments
The Agency's understanding of potential risks to people isusually based on many tests performed with laboratory animals.These tests differ in the kinds of animals used, the duration ofexposure, the age of test animals, and the pathway ofexposure-through food, air, or the skin. When they areconsidered together, the results of all these studies provide agood general understanding of a pesticide's potentialeffects.
Animal studies, however, are not the only source of relevantinformation for characterizing potential risks of a substance.Epidemiological studies, for example, provide valuableinformation about the relationship between chemical exposure andeffects of concern. Monitoring studies that measureconcentrations of a substance in air, water, food, or on surfacesalso provide valuable insights into chemical exposures.Sometimes, however, the relationship between environmentalconcentrations of a substance and potential human exposure isunclear, and can be understood only through research involvinghuman subjects. For example, a farmer's actual exposure to apesticide he or she is applying will depend on his or herequipment, the kind and quantity of pesticide he or she uses,what protective clothing or equipment he or she uses, and howmany hours he or she works each day. To be able to take thesefactors into account, workers will often wear monitors in thefield to measure exposure levels in their routine work. Researchlike this provides critical data for defining protectivestandards for pesticide handlers and applicators. Without theseand similar studies characterizing the exposures received byindividuals in the normal course of their work and daily life,the Agency would not understand adequately either what types ofapplication equipment and protective clothing to require for apesticide, or how soon harvesters or other workers could safelyenter pesticide-treated areas.
Some human research, however, involves intentional exposure ofhuman subjects-defined in this rule as exposure they wouldnot have experienced had they not participated in the research.One kind of research involves exposing subjects to low doses of asubstance to measure how it is absorbed, distributed,metabolized, and excreted. Humans process some substancesdifferently from animals, and studies of this kind can provideessential support for safety monitoring programs, such as thosewhich measure the known metabolites of a substance in the bloodor urine of workers to estimate their exposure to thesubstance.
Although EPA has not required or encouraged it, some thirdparties have occasionally conducted and submitted to EPA reportsof research involving intentional exposure of human subjects to asubstance to identify or measure its toxic effects. These studiesoccur in a controlled laboratory or clinical setting.
Animal data alone can sometimes provide an incomplete ormisleading picture of a substance's safety or risks. Sometimeshuman research shows people to be more susceptible than animalsto the effects of a chemical, and supports regulatory measuresmore protective than could be justified by animal data alone.This has been the case, for example, for arsenic, certain airpollutants, and the pesticide ingredients methyl isothiocyanate(MITC) and hexavalent chromium. Even when human research doesnot show people to be more sensitive than animals, scientificallysound human data developed under strict ethical standards canstrengthen the basis for EPA regulatory actions.
C. Societal Concern over the Ethics of Human Research
Scientific experimentation with human beings has always beencontroversial. The history of human research contains well-knownexamples of unethical behavior in the name of science, which haveled to reforms in the way the government and others carry out andoversee human research. Through these reforms, the standards forethical human research have evolved to become progressively morestringent and protective of the subjects of the research. In theUnited States the "Common Rule," a regulationfollowed by EPA and 17 federal departments and agencies, containsa widely accepted set of standards for conducting ethicalresearch with human subjects, together with a set of proceduresdesigned to ensure that the standards are met. See Unit V.
For several years EPA has been at the center of an intensedebate about the acceptability of intentional dosing humantoxicity studies for pesticides, and about what to do with humanstudies that are ethically deficient. In this debate some haveargued that all research involving intentional exposure of humansubjects to pesticides is fundamentally unethical and shouldnever be conducted or accepted. Others, while acknowledging thepossibility of ethical human research with pesticides, haveargued that EPA should simply refuse to consider data fromethically problematic research in its regulatory decisions. Thosewho hold this view interpret Agency reliance on an ethicallyflawed study as an endorsement of the investigators' behavior,and as encouragement to others to engage in similarly unethicalresearch. Some also argue that EPA's reliance on ethicallydeficient human data could directly benefit the wrong-doer. Forexample, if EPA based a regulatory decision on a human study thatshows humans to be less sensitive than animals, the result mightbe a less stringent regulatory measure, advantageous to thecompany that conducted the study. If the key study wasunethical, the company could benefit from its own misconduct.
On the other hand, human research has contributed enormouslyto scientific understanding of the risks posed by many substancesin the environment, and to some of EPA's past regulatory actions.With this in mind, others argue that the Agency should considerall relevant and scientifically sound information-notexcluding ethically deficient human data-because to do sowill lead to better decisions, based on assessments that betterreflect actual risks. Holders of this view argue that theethical deficiencies of the research are the responsibility ofthe researchers, not of EPA. They further argue that EPA can dono additional harm to the subjects of the research by relying onscientifically valid and relevant data from an ethicallydeficient study, whereas EPA's refusal to rely on such data coulddo nothing to benefit the subjects of the research. Moreover,they assert that while the Agency cannot undo what has alreadyhappened, EPA can clearly express its disapproval of pastunethical conduct. Holders of this view also stress theimportance of strengthening protections for volunteers whoparticipate in future studies, while taking advantage of all thatpast research can offer to benefit society.
D. EPA's Solicitation of Expert Advice
In response to public concerns over human research withpesticides, EPA convened an advisory committee under the jointauspices of the EPA Science Advisory Board (SAB) and the FIFRAScientific Advisory Panel (SAP) to address issues of thescientific and ethical acceptability of such research. Thiscommittee, known as the Data from Testing of Human SubjectsSubcommittee (DTHSS), met in December 1998 and November 1999, andcompleted its report in September 2000. Their report is availablein the public docket for this rulemaking, and on the web at: http://www.epa.gov/science1/pdf/ec0017.pdf .
The DTHSS advisory committee agreed unanimously on severalbroad principles, including the following:
• Any policy adopted should reflect the higheststandards, and special concern for the interests of vulnerablepopulations.
• The threshold of justification for intentionalexposure of human subjects to toxic substances should be veryhigh.
• The justification cannot be to facilitatecommercial interests, but only to safeguard public health.
• Not only the nature and magnitude of risks andbenefits but their distribution must be considered in assessingresearch protocols.
• Bad science is always unethical.
No clear consensus, however, emerged from the committee onmany other points, including either the scientific merit or theethical acceptability of studies to identify or measure toxiceffects of pesticides in human subjects. A vigorous publicdebate continued about the extent to which EPA should accept,consider, or rely on third-party intentional dosing human studiesfor pesticides.
In December 2001, EPA asked the advice of the National Academyof Sciences (NAS) on the many difficult scientific and ethicalissues concerning intentional human dosing studies. At EPA'srequest, the NAS convened a committee to provide the requestedadvice. The committee met publicly in December 2002, and again inJanuary and March 2003. After long and thoughtful considerationof the full range of issues, the committee released its finalreport, "Intentional Human Dosing Studies for EPARegulatory Purposes: Scientific and Ethical Issues," inFebruary 2004. Their report is available at: http://www.nap.edu/books/0309091721/html/ .
The NAS recommendations addressed what standards should guidethe conduct of future human research and whether or not EPAshould rely on the results of ethically deficient human studies.The NAS Report concluded that the answers to these questionsshould start from the existing standards for the ethicaltreatment of human research embodied in the Common Rule. The NASReport then offered numerous recommendations, supported bydetailed rationales, for how to apply the principles of theCommon Rule to the particular issues confronting EPA. EPA hasrelied heavily on the advice of this committee in developing thisrule. The NAS Report discusses the full range of types of humanstudies available to EPA and the full breadth of statutoryprograms under which they might be considered.
E. Balancing Conflicting Societal Goals
EPA's mission is to make the best possible regulatorydecisions to protect public health and the environment. EPA doesnot want to ignore potentially important information that mightbenefit its assessments and decision-making. At the same time,the Agency's conduct should encourage high ethical standards inresearch with human subjects. If all research with humansubjects always met the highest contemporary ethical standards,these goals could all be pursued together. But sometimes theyconflict.
Two salient issues illustrate the difficulty in striking anappropriate balance between societal goals in conflict. First,the Agency must decide what standard to apply to assess theethical acceptability of research performed before the new ruletakes effect. The choices are: To apply today's standards ofethical conduct to research performed in the past, or to judgepast research against the ethical norms prevailing when it wasconducted.
Codes of ethical research conduct regulate the behavior ofinvestigators before and during the research. It is reasonableto expect investigators to follow ethical codes that prevail whenthey do their work; but EPA believes it is unreasonable to expectthem to anticipate and follow standards that may be developedafter their work is done. EPA believes that scientificallymeritorious research that adhered to accepted high ethicalstandards when it was conducted should not be set aside becauseethical standards have subsequently changed. EPA also believesthat ethical standards are likely to continue to change in thefuture and that if and when they do, such a change should notinvalidate or make unacceptable otherwise meritorious researchconducted now, in conformity with high ethical standards oftoday. Other parts of the U.S. government, and other countries,have arrived at a similar position.
In the final rule, EPA has implemented the applicablerecommendation of the NAS, and will accept scientificatiatedbefore the rule becomes effective unless there is clear andconvincing evidence that it was fundamentally unethical orsignificantly deficient with respect to the ethical standardsprevailing when the research was conducted.
The second salient issue concerns whether it is ever justifiedto rely on a report of scientifically sound research judged to beunethical. To illustrate this problem, assume that EPA receiveda report of scientifically valid research involving intentionalexposure of children, which is defined by this rule asunacceptable. But assume this study shows that the level ofexposure to the tested substance safe for children is 5 parts perbillion (ppb), whereas all other information available fromanimal studies and ethical human studies suggests that childrenwould be safe if exposed at levels up to 90 ppb. A regulatorystandard of 5 ppb based on the unacceptable study wouldadequately protect exposed children; a standard which did notrely on the unacceptable study would be set at 90 ppb, and wouldnot adequately protect exposed children.
In such a situation, what should the Agency do? If EPArefused to rely on the unethical research in this example, itwould set its standard at 90 ppb and would not adequately protectexposed children. Moreover, if the final rule always prohibitedreliance on data from research involving intentional exposure ofchildren, even in this exceptional case, using the data tojustify a level at 5 ppb would be a plain violation of aregulation that could be subject to legal challenge.
The ethical and responsible course, EPA believes, would be torely on the data to set a fully protective standard, whilestrongly condemning unethical research conduct and imposingappropriate administrative sanctions. Moreover, the number ofpeople who would benefit from EPA's regulatory intervention couldbe far greater than the number of subjects involved in theresearch. Thus EPA has retained the proposed exception, topermit it to take legally defensible action to protect publichealth in this kind of exceptional situation.
EPA expects a circumstance like this example to arise onlyrarely, if at all. But however rarely it might occur, anydecision to rely on unacceptable data, should only be made withgreat care, with full opportunity for public discussion, and inreliance on expert advice. As discussed further later, the finalrule both provides for the essential public health protectionexception, narrowly defined, and meets all these additionalcriteria.
III. EPA's Proposed Human Studies Rulemaking andGeneral Public Comments
Summary : This unit reviews the general publiccomments on EPA's proposed rulemaking. The detailed commentsare addressed in subsequent units of this preamble.
An extensive review of the historical development of ethicalstandards for the conduct of human research and the eventsleading up to the promulgation of this final rule appeared in thepreamble to the proposed rule, available in the public docket forthis action.
Today's final rule is the first to emerge from the processwhich began with publication of an Advance Notice of ProposedRulemaking in the Federal Register on May 7, 2003(68 FR 24410) (FRL-7302-8). On February 8, 2005 (70FR 6661) (FRL-7695-4), EPA published and invitedpublic comment on a Federal Register noticeannouncing its plan to establish a comprehensive framework fordeciding whether to consider or rely on certain types of researchwith human subjects.
On September 12, 2005 (70 FR 53838) (FRL-7728-2),EPA published in the Federal Register a notice of proposed rulemakingto strengthen the protections for people who participate assubjects in human research. The Agency proposed to banintentional dosing human testing for pesticides when the subjectsare pregnant women or children, to formalize and furtherstrengthen existing protections for subjects in human researchconducted or supported by EPA, and to extend new protections toadult subjects in human research for pesticides, involvingintentional exposure of human subjects and conducted by otherswho intend to submit the research to EPA. The proposal alsocontained provisions to establish an independent Human StudiesReview Board responsible for reviewing proposals to conduct new,intentional-exposure human research under the pesticide laws andEPA decisions to rely on the results of certain types ofcompleted human research in its actions under the pesticideslaws.
EPA received approximately 50,000 comments during the90-day public comment period. The vast majority of thecomments were submitted by private individuals as part of e-mailand letter-writing campaigns. The remaining unique comments camefrom individuals and organizations representing a range ofstakeholders including pesticide companies, farm groups and otherpesticide users, and environmental and public health advocacygroups. EPA has reviewed, summarized, and responded to thesecomments in the Response to Comments document available in thedocket for this rule. In addition, this unit summarizes themajor themes raised by the comments on the proposal, and explainshow EPA has addressed them in the final rule.
Comment : All human research with pesticides isfundamentally unethical.
Response : EPA agrees with the advice it hasreceived, as discussed in Unit II., from its advisory committees.The SAB/SAP Data from Testing of Human Subjects Subcommitteeagreed that although ethical human research with pesticides waspossible, the threshold of justification should be set very high.The NAS Committee likewise counseled care, recommending manyspecific conditions which should be satisfied, but nonethelessacknowledged the possibility of ethical research when thoseconditions were met. On that basis EPA has gone forward withthis final rule.
Comment : Comments objected to the Agency'srulemaking on the ground that it would promote unethical researchon human subjects by pesticide companies.
Response : EPA expects its tougher new ruleswill eliminate all unethical research and will decrease theoverall number of future intentional dosing studies conducted forpesticides. The additional science and ethics reviews by EPA andthe Human Studies Review Board should eliminate any proposedunethical research.
Over the period 1996 to 2001, EPA received approximately 33intentional dosing studies of all types annually. These includedstudies measuring worker exposure; the efficacy of insectrepellents; studies of absorption, distribution and excretionthat help EPA assess exposure; and studies of systemic toxicity.Of these 33, only 4 a year, on average, involved intentionalexposure of human subjects to measure minor, reversible systemictoxic effects. (Systemic effects are those that occur within thebody, such as trembling, nausea, or headaches resulting fromchemical changes in the nervous system.) See the EconomicAnalysis, Appendix B.
Since 1996 we have received about 26 intentional dosing,systemic toxicity studies on humans. After this rule isfinalized, we expect that number to decrease from an average of 3a year to as few as 0 or 1 per year. We expect that number ofnon-toxicity intentional dosing studies to remain about the same.
Comment : The proposal was unclear.
Response : Many comments on the proposed rulereflected confusion about which provisions applied to EPA andwhich to regulated third parties, and about how the standardsapplying to the conduct of new research by EPA or third partiesdiffered from the standards applying to EPA decisions to consider completed research. These different elements were mingled insome subparts of the proposed rule, contributing to thisconfusion. A concerted effort has been made in the final rule toeliminate these potential causes of confusion, by sharpening thefocus of each subpart and grouping subparts in three broadgroups:
• Rules applying to EPA's conduct and support ofnew research with human subjects.
• Rules applying to certain types of newthird-party research for pesticides with human subjects.
• Rules applying to EPA in its regulatory capacity.
Comment : Ethical standards can be evaded simplyby denying intent to submit the results of the research toEPA.
Response : The final rule, like the proposal,extends the Common Rule requirements only to third-party researchintended for submission to EPA under the pesticide laws, FIFRAand FFDCA. EPA believes this is appropriate because there hasnot been adequate consideration of the policy consequences ofextending the provisions of the final rule to investigators whohave no intent to provide their research results to EPA and wouldotherwise have no reason to be aware of these requirements.
EPA also disagrees that the approach used in the final rulemakes it easy to evade ethical standards for research by denyingthe intent to submit. Several elements in the final ruleinteract to ensure the application of appropriate standards.First is the explicit presumption in the rule that all researchsubmitted by a pesticide registrant was intended for submissionto EPA. Specific, credible documentation would have to beprovided to rebut this presumption; a denial of intent, standingalone, could not serve as a rebuttal.
Second, if a submitter successfully rebutted the presumptionof intent, it would make little practical difference, and wouldcertainly not compel the Agency to accept unethically conductedresearch. Under the final rule, whether or not it was intendedfor submission to EPA when research was initiated, and whether ornot it was otherwise subject to the requirements of subpart K:(1) After the effective date of the rule, all reports of humanresearch submitted to EPA under the pesticide laws are requiredby subpart M to be accompanied by documentation of ethicalconduct of the research, (2) all completed post-ruleintentional-exposure research, on which the Agency intends torely in actions under the pesticide laws, is required by subpartP to be reviewed by the Human Studies Review Board, and (3) allpost-rule intentional-exposure research considered under thepesticide laws is subject under subpart Q to the Common Rule asthe ethical standard of acceptability.
Consequently, the likelihood that unethical research will beused by EPA in actions under its pesticide laws is verysmall-only when it is determined that the data are crucialto support more protective public health actions would the Agencyconsider such data.
Comment : Limitation to research involvingintentional exposure of human subjects excludes many kinds ofstudies.
Response : Most third-party human research forpesticides conducted by or for EPA, or intended for submission toEPA, meets the rule's definition of research involvingintentional exposure, and thus will be subject to therequirements of subpart K. But whether or not research issubject to subpart K, all reports of all post-rule human researchsubmitted to EPA are required by subpart M to be accompanied bydocumentation of ethical conduct.
Comment : Prohibitions of new research involvingintentional exposure of pregnant women, fetuses, and children aresubject to exceptions.
Response : The rule provides for no exceptionsunder any circumstances to the bans on the conduct of newresearch involving intentional exposure of pregnant women,fetuses, and children as subjects. The final rule has beenrevised for clarity; the prohibitions have been moved to subpartsB (applying to EPA) and L (applying to third parties,) where theystand alone, and they have been reworded to emphasize that theyapply notwithstanding any other provisions anywhere in 40 CFRpart 26.
Comment : The prohibition on considering humansubjects research involving intentional exposure of pregnantwomen, fetuses, and children applies only to regulatorydecisions, and not to such non-regulatory agency actions as riskassessments.
Response : The final rule has been changed fromthe proposal to make this prohibition applicable to all Agencyactions taken under the pesticide laws.
Comment : The proposed exception permitting EPAto consider unethically obtained data when to do so would be"crucial to protection of public health" underminesall other provisions of the rule. Anything from a more accuraterisk assessment to increased agricultural production could beinterpreted as "crucial to protection of publichealth," and used to justify reliance on unethicaldata.
Response : Such a broad interpretation was neverintended by the Agency, but EPA acknowledges that its intentionswere not perfectly clear from the language of the proposal. Thefinal rule retains a "public health exception," butit is reworded to make it very clear that it could never beinvoked to support a less stringent regulatory outcome than couldbe justified without consideration of the unethical research.
Comment : Many provisions of the Common Ruleallow for exceptions to its requirements at the discretion of theAdministrator or Institutional Review Boards (IRBs); theseexceptions should not be allowed for third-party research.
Response : EPA agrees that some exceptions inthe Common Rule are not appropriate for the kinds of third-partyhuman research covered by this rule. In mirroring the coreprotections of the Common Rule as they apply to third parties insubpart K of the final rule, EPA has eliminated or narrowed manyof these exceptions, as discussed in detail in Unit VII.
IV. Reorganization of the Rule Structure
Summary : To clarify the various requirements inthe proposal and how they apply to first, second, and thirdparties, the Agency has extensively reorganized the final rule.The new organization regroups the provisions of the proposal intoseveral new subparts.
In this final rule, EPA's codification of the Common Ruleremains in force with no changes except to designate it assubpart A of part 26. Following today's action, the text of 40CFR 26.101 through 26.124 remains identical to the codificationsof the Common Rule by the other federal departments and agenciesthat have promulgated it.
The remaining subparts in the final rule, each discussed in alater unit of this preamble, are grouped as follows:
• Subparts A through D apply to EPA as aninvestigator or sponsor of new research with human subjects, andto second-party investigators whose research EPA supports.Subpart A contains the basic policy for human research (theunchanged Common Rule). Subpart B prohibits EPA human subjectsresearch on any substance involving intentional exposure ofpregnant women, fetuses, or children. Subparts C and D provideadditional protections for pregnant women, fetuses, and childrenwhen they are subjects of observational studies conducted orsupported by EPA.
• Subparts K and L apply to third parties asinvestigators or sponsors of new research involving intentionalexposure of human subjects and intended for submission to EPAunder the pesticide laws. Subpart K establishes the basicprotections for non-pregnant adult subjects in coveredthird-party research, corresponding in substance to subpart A.Subpart L prohibits covered third-party human subjects researchfor pesticides involving intentional exposure of pregnant womenor children.
• Subpart M applies to all third parties who submitreports of any research with human subjects to EPA under thepesticide laws, whether or not the research is covered by subpartK, and requires concurrent submission of information documentingthe ethical conduct of such research.
• Subparts O-Q apply to EPA in its regulatorycapacity. Subpart O identifies potential actions fornoncompliance with subparts A through L. Subpart P addresses theestablishment and operation of the Human Studies Review Board,and subpart Q defines the ethical standards EPA will use todecide whether to rely on data from human research in EPAactions.
Because this reorganization causes extensive changes in thenumbering of the provisions of the final rule, EPA provides thefollowing table to make it easier to follow how thereorganization affects the location of specific provisions.
| Location in Final Rule | Subpart | Section | Title/Description | Location in Proposed Rule | Subpart | Section |
|---|---|---|---|---|---|---|
| A | §§ 26.201 thru 26.124 | Basic Policy for Protection of Subjects in HumanResearch Conducted or Supported by EPA | A | §§ 26.101 thru 26.124 | ||
| B | §§ 26.201 thru 26.203 | Prohibition of Human Subjects Research Conducted orSupported by EPA Involving Intentional Exposure of PregnantWomen, Fetuses, or Children | B and D | §§ 26.220 and 26.420 | ||
| B | § 26.201 | To what does this subpart apply? | n/a | n/a | ||
| B | § 26.202(a) | Definition of research involvingintentional exposure of a human subject | A | § 26.102(k) | ||
| B | § 26.202(b) | Definition of child | D | § 26.402(a) | ||
| B | § 26.203 | Prohibition of EPA human subjects research involvingintentional exposure of pregnant women, fetuses, or children | B and D | §§ 26.220 and 26.420 | ||
| C | §§ 26.301 thru 26.305 | Additional Protections for Pregnant Women or FetusesInvolved as Subjects in Observational Research Conducted orSupported by EPA | B | §§ 26.201 thru 26.206 | ||
| D | §§ 26.401 thru 26.406 | Additional Protections for Children Involved asSubjects in Observational Research Conducted or Supported by EPA | D | § 26.401 thru 26.408 |
| Location in Final Rule | Subpart | Section | Title/Description | Location in Proposed Rule | Subpart | Section |
|---|---|---|---|---|---|---|
| K | §§ 26.1101 thru 26.1125 | Basic Ethical Requirements for Third-Party HumanSubjects Research for Pesticides Involving Intentional Exposureof Non-Pregnant Adults | A | §§ 26.101 thru 26.124 | ||
| K | § 26.1101(a) | To what does this subpart apply? | A | § 26.101(j) | ||
| K | § 26.1101(b) | Exemption of research involving only the collectionor study of existing data . . . | A | § 26.101(b)(4) | ||
| K | § 26.1101(c) | Administrator retains final judgment as to whether aparticular activity is covered by this subpart | A | § 26.101(c) | ||
| K | § 26.1101(d), (e), and (f) | Relation to other Federal, State, Tribal, Local, orforeign laws or regulations | A | § 26.101(e), (f), and (g) | ||
| K | § 26.1101(g) | For purposes of determining a person's intent underparagraph (a) of this section . . . | A | § 26.101(k) | ||
| K | §§ 26.1102(a) thru 26.1102(h) | Definitions | A | §§ 26.102(a) thru 26.102(i) | ||
| K | § 26.1102(i) | Definition of research involving intentional exposure. . . | A | § 26.102(k) | ||
| K | § 26.1102(j) | Definition of person | n/a | n/a | ||
| K | §§ 26.1107 thru 26.1117 | IRB and informed consent requirements | A | §§ 26.107 thru 26.117 | ||
| K | § 26.1123 | Early termination of research | A | § 26.123(a) | ||
| K | § 26.1125 | Prior submission to EPA of proposed human research | A | § 26.124(b) | ||
| L | §§ 1201 thru 26.1203 | Prohibition of Third-Party Human Subjects Researchfor Pesticides Involving Intentional Exposure of Pregnant Women,Fetuses, or Children | B and D | §§ 26.220 and 26.420 | ||
| M | §§ 1301 thru 26.1303 | Requirements for Submission of Information on theEthical Conduct of Completed Human Research | A | § 26.124(c) |
| Location in Final Rule | Subpart | Section | Title/Description | Location in Proposed Rule | Subpart | Section |
|---|---|---|---|---|---|---|
| O | §§ 26.1501 thru 26.1503 | Administrative Actions for Noncompliance | E | §§ 26.501 thru 26.506 | ||
| P | §§26.1601 thru 26.1603 | Review of Proposed and Completed Human Research | A | § 26.124(b) | ||
| P | § 26.1601(c) | Determination of Equivalence of Foreign EthicalStandards | A | § 26.101(h) | ||
| P | § 26.1603 | Operation of the Human Studies Review Board | A | § 26.124(b)(5) | ||
| Q | §§ 26.1701 thru 26.1703 | Ethical Standards for Assessing Whether to Rely onthe Results of Human Subjects Research in EPA Actions | B, D, and F | §§ 26.221, 26.421, 26.601, 26.602,and 26.603 | ||
| Q | §§ 26.1701 and 26.1702 | Applicability and Definitions | n/a | n/a | ||
| Q | § 26.1703 | Prohibition of reliance on research involvingintentional exposure of pregnant women, fetuses, or children | B and D | §§ 26.221 and 26.421 | ||
| Q | § 26.1704 | Prohibition of reliance on unethical human researchconducted before the effective date of the final rule | F | § 26.601 | ||
| Q | § 26.1705 | Prohibition of reliance on unethical human researchconducted after the effective date of the final rule | F | § 26.602 | ||
| Q | § 26.1706 | Criteria and procedures for decisions to protectpublic health by relying on otherwise unacceptable research | F | § 26.603 |
V. Subpart A-Basic Ethical Protections for Subjectsof Human Research Conducted or Supported by EPA
Summary : This unit describes the basic ethicalprotections that apply to human research conducted or supportedby EPA. Unit V.A. discusses the comprehensive system of ethicalprotections created by the "Basic Federal Policy forProtection of Human Research Subjects," generally referredto as the Common Rule. The Common Rule applies to all humanresearch conducted or supported by EPA and 17 other federaldepartments and agencies. Unit V.B. discusses the proposed rule,Unit V.C. discusses public comments, and Unit V.D. discusses thefinal rule.
A. The Common Rule
The Common Rule defines the core protections for humansubjects of research, and it is important to understand just whatthose protections are.
First, the Common Rule requires that research with humansubjects be overseen by a qualified, independent IRB meetingspecific requirements laid out in the rule governing membership,procedures, decision-making, recordkeeping, and avoidance ofconflicts of interest. The IRB is vested with responsibility toreview proposed research, and with authority to approve ordisapprove it. The IRB is also responsible for overseeing theconduct of approved research, and investigators are required toreport any unanticipated events to the responsible IRB. IRBmembers must be trained, and must remain current with extensiveguidance promulgated by the Office for Human Research Protectionsin HHS.
Under the Common Rule an IRB may approve proposed humansubjects research only when it concludes that all of the following conditions are satisfied:
• Risks to subjects have been minimized.
• Risks to subjects are reasonable in relation toanticipated benefits, if any, to subjects, and the importance ofthe knowledge that may reasonably be expected to result.
• Selection of subjects is equitable.
• Informed consent will be sought from eachprospective subject or the subject's legally authorizedrepresentative.
• Informed consent will be appropriatelydocumented.
• The research plan makes adequate provision formonitoring the data collected to ensure the safety ofsubjects.
• There are adequate provisions to protect theprivacy of subjects and to maintain the confidentiality ofdata.
• Additional safeguards have been included in thestudy to protect the rights and welfare of subjects who arelikely to be vulnerable to coercion or undue influence, such aschildren, prisoners, pregnant women, mentally disabled persons,or economically or educationally disadvantaged persons.
The Common Rule also requires each IRB to maintain records ofeverything it reviews, of its discussion of controversial issues,and of its decisions and their rationale.
The second major element in the Common Rule is its requirementthat no investigator involve a human being as a subject inresearch without the informed consent of the subject or thesubject's legally authorized representative. The Common Rulefurther specifically requires that:
• An investigator shall seek such consent onlyunder circumstances that provide the prospective subjectsufficient opportunity to consider whether or not to participateand that minimize the possibility of coercion or undueinfluence.
• The information given to the subject must be inlanguage understandable to the subject.
• No informed consent, oral or written, may includeany exculpatory language through which the subject is made towaive or appear to waive any of the subject's legal rights, orreleases or appears to release the investigator, the sponsor, theinstitution or its agents from liability for negligence.
The Common Rule defines the following mandatory elements in informed consent:
• A statement that the study involves research, anexplanation of the purposes of the research and the expectedduration of the subject's participation, a description of theprocedures to be followed, and identification of any procedureswhich are experimental.
• A description of any reasonably foreseeable risksor discomforts to the subject.
• A description of any benefits to the subject orto others which may reasonably be expected from the research.
A disclosure of appropriate alternative procedures or coursesof treatment, if any, that might be advantageous to thesubject.
• A statement describing the extent, if any, towhich confidentiality of records identifying the subject will bemaintained.
• For research involving more than minimal risk, anexplanation as to whether any compensation and any medicaltreatments are available if injury occurs and, if so, what theyconsist of, or where further information may be obtained.
• An explanation of whom to contact for answers topertinent questions about the research and research subjects'rights, and whom to contact in the event of a research-relatedinjury to the subject.
• A statement that participation is voluntary,refusal to participate will involve no penalty or loss ofbenefits to which the subject is otherwise entitled, and that thesubject may discontinue participation at any time without penaltyor loss of benefits to which the subject is otherwiseentitled.
The Common Rule specifies additional elements of informedconsent that are sometimes required, and defines standards fordocumenting informed consent by use of a written consent formapproved by the IRB and signed by the subject. The Common Rulerequires that a copy be given to the person signing the form.
The Common Rule extends these core protections to all humansubjects of covered research, including those in vulnerablepopulations. It is to this base of core protections for allsubjects that "additional protections" for pregnantwomen, fetuses, and children as subjects of observationalresearch conducted or supported by EPA, as contained in subpartsC and D of this final rule, are added. Vulnerable populationsfor which no "additional protections" are provided byrule are not left defenseless or exploited; they are covered bythese core protections of the Common Rule, including itsrequirement that IRBs ensure, on a case-by-case basis, thatadditional safeguards are employed in any study involvingvulnerable populations to protect their rights and welfare.
In addition to these substantive protections for researchsubjects, the Common Rule as it applies to research conducted orsupported by EPA or any other signatory department or agency alsocontains many administrative provisions intended to accommodatethe wide range of circumstances in all the departments andagencies to which it applies. Among others, these administrativeprovisions include:
• Authority for the agency head to extend coverageof the rule to research "otherwise subject toregulation" (§ 26.101(a)) and to determine whatis within its scope (§ 26.101(c) and (d)).
• Provision that only certain sections apply tothird-party research subject to regulation(§ 26.101(a)(2)).
• A list of six kinds of human research exemptedfrom coverage by the rule (§ 26.101(b)).
• Provision for approving research conducted underforeign standards that "afford protections that are atleast equivalent to those provided in" the Common Rule(§ 26.101(h)).
• A grant of discretion to the agency head to waiveprovisions of the rule, with public notice in the Federal Register and to the DHHS Office for HumanResearch Protections (§ 26.101(i)).
• A grant of discretion to IRBs to waive or alterrequirements for informed consent (§ 26.116(c) and(d)) or documentation of informed consent(§ 26.117(c)).
B. The Proposed Rule
The September 12 proposal to extend EPA's Common Rule tothird-party research involved extending all the provisions ofsubpart A,§§26.101 through 26.124, to covered third-partyresearch. It also would have altered the shared text of theCommon Rule by adding:
• A new paragraph defining the scope of third-partyresearch to which it applied (proposed§ 26.101(j)).
• A new paragraph defining how a party's intent tosubmit research to EPA would be determined (proposed§ 26.101(k)).
• A new definition of research involvingintentional exposure of a human subject (proposed§ 26.102(k)).
• A new requirement for prior submission to EPA ofproposals for covered third-party research (proposed§ 26.124(b)).
• A new requirement for submission to EPA ofdocumentation of the ethical conduct of completed research(proposed § 26.124(c)).
As noted in the preamble to the proposal, HHS requested EPAnot to make any alterations in the text of the shared CommonRule, and to codify the extension of the Common Rule standards tothird-party research in the final rule in a way that left subpartA-the Common Rule-intact and unchanged. EPA agreedthat the Common Rule should not be altered, and committed tomaking this change in the final rule.
C. Public Comment
Comment : The proposed extension of the entireCommon Rule, including its provisions for administrative waiversof many requirements, alarmed many commenters. Theseadministrative provisions were perceived as loopholes which couldbe exploited to undermine the whole purpose of extending theCommon Rule.
Response : Such exploitation of these provisionswas never the Agency's intent, and EPA agrees with the commenterswho argued that many of these administrative provisions were notappropriate in a rule applying to third-party research. Thus,while subpart K in the final rule does extend all the substantivecore protections of the Common Rule to non-pregnant adultsubjects of covered research, it also eliminates or narrows theexceptions in the Common Rule. Unit VII. discusses each changefrom the Common Rule to subpart K in detail.
D. The Final Rule
In the final rule subpart A is the unaltered Common Rule,exactly as promulgated in 1991 except for its designation as"Subpart A." It applies to all research with humansubjects conducted or supported by EPA.
VI. Subpart K-General Provisions Applying to ThirdParty, Intentional Exposure Human Research under the PesticideLaws
Summary : Subpart K extends the basicprotections of the Common Rule to subjects in certain researchconducted or supported by third parties. It applies tothird-party human research involving intentional exposure ofnon-pregnant adult subjects and that is intended to be submittedto EPA under the pesticide laws. In addition to the basicprocedures and protections contained in the Common Rule, it alsorequires researchers who propose to conduct new research coveredby the rule to submit protocols and other materials for scienceand ethics review by both EPA and a newly created Human StudiesReview Board (HSRB). Unit VI.A. summarizes EPA's proposal, UnitVI.B. discusses public comment, and Unit VI.C. discusses theprovisions of the final rule.
A. EPA's Proposed Rule
EPA's proposal added to the "Scope" section of theCommon Rule additional paragraphs, proposed§ 26.101(j) and (k), to make the provisions of theCommon Rule applicable to certain third-party human research.Thus, the Agency's proposal would have extended the Common Rulerequirements to third parties, without substantive or editorialmodification.
The scope of the third-party human research covered by theproposal was defined as:
[A]ll research involving intentional exposure of a humansubject if, at any time prior to initiating such research, anyperson who conducted or supported such research intended:
(1) To submit results of the research to EPA for considerationin connection with any regulatory action that may be performed byEPA under the Federal Insecticide, Fungicide, and Rodenticide Act(7 U.S.C. 136 et seq. ) or section 408 of the Federal Food, Drug,and Cosmetic Act (21 U.S.C. 346a); or
(2) To hold the results of the research for later inspectionby EPA under the Federal Insecticide, Fungicide, and RodenticideAct (7 U.S.C. 136 et seq. ) or section 408 of theFederal Food, Drug, and Cosmetic Act (21 U.S.C. 346a).
In effect, this provision would have included allintentional-exposure human research conducted with the intent tosubmit the results to the Agency under the pesticide laws. Theproposal also established a rebuttable presumption that anyinformation submitted by a person regulated under the pesticidelaws was generated with the intent to submit it to EPA.
In § 26.102(k), the proposal defined"research involving intentional exposure of a humansubject" to mean "a study of a substance in whichthe exposure to the substance experienced by a human subjectparticipating in the study would not have occurred but for thehuman subject's participation in the study." The preambleto the proposed rule explained that this term did not include astudy that "monitored agricultural workers (such asprofessional fruit thinners or harvesters or other workers) whoperform their usual work in areas that have been treated withpesticides at rates and using methods registered and approved byEPA" (70 FR 53846). The preamble also explained thatintentional exposure studies did not include "mostoccupational exposure studies, and studies involving use ofregistered pesticides for approved uses according to labeldirections" (70 FR 53845).
In addition, the proposed rule included a new section,proposed § 26.124, that would have required any personproposing to conduct a new human study covered by the rule tosubmit the protocol and other materials for a science and ethicsreview by EPA. The same proposed section also created a newindependent panel of experts, called the Human Studies ReviewBoard, to review all proposed new research covered by the rule.The HSRB would also review all completed human research that EPAintended to rely on under the pesticide laws.
B. Public Comments
The major public comments applicable to subpart K of the finalrule are discussed in Unit III.
C. The Final Rule
The final rule establishes new requirements for third-partyresearch in a separate subpart K, and the rule text defining thescope of the types of third-party research covered by theproposed rule remains unchanged in the final rule. The Agency,however, has decided that the types of research captured by thedefinition of "research involving intentional exposure of ahuman subject" is broader than suggested by the preambleto the proposal. Although the text of the definition remains thesame, EPA thinks it is important to clarify that the term coversany research on a substance, unless the subjects of the researchretain complete control over whether, when, and how they areexposed to the substance. Thus, if the researcher decides aparticular compound will be studied in the research anddetermines the manner in which subjects will be exposed, theresearch falls within the scope of "research involvingintentional exposure."
The substantive requirements applicable to covered third-partyresearch are similar to the requirements contained in the CommonRule. In most cases the text is identical, and the sectionsemploy a parallel numbering system. The sections in subpart Kare designated as §§ 26.1101 through 26.1125 andcorrespond to the sections of the Common Rule designated§§ 26.1xx. For example, § 26.1107 insubpart K corresponds to § 26.107 of the CommonRule.
EPA also made a number of minor modifications to the text ofthe Common Rule in order to reflect the applicability of subpartK to a particular subset of human subjects research studiesinvolving intentional exposure of non-pregnant adults intendedfor submission under the pesticide laws. These modifications arediscussed in paragraph 1 below.
1. Modifications to the text of the Common Rule insubpart K . In a number of its provisions the Common Rulerefers to itself as a "policy." Throughout subpartK, EPA has replaced the word "policy" with"subpart," to remove any doubt about whether theprovisions of subpart K create binding requirements.
Throughout subpart K, EPA replaced references to"department or agency head" with "theAdministrator." Section 26.1102 includes a definitionstating that Administrator refers to the Administrator of EPA orany officer or employee to whom authority has been delegated.
Section 26.101(b) of the Common Rule exempts research in sixcategories from the requirements of the Common Rule. Theseexemptions generally cover:
(i) Research on educational practices conducted in aneducational setting.
(ii) Research involving surveys, educational tests,observation, or interviews that involve no collection ofsensitive personal information on identifiable individuals.
(iii) Research involving surveys, educational tests,observation, or interviews that involve public officials orcandidates for public office.
(iv) Research involving the collection or study of existingdata, documents, specimens, etc. from publicly available sourcesor sources that do not disclose the identity of individualsubjects.
(v) Research examining the delivery of public benefitprograms.
(vi) Research involving taste and food quality evaluation andconsumer acceptance.
Subpart K, however, covers only third-party research forpesticides involving intentional exposure of non-pregnant adults.Because five of these exemptions describe types of research thateither could not possibly or should not involve"intentional exposure" to a pesticide, EPA deletedthem from subpart K. Because the fourth category, above, couldencompass the examination of results from research involvingintentional exposure, the Agency did retain exception number 4 insubpart K. See § 26.1101(b) of the regulatorytext.
Section 26.101(d) of the Common Rule states that, withoutprior notice, an agency head may extend the requirements of theCommon Rule to specific research activities or classes ofresearch. As a legal and policy matter, EPA believes that thepublic should receive notice of and an opportunity for publiccomment on any extension of these requirements to additionalcategories of third-party research. Accordingly, subpart K doesnot contain a provision comparable to § 26.101(d).
Section 26.101(f) of the Common Rule indicates that State andlocal laws may contain additional requirements governing theconduct of human research and that the Common Rule does notsupersede those requirements. Recognizing that Native Americangovernmental entities also have legal authority to regulate theconduct of human research, EPA has added Tribal authority to thelist of legal sources that may establish additional requirementsbeyond those in the final rule. See § 26.1101(e) ofthe regulatory text.
Section 26.101(h) of the Common Rule authorizes the head of anagency to allow human research conducted in a foreign country toproceed in accordance with the requirements of that country, evenif foreign authorities require behavior that does not fullycomply with the Common Rule, so long as the agency headdetermines that the requirements of the foreign country provideprotections "at least equivalent to those [of the CommonRule.]" This section further provides that when an agencyhead makes such a decision, he must publish a notice of theaction in the Federal Register . In promulgatingsubpart K, EPA retained a comparable provision, but with severalchanges. First, EPA moved this provision to subpart P of thefinal rule, which addresses EPA's decisions on the acceptabilityof proposed research, where it appears as§ 26.1601(c). Second, EPA did not adopt the CommonRule's requirement to publish a Federal Register Notice announcing such a decision on proposed third-partyresearch. The Agency concluded that such a procedure wasredundant with the HSRB process, which will involve both atransparent presentation of EPA's positions regarding proposedresearch and public meetings about such positions and anopportunity for the public to comment on them.
Section 26.101(i) contains language allowing the Administratorto waive any of the requirements of the Common Rule. While everyother federal Common Rule agency and department has suchdiscretion, and while such discretion seems appropriate forfirst- and second-party research, EPA has never exercised thisauthority under the Common Rule and sees no need for suchdiscretion under subpart K. Accordingly, subpart K does notcontain a provision comparable to § 26.101(i).
The definitions in the Common Rule include the term research subject to regulation ; see§ 26.102(e). Subpart K omits this definition becausethe types of third-party research covered by the rule arespecified by the paragraphs in § 26.1101 delineatingthe scope of subpart K.
Section 26.102(j) contains a definition of the term certification . Because this definition actuallyestablishes a substantive obligation to submit documentation ofIRB approval, the substantive requirement appears in§ 26.1125 as one of the items that must be submittedto EPA in connection with review of proposed research. See§ 26.1125(f) of the regulatory text.
EPA added a new definition of person in§ 26.1102(j) of the final rule to clarify that therequirements of subpart K (as well as subparts L and M) do notapply to first-party and second-party human research by otherfederal departments and agencies that are subject to the CommonRule. Having operated under the Common Rule for many years,these agencies and departments are very familiar with its meaningand application and have well developed procedures for assuringcompliance. Therefore, EPA sees no reason either to promulgaterequirements that duplicate regulations already in force, or toimpose on these agencies the new requirements of subpart Kconcerning submission of proposals for future research for EPAand HSRB review. Of course, the Agency will, on request, workwith other agencies intending to submit the results of humanresearch to EPA to ensure that the results may be consideredunder subpart Q.
Several sections of the CommonRule-§§ 26.107(a), 26.111(a)(3), 26.111(b),and 26.116(b)(1)-refer to additional measures required whenresearch involves pregnant women, children, or other specialpopulations as subjects. Subpart L, however, prohibitsthird-party research involving intentional exposure of humansubjects who are pregnant women (and therefore their fetuses) orchildren. Thus subpart K covers only third-party researchinvolving intentional exposure of non-pregnant adults. To beconsistent with this scope, EPA removed from subpart K allreferences to pregnant women, fetuses, newborns, or children.
The first sentence of § 26.107 of the Common Rulestates:
Each IRB shall have at least five members, with varyingbackgrounds to promote complete and adequate review of researchactivities commonly conducted by the institution.
This provision reflects the assumption that IRBs are alwaysassociated with an "institution." It also arguablywould excuse an IRB from having adequate expertise to assessstudies beyond those "commonly conducted" at theinstitution. EPA believes that IRBs should acquire whateverexpertise they need to evaluate the types of studies they agreeto review. Accordingly, EPA has revised that sentence toread:
Each IRB shall have at least five members, with varyingbackgrounds to promote complete and adequate review of researchactivities which are presented for its approval.
Section 26.108(a) of the Common Rule contains across-reference to certain earlier sections of the Common Rule.For greater clarity, and consistent with FDA's approach in itssimilar rules. EPA simply repeated the substantive requirementsof the referenced sections in § 26.1108(a) of subpartK. This led to redesignation of some paragraphs.
Section 26.109(c) of the Common Rule includes a reference to§ 26.117(c), which gives IRBs the authority, undercertain circumstances, to waive the requirement for writtendocumentation of informed consent. Since EPA has not included insubpart K a paragraph comparable to § 26.117(c) ofthe Common Rule, the Agency has deleted the cross-reference in§ 26.1109(c) of subpart K.
Section 26.114 of the Common Rule contains a provisiondesigned to facilitate cooperative research among multipleinvestigators in different institutions. This section authorizesthe head of an agency to accept a joint review or review by asingle IRB to avoid duplication of effort. Rather than use thetext of the Common Rule provision, EPA has adopted in§ 26.1114 a similar but clearer provision from FDAregulation; see 21 CFR 56.114.
Section 26.115(a)(5) of the Common Rule cites anotherprovision of the Common Rule that specifies the information aboutthe members of an IRB which the IRB is required to provide in itsrecords. In the parallel section of subpart K,§ 26.1115(a)(5), EPA followed the approach FDA used inits regulations and repeated the substantive provisions of thereferenced sections.
Sections 26.116(c) and (d) of the Common Rule authorize an IRBto waive or alter the requirement for informed consent in certaincircumstances for research conducted or supported by EPA. EPAdeleted these paragraphs from subpart K because of the centralimportance of informed consent to ensuring ethical treatment ofsubjects in human research. In addition, EPA concluded that thetypes of human research covered by subpart K-researchinvolving intentional exposure of non-pregnant adults intendedfor submission under the pesticide laws-would not meet anyof the Common Rule criteria for waiving or altering the informedconsent procedures.
EPA added a new paragraph to § 26.1116 to clarifythat the informed consent materials for research covered bysubpart K must include "the identity of the pesticide andthe nature of its pesticidal function." While implicit inthe requirements of § 26.1116(a)(1), which is derivedfrom § 26.116(a)(1) of the Common Rule, the Agencythought that the final rule should make this obligationexplicit.
In a provision that parallels the waiver authority discussedabove, § 26.117(c) of the Common Rule authorizes anIRB to waive the requirement for an investigator to obtain asigned consent form from each subject for research conducted orsupported by EPA. Because of the importance of being able todemonstrate that each subject was fully informed and freelyvolunteered to participate in the types of research covered bysubpart K, EPA decided not to adopt this Common Rule provision insubpart K. The Agency also made minor editorial changes to§ 26.1117(a) and (b) to reflect the deletion ofparagraph (c).
Section 26.101(a)(2) identifies the sections of the CommonRule which apply to "research that is neither conducted norsupported by a Federal department of agency but is subject toregulation as defined in § 26.102(e)." Thesesections include §§ 26.107 through 26.117, butnot § 26.103 or §§ 26.118 through26.124. Sections 26.118 through 26.124 generally apply toprocedures associated only with first-party and second-partyresearch, but which would not be relevant to third-partyresearch. Consistent with the thrust of§ 26.101(a)(2) and in order to reduce confusion, EPAhas not created parallel sections for § 26.103 or,with two exceptions, any of the sections after§ 26.117.
The first of these exceptions is to include in subparts K andP of the final rule two passages parallel to § 26.123of the Common Rule. Section 26.1123, which corresponds to§ 26.123(a) in subpart A, authorizes the Administratorto suspend or terminate research if EPA determines that asponsor, IRB, or investigator has materially failed to complywith the terms of subpart K. (FDA's regulations contain asimilar provision at 21 CFR 56.113.) In addition, EPA hasincluded the substance of§ 26.123(b)-authorizing EPA to consider aninvestigator's record in past ethical (or unethical) humanresearch when reviewing proposals for new research-in§ 26.1601(b) of subpart P, which governs EPA's reviewof proposed new research.
The second exception is to include in subpart P of the finalrule a § 26.1601, parallel to § 26.124 ofsubpart A. This provides that, in its review of proposed newresearch, EPA may, on a case-by-case basis, impose additionalconditions applicable to the conduct of a study that arenecessary for the protection of human subjects.
2. Revisions to the requirements for informationconcerning proposed research . In reorganizing the finalrule, EPA has moved the substantive content of proposed§ 26.125, which would have required third parties tosubmit proposals for new human research for EPA review, to§ 26.1125 of subpart K. In addition, EPA has revisedthis section in the final rule in two ways. A new§ 26.1125(d) adds "a description of thecircumstances and methods for presenting information to potentialhuman subjects for the purpose of obtaining their informedconsent" to the list of what information must be includedwith a submitted proposal for new research, and§ 26.1125(f) adds an explicit requirement fordocumentation of IRB approvals.
VII. Intentional Exposure Research: Subparts B andL-Prohibitions of Human Research Involving IntentionalExposure of Pregnant Women, Fetuses, and Children
Summary : Subpart B of the final rulecategorically prohibits EPA from conducting or supporting humansubjects research on a substance that involves intentionalexposure of pregnant women, fetuses, and children to thesubstance. See 40 CFR 26.203 of the regulatory text.
Subpart L of the final rule prohibits human subjects researchfor pesticides conducted or supported by third parties thatinvolves intentional exposure of pregnant women, fetuses, orchildren. See 40 CFR 26.1203 of the regulatory text.
Unit VII.A. summarizes EPA's proposal, Unit VII.B. discussespublic comments, and Unit VII.C. discusses the provisions of thefinal rule.
A. The Proposed Rule
The September 12 proposal contained, in § 26.220 ofproposed subpart B, a clear prohibition of any future EPAresearch involving intentional dosing of pregnant women, fetusesor certain newborns. Section 26.420 of proposed subpart Dcontained an equally clear prohibition of any future EPA researchinvolving intentional dosing of children.
The same sections of the proposal-§ 26.220 insubpart B and § 26.420 in subpart D-alsoprohibited any new third-party research intended for submissionto EPA under the pesticide laws, and involving intentional dosingof pregnant women, fetuses, or children. The proposedprohibition would, as a practical matter, have applied to anyresearch conducted by pesticide companies or by investigatorsworking on their behalf.
B. Public Comments
Almost without exception, comments on the prohibitionscontained in the proposed rule drew no distinction betweenthird-party research and first- and second-party research.Therefore, unless otherwise indicated, the following discussionapplies both to the proposed prohibitions against human subjectsresearch conducted or supported by EPA that involves intentionalexposure of pregnant women, fetuses, or children and to theprohibitions against such research by third parties who intend tosubmit the results to EPA under the pesticide laws. In addition,comments generally made the same recommendations regarding theprohibition on research involving intentional exposure ofchildren as for the prohibition on research involving intentionalexposure of pregnant women and fetuses. Again, unless otherwiseindicated, the discussion below refers to both sets ofprohibitions.
Comment : Some commenters argued that theproposed prohibitions were too narrow and should be expanded inorder that all potentially affected test subjects receivedprotection. Specifically, these comments recommended that: (1)The prohibition on research with children should not be limitedto research involving intentional exposure, but should cover alltypes of human research (including scientific observation ofpublic behavior of children); (2) the prohibition on researchwith pregnant women should be similarly broad; and (3)additional groups should be protected under the ban onintentional exposure research, including prisoners, all women ofchildbearing age, the elderly, and people with chronic diseasesor developmental disabilities.
Response : EPA believes that"observational research," i.e., research that doesnot involve intentional exposure of human subjects, oftenprovides a great deal of valuable scientific information that canbe critical for effective environmental and public healthregulation. To adopt the commenters' approach would mean, forexample, that EPA could not collect, through research involvinglittle or no risk to the subjects, information on the amount oftime that children spend outdoors, the types of food consumed bypregnant women, or the possible correlation between air pollutionand asthma in newborns. Therefore, EPA has decided not to acceptthe comments recommending expansion of the prohibitions to coverall types of human research.
EPA agrees with the commenters who point out that other groupsdeserve special consideration if they are to be included inresearch as test subjects. The Common Rule and EPA's extensionof it to certain types of third-party research already directIRBs to pay particular attention to the issues involved withresearch on several of these groups. See § 26.111(b)and § 26.1111(b) of the regulatory text. EPA believesthat the approach created by the final rule-which requiresboth EPA and HSRB review of all future third-party researchcovered by the rule-will successfully identify thosestudies that may proceed ethically and those for which it wouldnot be ethical to involve individuals from the identifiedgroups.
Comment : Some commenters argued that theproposed prohibitions were too broad and that certain kinds ofresearch should be excluded from the bans on conduct of futureresearch involving intentional exposure of human subjects.Specifically, these comments recommended exclusion of: (1)Pharmaceutical studies, particularly products for control of headand body lice; (2) nutrition studies with micronutrients that mayalso be pesticides; (3) research on the efficacy of insectrepellents; (4) research involving only use of registeredpesticides for approved uses, or "product-in-use"studies; and (5) research on the efficacy of swimming pool andspa sanitizers and disinfectants;
Response : For a variety of reasons, EPA is notpersuaded by these comments to modify the scope of its proposedprohibitions.
EPA notes that it does not conduct or support pharmaceuticalstudies and nutritional studies with any human subjects, andtherefore there is no need to modify the proposed prohibitionsfor first- and second-party research. Further, EPA did notintend its proposed prohibitions to apply to third parties whenconducting pharmaceutical or micronutrient research, and believesthat such third-party research generally would fall outside thescope of the prohibitions because they would not meet the"intent to submit" criterion in § 26.1201.In fact, EPA thinks it would be contrary to the public interestto ban research of the effects on pregnant women and children ofdrugs, like streptomycin, or micronutrients, like copper oriodine, simply because these compounds also have approved uses aspesticides. Given that it is unlikely an investigator wouldundertake such research for submission to EPA in support of apesticide action, these types of studies would not beprohibited.
EPA believes that there is no need to perform research on theefficacy of insect repellents with pregnant women or children.The efficacy of a repellent depends primarily on the propertiesof the pesticide formulation and does not vary with the age ofthe person to whom it is applied. Therefore, studies usingnon-pregnant adults should provide adequate information to assesshow well insect repellents work, and there is no reason toexclude this type of research from the prohibition.
Similarly, EPA does not believe that comments have presented acompelling argument for recommending the Agency exclude from theprohibitions "product-in-use" research on pesticides.The Agency agrees with comments that such product-in-use researchwill generally pose relatively little risk to test subjects,because the exposures occurring during the research wouldcorrespond to exposures authorized by the Agency under itspesticide regulatory program-exposures that EPA has foundcause no unreasonable adverse effects on human health or theenvironment. But these comments contain no satisfactoryexplanation of why it is necessary to conduct such product-in-useresearch with pregnant women, fetuses, or children. Likeresearch on insect repellents, the Agency believes that generalproduct-in-use research with non-pregnant adults should providesufficient information to meet legitimate scientific needs.
Finally, research on the efficacy of antimicrobial agents usedin swimming pools, spas, and hot tubs raises unusual anddifficult issues. The Agency issues experimental use permits forthese studies to determine whether, under typical use conditions,the antimicrobial can successfully control the additional microbial load introduced by bathers. The Agency, however, doesnot approve such field research until the Agency can concludethat both the experimental use is likely to be effective and thelevels of the antimicrobial in water will pose no risk to thebathers.
EPA, however, does not regard such studies as "researchwith human subjects" under the definitions in the CommonRule at §§ 26.102 and 26.1102, and therefore doesnot believe they are subject to the prohibitions or any otherprovisions in part 26. The definitions of "research"and "human subject" make clear that the phrase"research with a human subject" applies to asystematic investigation in which an investigator collectsinformation through an intervention or interaction with anindividual for the purpose of developing generalizable knowledgeabout humans. In the case of these antimicrobial efficacystudies, the research does not involve interactions with, orcollection of information on, identifiable individuals for thepurpose of producing generalizable knowledge.
Comment : A number of comments objected to whatthey perceived to be "loopholes" in the proposedrule's prohibition on research involving intentional exposure ofchildren. Specifically, they argued that: (1) Proposed§ 26.401(a)(1) permitted EPA to waive the prohibitionwhen research was conducted outside the United States; (2)proposed § 26.401(a)(2) permitted EPA to waive anyprovision of proposed subpart D, including the prohibition; and(3) proposed § 26.408, which authorized an IRB towaive the requirement for assent from children lacking thecapacity to give it, and to waive the requirement for permissionfrom abusive or neglectful parents, meant that EPA intended toallow research on mentally retarded, abused, or neglectedorphans.
Response : Many commenters misinterpreted EPA'sproposed language. Contrary to public comments, none of thealleged "loopholes" ever existed, because theprohibition in proposed § 26.420 stated"Notwithstanding any other provision of this part, under nocircumstances shall EPA or a person when covered by§ 26.101(j) conduct or support research involvingintentional dosing of any child." The words,"Notwithstanding any other provision of this part,"mean that the provisions in proposed § 26.420 overrideall other provisions of the entire regulation, including§§ 26.401 and 26.408. Even though those twosections would have given EPA authority to waive certainrequirements, they would not have authorized any departure fromthe ban in proposed § 26.420.
Nonetheless, in order to remove any doubt about the scope ofthe prohibitions, EPA has made several changes in the final rule.The prohibitions appear in separate subparts so that there isless chance someone will misread the provisions intended toconfer flexibility in the approach to observational research asapplying to research involving intentional exposure. In subpartD, which addresses observational research with children conductedor supported by EPA, EPA has removed or revised the text of§§ 26.401 and 26.408 to make clear that they donot create an opportunity to relax the protections forchildren.
C. The Final Rule
After careful consideration of publiccomments-particularly the thousands of comments expressingstrong opposition to EPA's ever conducting human subjectsresearch that involves intentional exposure of pregnant women,fetuses, or children, the Agency has retained in the final rulethe proposed prohibitions, essentially without change. Subpart Bcontains the proposed prohibitions against EPA conducting orsupporting new research involving intentional exposure ofpregnant women, fetuses, and children. This prohibition appliesto EPA's first- and second-party research with any substance, andis not restricted to pesticides.
Subpart L of the final rule contains a parallel prohibition ofnew third-party human subjects research for pesticides involvingintentional exposure of pregnant women, fetuses, or children.Subpart L applies to research conducted or supported by anyperson who intends to provide the results of the research to EPAunder FIFRA or the FFDCA. The final rule retains the text fromthe proposal establishing how EPA will determine a person'sintent for purposes of applying the prohibition.
The Agency recognized that the wording of the proposedprohibitions and other requirements could be interpreted to applyto studies, which do not constitute "research" with"human subjects," as these terms are defined in theCommon Rule, but in which humans who are not subjects of theresearch may be incidentally exposed. The Agency did not intend,for example, that the proposal would affect animal research on apesticide simply because a person might be intentionally exposedto a test material as a consequence of working as a labtechnician. Accordingly, EPA has revised the rule text insubparts B, C, L, and Q to clarify that the prohibitions andother provisions apply only to research with human subjects andnot to other types of research.
The Agency hopes that the reorganization of the final rulegives greater prominence to these prohibitions, and clarifiesEPA's intent that there be no exceptions to or loopholes in theseprohibitions. Both subparts B and L begin by expressly statingthe universe of research activities to which they apply. Tofurther reinforce the point that the bans on these types oftesting are not subject to any exceptions, the prohibitoryprovisions use the introductory phrase "Notwithstanding anyother provision of this part, under no circumstances . . . ." This language means that this provision is to beenforced over all other provisions of every other subpart of part26.
VIII. Observational Research: Subparts C andD-Additional Protections for Pregnant Women, Fetuses, andChildren Involved as Subjects in Observational Research Conductedor Supported by EPA
Summary : This unit discusses protectionsadditional to the core protections provided by the Common Rule(subpart A), which are established by the final rule for pregnantwomen and fetuses (subpart C) and children (subpart D) when theyare subjects in observational research conducted or supported byEPA. The final rule defines observational research as research not involving intentional exposure. The provisionsof the final rule are similar to regulations promulgated by HHSto govern studies with these populations when conducted orsupported by HHS. Unit VIII.A. summarizes the proposal, UnitVIII.B. discusses public comment, and Unit VIII.C. describes theposition taken in the final rule.
A. The Proposed Rule
Most of the provisions of proposed subparts B and D would havedefined additional protections for individuals from vulnerablepopulations when they were subjects in observational researchconducted or supported by EPA-i.e., studies that do notinvolve intentional exposure. Proposed subpart B containedprotections for pregnant women, fetuses, and certain newborns,and proposed subpart D contained protections for children. Theprotections in both proposed subparts were in addition to thebasic protections created by the Common Rule, 40 CFR part, 26subpart A. Because the HHS regulations affording additionalprotections for pregnant women and fetuses and for children hadbeen in existence for over 20 years and enjoyed widespreadacceptance by the research ethics community, EPA proposed toadopt the HHS rules without substantive change, except as notedbelow.
1. Proposed subpart B . EPA proposed to adoptby reference much of the content of subpart B of the HHS rule, 45CFR part 46, with only a few changes. Thus, EPA proposed to adoptseveral sections from the HHS rule:
• In proposed § 26.201, EPA adapted thetext of 45 CFR 46.201, thereby defining the scope of thesubpart-research conducted or supported by EPA thatinvolved research with pregnant women, fetuses, or certainnewborns.
• Proposed § 26.202 cross referencedseveral paragraphs of 45 CFR 46.202 defining such terms as delivery , fetus , neonate ,and pregnancy .
• Proposed § 26.203 cross referenced therequirement of 45 CFR 46.203 that assigns to IRBs the primaryresponsibility for ensuring that investigators follow therequirements of the subpart.
• Proposed § 26.204 cross referenced therequirements of 45 CFR 46.204 defining the findings an IRB mustmake (in additional to those required by the Common Rule at§ 26.111) before approving proposed research withpregnant women or fetuses. (Because of the prohibition inproposed § 26.220, the provisions in proposed§§ 26.204 and 26.205 would have applied only toEPA's observational research.) In summary, these includefindings that: Adequate preliminary research exists tocharacterize potential risk, the risks to pregnant women andfetuses have been minimized, either the risks are minimal or theresearch holds out the prospect of direct benefit, andappropriate informed consent is obtained, in some cases from boththe father and the pregnant woman.
• Proposed § 26.205 cross referenced therequirements of 45 CFR 46.205 defining the findings an IRB mustmake before approving observational research with certainnewborns, including, where applicable, that the observationalresearch has the prospect of improving the chances of survival ofneonates of uncertain viability or that the observationalresearch will develop important biomedical knowledge which couldnot otherwise be obtained.
• Proposed § 26.206 cross referenced therequirements of 45 CFR 46.206 concerning observational researchinvolving, after delivery, the placenta, the dead fetus, or fetalmaterial.
The major substantive change EPA made to the HHS rule inproposed subpart B was the choice not to propose adopting theprovisions in 45 CFR 46.207, which provide a special procedurefor approving in exceptional cases observational research whichdoes not meet the standards of 45 CFR 46.204 or 46.205. EPAconsidered such a provision both inappropriate and unnecessaryfor observational research with environmental substances.
2. Proposed subpart D . EPA proposed to adoptmuch of the content of subpart D of the HHS rule, 45 CFR part 46,specifically:
• In proposed § 26.401, EPA adopted thetext of 45 CFR 46.401, thereby defining the scope of thesubpart-research conducted or supported by EPA involvingchildren as subjects. The proposed rule text contained the sameexceptions that appear in the HHS rule.
• Proposed § 26.402 contained the samedefinitions that appear in the HHS rule in 45 CFR 46.402, exceptthat EPA proposed to define a child as a personyounger than 18 years old, in contrast to the HHS definition,which relies on local law to determine when a person becomes anadult.
• Proposed § 26.403 cross referenced therequirement of 45 CFR 46.403 that assigns to IRBs the primaryresponsibility for ensuring that investigators follow therequirements of the subpart.
• Proposed § 26.404 adapted, essentiallyverbatim, the text of the HHS regulation in 46 CFR 46.404 thatauthorizes IRBs to approve observational research with children(which also meets the criteria in § 26.111), whichinvolves "no more than minimal risk" only if thereare adequate procedures, as specified in § 26.408, forsoliciting the assent of the children and the permission of theirparents or guardians. (Because of the prohibition in proposed§ 26.420, the provisions in proposed§§ 26.404, 26.405, and 26.408 would have appliedonly to EPA's observational research.)
• Proposed § 26.405 adopted, essentiallyverbatim, the text of the HHS regulation in 46 CFR 46.405 thatauthorizes IRBs to approve observational research with children(which also meets the criteria in § 26.111), whichinvolves "greater than minimal risk" only if the IRBfinds the observational research offered the prospect of directbenefit to the individual subjects or would otherwise contributeto their well-being, and there are adequate procedures, asspecified in § 26.408, for soliciting the assent ofthe children and the permission of their parents orguardians.
• Proposed § 26.408 adopted, essentiallyverbatim, the text of the HHS regulation in 45 CFR 46.408establishing special requirements for obtaining permission byparents or guardians and for assent by children. Among otherprovisions this section provided that in some cases an IRB coulddetermine that a child was not capable of assent, in light oftheir age, maturity, or psychological state. If so, theinability of the investigator to obtain assent could not be abasis for excluding a child from research that held out theprospect of benefit to the child. The proposal also allowed anIRB to waive assent on the same grounds that it could waiveinformed consent by adults (see § 26.116(d)). Thisproposed section also granted to IRBs discretion to determinethat, in some cases, it would not be reasonable to require thepermission of a child's parent or guardian because, for example,the adult abused or neglected the child. In such instances, thissection authorizes the IRB to approve an alternative mechanism ofobtaining permission from an adult who would better represent thechild's interests.
As noted above, most of the proposed rule text came directlyfrom the existing HHS regulations establishing additionalprotections. The Agency did propose a few revisions. Inaddition to minor editorial changes necessary to reflect that theproposed rule would be implemented by EPA, the most notablesubstantive changes were: (1) Defining a child as a person underthe age of 18 years, (2) choosing not to propose adopting theprovisions in 45 CFR 46.406 and 46.407, and (3) choosing not topropose adopting the provisions in 45 CFR 46.409.
In 45 CFR 46.406 and 46.407, HHS establishes special standardsand procedures for approving in exceptional cases research whichdoes not meet the standards of 45 CFR 46.404 or46.405-i.e., research which poses more than minimal risk tothe children in the study but which offers no prospect of directbenefit to them. EPA considers such provisions bothinappropriate and unnecessary for research with environmentalsubstances, particularly observational studies. Consistent withthe choice not to adopt those two sections, EPA chose to omit 45CFR 46.409 of the HHS rule as well, since it specifies measureswhich are required only when the children in a study approvedunder the authority of 45 CFR 46.406 or 46.407 were wards of thestate.
B. Public Comment
Most comments on proposed subparts B and D addressed theproposed prohibitions on research involving intentional exposureof pregnant women, fetuses, or children. These comments areaddressed in Unit VIII. This unit covers the public commentswhich addressed the adoption of additional protections forpregnant women and children as subjects in observational researchconducted or supported by EPA.
Comment : Some commenters supported EPA'sproposal to adopt only some of the provisions of the HHSregulations in 45 CFR part 46, subparts B and D that createadditional protections for pregnant women, fetuses, and childrenin observational research. Other comments recommended the Agencyadopt these HHS regulations in their entirety. By doing so, EPAand HHS would follow consistent approaches. These comments alsonoted HHS has operated under these regulations for over 20 yearswithout significant debate over their ethical adequacy.
Response : The Agency agrees there isconsiderable value in employing consistent approaches in similarareas of research. Consistency makes it easier for affectedresearchers to comply and helps to build a broader consensus onwhat constitutes ethical behavior. Accordingly, EPA is adoptinglarge parts of the HHS regulations from 45 CFR part 46, subpartsB and D essentially verbatim. The Agency, however, is notpromulgating all of these HHS rules because, in EPA's judgment,the omitted provisions would never apply to observationalresearch. Specifically, EPA has not adopted the followingsections from the HHS rules: 45 CFR 46.205, 46.207, 46.406,46.407, and 46.409. These sections would apply only whenproposed research would present more than a minimal risk to thesubjects and would have no prospect for direct benefit to thesubjects. EPA simply cannot conceive of observational researchthat could not meet such criteria, and in the unlikely event thatan investigator proposed such research, EPA would not expect toapprove it.
Comment : Some comments objected to theinclusion in the proposed rule of provisions that allowedobservational research if an IRB judged the potential risks tosubjects as "minimal." These comments claimed thatthe concept of "minimal risk" was not adequatelydefined and potentially subject to abuse. These commentsrecommended that no observational research be allowed unlessthere was "no risk" to subjects. (Many of thesecomments further argued that no human research was totally riskfree and therefore no human research should be allowed.)
Response : The Common Rule and subpart D of thefinal rule define minimal risk as "the probability andmagnitude of harm or discomfort anticipated in the research arenot greater in and of themselves than those ordinarilyencountered in daily life or during the performance of routinephysical or psychological examinations or tests." 40 CFR26.402. The Agency agrees that this definition leaves room forthe exercise of expert judgment by a person reviewing a proposedprotocol, and that different people may disagree on whether aparticular research technique poses minimal risk. Nonetheless,this definition has been part of the Common Rule since 1991, andthis provision has been in the HHS regulations since 1983. Basedon its long history of application and the benefits ofconsistency with HHS, EPA has decided to retain proposed§ 26.404 without change. In addition, EPA thinks theprospects for abuse are extremely small since all researchallowed using these criteria would need approval both from alocal IRB and from EPA's Human Subjects Research Review Official(HSRRO).
Comment : Some comments objected to EPA'sproposal to adopt 45 CFR 46.405, which would allow an IRB toapprove observational research with children if the IRB found therisks to children were "greater than minimal," butpresented "the prospect of direct benefits to theindividual subjects." These comments argued thatobservational research would never meet such criteria.
Response : EPA rarely expects observationalresearch to pose "greater than minimal risk." By itsvery nature, observational research leaves all decisionsregarding exposure to the subjects. Thus, an investigatorordinarily just measures and records information about exposureand effects that the subjects, in their own discretion, choose toexperience. EPA, nonetheless, believes its final rule shouldinclude a provision comparable to 45 CFR 46.405. Althoughunlikely, EPA thinks some measurement techniques used inobservational research could theoretically involve more thanminimal risk to subjects and therefore would fail to meet thecriteria for approval under § 26.304 of the finalrule. Consistent with the HHS approach in 45 CFR 46.205, EPAbelieves that, if such risks exist, the research should not beallowed unless an IRB finds that the "greater than minimalrisks" were justified by the prospect of direct benefits tothe subjects. Because EPA does not want to prevent potentiallyvaluable research that requires non-standard measurementtechniques, EPA has adopted in § 26.305 of its finalrule the content of the provision of the HHS regulations.
Comment : Although most comments agreed withEPA's proposal to define child as a person younger than 18 years old, somecomments recommended using the text in the HHS rule, which defersto the legal standards defining children and adults in the localjurisdictions where the research is conducted. These commentspointed out that EPA's proposed definition could lead to theexclusion of an emancipated minor, typically an older teenagerwho has married. Excluding these potential subjects could denythem the benefits of participating in the research simply becauseof their age. Other comments favored raising the age to 21 yearsold because the human body, particularly the brain, continues tomature after the age of 17 years and research might adverselyaffect 18-21 year olds during this developmental period ofpotentially increased sensitivity.
Response : EPA is not persuaded that thepotential increased sensitivity of people between the ages of 18and 20 years to some effects warrants defining a child as aperson under 21 years old. The Agency notes that suchsensitivity is not likely to exist for all chemicals. If,however, a proposal to perform observational research did raiseconcerns about an increased sensitivity of subjects, thoseconcerns can be addressed on a case-by-case basis by the IRB andEPA's HSRRO. It is not necessary, in EPA's view, to deal withthese theoretical concerns by redefining who is a child.
While EPA sees benefit to using a definition consistent withHHS, the Agency is concerned about the added complexity forinvestigators who are conducting research in multiplejurisdictions. In addition, EPA questions whether youngsters noolder than 15 years, as an adult is defined in some states, aresufficiently mature to make decisions about whether to volunteerto participate in human research. In light of these concerns andthe broad support for EPA's proposal, EPA has decided to retainthe proposed definition of child as a person younger than 18years old.
Comment : Some comments found unclear theprovisions in proposed subpart D allowing the waiver, undernarrow conditions, of the requirements for permission of parentsand assent of children to participate in observational researchconducted or supported by EPA. Other comments objected to theseproposed provisions asserting that children should never becomesubjects in research without their parent's permission andwithout their own assent. Still other commenters asserted thatthe rule should not allow parents to permit their children'sparticipation in human research unless the children will benefitdirectly from doing so.
Response : EPA's final rule has retained theproposed rule text, with only minor changes. EPA believes thatthese provisions give the Agency needed flexibility to protectthe interests of the child when either the child or the parent(s)cannot. For example, the proposal would allow waiver of assentwhen the child is too young or otherwise unable to makeresponsible choices, and where the child's refusal to assentwould cause his or her exclusion from research that provides adirect benefit. The proposal also allows waiver of parentalpermission from a parent who abuses or neglects their children;clearly such parents do not have adequate concern for the child'swelfare to make decisions about whether the child shouldparticipate in research. (This provision strengthening theprotections for children was widely misinterpreted as indicatingEPA's intention to authorize or conduct research involvingintentional exposure of mentally retarded, abused, and neglectedchildren.)
To clarify the operation of the provision allowing waiver ofparental permission, EPA has modified the text to make clear thatany alternative procedure must be "equivalent" to theprocess of parental permission. By "equivalent" EPAmeans that the child's participation must be approved by an adultwho by position or relationship puts the child's well beingforemost and who will exercise sufficient diligence to make aconsidered and informed decision. Otherwise, EPA has decided notto accept the changes recommended by the commenters. EPA relieson the facts that the concepts in this provision comport with thegenerally accepted legal principles defining the scope ofparental authority and that HHS has operated successfully underthese provisions for over 20 years. Finally, as noted above, EPAsees considerable benefit from using an approach consistent withthat of HHS.
C. The Final Rule
Subpart C of the Agency's final rule retains most of the ruletext appearing in proposed subpart B. The most significantchanges from the proposal are the isolation in subparts B and Lof the prohibition of new research proposed at§ 26.220, and removal to subpart Q of the restrictionon EPA reliance on completed research proposed at§ 26.221. To make the applicability of the remainingprovisions of subpart C as clear as possible, EPA has revised thetitles of the subpart and of § 26.301, and rewordedthe text to emphasize repeatedly that these provisions apply onlyto observational research, and only to research conducted orsupported by EPA. In the final rule observationalresearch is defined in § 26.302 as research thatdoes not involve intentional exposure of research subjects. Inaddition, EPA has deleted from the final rule proposed§ 26.205 (which referenced 45 CFR 46.205) because itsprovisions would never apply to the kinds of observationalresearch that this subpart permits.
Subpart D of the Agency's final rule retains most of the ruletext appearing in proposed subpart D. The most significantchange from the proposal is the isolation in subparts B and L ofthe prohibition of new research proposed at § 26.420,and the removal to subpart Q of the restriction on EPA relianceon completed research proposed at § 26.421. To makethe applicability of the remaining provisions of subpart D asclear as possible, EPA has revised the titles of the subpart andsome of its sections, and reworded the text to emphasizerepeatedly that these provisions apply only to observationalresearch, not involving any intentional exposure to anysubstance, and only to research conducted or supported byEPA.
In addition, EPA has made the following revisions in subpart Dto the proposed rule text:
• In § 26.401(a)(2), EPA clarified thatthe authority to waive requirements related only to the sectionsof subpart D and did not confer broad authority on the Agency towaive any requirement in any other subpart.
• In § 26.402(a) and (f), EPA addeddefinitions of Administrator and observational research.
• In § 26.403, the text from 45 CFR46.403 of the HHS regulation is incorporated explicitly, ratherthan by reference as was done in the proposal.
• In § 26.405, EPA reordered the text tomake its applicability clearer. The revision was not intended tomake a substantive change.
• In § 26.406(c), EPA has revised thetext to clarify that if an IRB determines that it is notappropriate to require the permission of the parent or guardianfor a child to participate in a study, the IRB must approve anequivalent, alternative procedure for obtaining permission fromanother adult who will appropriately represent the interests ofthe child.
IX. Additional Protections Pertaining to Research InvolvingPrisoners Involved as Subjects
Summary : Research with prisoners conducted orsupported by EPA is subject to basic ethical requirements in theCommon Rule; the parallel requirements in subpart K of the finalrule apply to the conduct of research by third parties involvingintentional dosing of prisoners, if the research is intended tobe submitted under the pesticide laws. The Agency has notreached a final position on either the need or the mostappropriate form for any additional protections for prisonersbeyond these basic requirements. The Agency may, in a futureaction, issue a final rule to address the aspects of itsSeptember 12, 2005, proposal that relate to establishingstandards for the ethical protections of imprisoned subjects ofresearch. Unit IX.A. summarizes EPA's proposal and Unit IX.B.explains EPA's decision not to adopt additional protections forprisoners in this final rule.
A. The Proposed Rule
In its September 12, 2005, proposal, EPA noted that HHS haspromulgated regulations that provide additional protections forprisoners in research conducted or supported by HHS, codified at45 CFR part 46, subpart C. The proposal explained that EPA haddecided not to propose adoption of the HHS subpart C rules for anumber of reasons, among them that HHS and its advisorycommittee, the Secretary's Advisory Committee on Human ResearchProtections (SACHRP), were actively considering revisions to theHHS subpart C, unchanged since its adoption in 1978.
In addition, the proposal noted that EPA has never conductedor supported any human studies with prisoner subjects, and has nointention to do so in the future. It also noted that somethird-party research with prisoner subjects was submitted to theAgency some 30 or more years ago; since HHS adopted subpart C,this type of research has essentially disappeared, and none hasbeen submitted to EPA for many years. Finally, the proposal notedif either EPA or third parties should consider performing studieswith prisoner subjects, such research would be subject to therequirements of the Common Rule and EPA's final rule.
B. The Final Rule
All provisions of the Common Rule would apply to any EPAresearch with imprisoned subjects. In particular, any suchresearch would be subject to the Common Rule requirements for IRBreview and approval and written informed consent. Sections26.111(a)(3) and 26.111(b) require an IRB to determine thatselection of research subjects is equitable and free fromcoercion or undue influence, and note that particular attentionto these aspects of subject selection is needed when prisonersare involved. Implicit in other sections, e.g.,§§ 26.102(i), 26.116, and 26.117, is the conceptthat research must treat each subject involved ethically, takinginto account their particular circumstances.
In addition, the prohibitions in subpart B and the additionalprotections in subparts C and D would also apply to imprisonedpregnant women or children under the age of 18 years if EPA wereto conduct observational research with subjects from thosepopulations.
EPA does not expect third parties to submit to EPA any newstudies on prisoners. In the unlikely event that a third partywished to conduct or sponsor research involving intentionalexposure of prisoners for submission under the pesticide laws, itwould be covered under subparts K and L. Unless prohibited bysubpart L, such research would have to meet the requirements ofsubpart K, which parallel the provisions of the Common Rule. Inaddition, an investigator would also be required to submit forEPA and HSRB review a proposal describing in detail how the studywould be carried out in an ethical manner. Should such a studyproposal involve prisoners, it would receive extremely closereview, and EPA almost certainly would not approve it, absent acompelling justification.
The Agency has concluded that the requirements of this finalrule should provide adequate protections for prisoners,especially since there are not likely to be any such studies.Nonetheless, the Agency is still considering the recommendationfrom public comments to prohibit both EPA and third-parties toconduct certain types of research with prisoners. EPA may, at alater date, adopt such a provision, if it determines that such ameasure is needed and cannot be effectuated under existingregulations. In addition, EPA will continue to monitor the workof the SACHRP committee on prisoner protections, and willreconsider adopting additional protections for prisoners assubjects of research when its recommendations are known.
X. Subpart M-Requirements for Submission ofInformation on the Ethical Conduct of Completed Human Research
Summary : Subpart M of the final rule requiresthird parties who submit the results of completed human researchto EPA for consideration under the pesticide laws to document theethical conduct of that research. Subpart M specifies the rangeof information required, including documentation of any IRBreviews, documentation of informed consent by subjects, and otherinformation required to support third-party proposals to conductnew human research for pesticides involving intentional exposureof non-pregnant adults. The final rule directs submitters toprovide this information about completed research to the extentit is available, and if any of it is not available, to describethe efforts made to obtain it. Unit X.A. describes the proposedrule, Unit X.B. addresses the major public comments, and UnitX.C. discusses the final rule.
A. The Proposed Rule
In the September 12 proposal, § 26.124(c) required"any person who submits to EPA data derived from humanresearch covered by this subpart" to provide informationdocumenting compliance with the requirements of the subpart. Therequired information included records required of the IRBs thatapproved the research; copies of sample informed consentdocuments; and copies of correspondence between EPA and theinvestigator or sponsor about the proposed protocol.
In addition, although the proposal contained no provisiondirected at data submitters requiring documentation of ethicalconduct of completed research, the proposal indicated that EPAwould not rely on the results of research conducted after theeffective date of the final rule unless the Agency had"adequate information to determine the research wasconducted in a manner that substantially complied" with therequirements of the rule.
B. Public Comments
EPA received no major public comments on the proposedprovisions addressing the content of reports of completed humanresearch.
C. The Final Rule
EPA has created a new subpart M that requires people whosubmit data from completed human research to EPA to accompanythat submission with information documenting the ethical conductof the research. The final rule requires that reports oncompleted human research contain essentially the same range ofinformation concerning the ethical conduct of the research aswould have been required by the proposal.
The final rule, however, differs from the proposal in severalrespects. First, the final rule clarifies that it applies onlyto reports of completed human research submitted after theeffective date of the final rule.
Second, EPA has broadened the scope of the proposedrequirement to apply to reports on all types of human researchsubmitted to the Agency for consideration under the pesticidelaws, FIFRA and FFDCA. This provision of the final rule isbroader than the proposal in two ways: It applies to all personswho submit data, whether or not they developed the data with theintent to provide it to EPA; and it applies to all types of humanresearch, not only to research involving intentional exposure ofhuman subjects. The Agency decided to extend the scope of thisreporting requirement because it expects to make ethicalassessments of all human research it receives under the pesticidelaws, irrespective of who did it, who submitted it, or what typeof human research was involved. Obtaining the informationspecified by subpart M as part of the initial submission willimprove the efficiency and quality of such ethical assessments.Under FIFRA sections 3(c)(2)(A) and 3(c)(2)(B), EPA has theauthority to require information necessary to support bothapplications for new registration and for continued registrationof a pesticide. Since the Agency regards information about theethical conduct of human research as relevant to the assessmentof the acceptability of such research, the Agency concludes thatthe reporting provision is consistent with these sections ofFIFRA.
Finally, the Agency made two changes to minimize the burden ofreporting information on the ethical conduct of completedresearch. First, the final rule provides that information neednot be resubmitted if it has previously been provided to theAgency, for example as part of the submission required forprotocol review under § 26.1125. Second, recognizingthat not all of the information specified by subpart M may beavailable to the data submitter in some cases-for example,if the research were conducted in the past, or if the submitterdid not conduct the study, § 26.1303 states that thespecified information should be provided "to the extentavailable" and asks the submitter to describe the effortsmade to obtain information which he or she was unable toprovide.
XI. Subpart O-Administrative Actions forNoncompliance
Summary : Subpart O contains provisions, adaptedfrom similar regulations issued by FDA, that describe the rangeof administrative actions EPA could take to address noncomplianceby third parties with the requirements of part 26. These actionsinclude: Withdrawal or suspension of a research institution'sFederal wide assurance; disqualification of an institution or anIRB; debarment; and public censure. This subpart describesprocedures EPA would follow in reaching a decision to take any ofthese administrative actions. Other than the addition of a newsection explaining the scope of research to which these actionscould be applied, the final rule is unchanged from theproposal.
A. The Proposed Rule
In proposed subpart E the Agency identified a number ofspecific administrative actions that could be taken, ascircumstances warrant, against any person or organization thatfailed to comply with requirements of the rule. These actionsincluded: (1) Withdrawal or suspension of a researchinstitution's FWA; (2) disqualification of a research institutionor its IRB; (3) debarment of an entity from receiving federalfunds for research; or (4) public censure-presenting forpublic review an objective analysis of the ethical deficienciesof any human research relied upon by EPA for regulatorydecision-making under any statutory authority. The provisions inproposed §§ 26.501 through 26.504 and§ 26.506 closely follow FDA's existing regulations in21 CFR 56.120 through 56.124.
B. Public Comment
EPA received only a few public comments on this subpart, mostsupporting the appropriate use of the actions identified inproposed subpart E to promote compliance. EPA also agreed withseveral commenters that refusal to rely on completed researchprovided the strongest incentives for investigators to follow thenew requirements. Other major comments, discussed below,addressed the operation of EPA's compliance oversightprogram.
Comment : One comment complained that theproposal gives EPA discretion not to impose any of thesesanctions at all, even for the most egregiously unethicalresearch, and argued that only mandatory sanctions couldeffectively deter unethical human research. Another commenterrecommended that EPA explain what types of actions it would applyto different types of violations.
Response : EPA generally believes thatenforcement programs work best when they employ a system ofgraduated penalties that increase as the gravity of the violationincreases. Such an approach requires the exercise of discretion,but that discretion should not operate entirely free fromconstraints. Accordingly, the Agency intends to establishpolicies to guide its exercise of discretion about the impositionof the sanctions. Although EPA does not regard such policies orpenalty structure as appropriate for inclusion in thisrulemaking, the Agency does intend to explain in guidance how itwill encourage compliance with the new requirements in the finalrule.
Comment : Several comments urged EPA to adoptprocedures similar to those of FDA by which it would decidewhether to disqualify an institution for violating therequirement of the final rule.
Response : EPA agrees it should have a procedurefor deciding whether to disqualify an IRB or institution, andthat it may be appropriate to establish such procedures throughrulemaking. EPA will further consider adopting proceduressimilar to those used by FDA and promulgated in 21 CFR part 16,but has decided not to adopt them at this time.
C. The Final Rule
Subpart O of the final rule is substantively unchanged fromsubpart E of the proposal. EPA has added a new§ 26.1501 entitled "To what does this subpartapply?" which clarifies that EPA will consider using theadministrative actions identified in the subpart only to addressinstances of non-compliance with the requirements of the new ruleoccurring after the new rule takes effect. Thus, actionsdebarring an institution from receiving federal funds forresearch or disqualifying an institution from performing researchcovered by subpart K could not be taken on the basis of eventsthat happened before the final rule becomes effective. TheAgency notes, however, that actions which violate therequirements of FIFRA section 12(a)(2)(P) would be subject tocivil or criminal penalties if they happened at any time afterthat provision became law in 1972. The Agency also made minorwording changes in § 26.1502 of the final rule toreflect FIFRA terminology and enforcement practices.
EPA recognizes the importance of an effective program toensure compliance with the requirements of the final rule. Theoffice of the Agency's Human Subjects Research Review Official(HSRRO) will have responsibility for ensuring compliance with thenew rule. The HSRRO will also have responsibility for managingthe development of any new guidelines needed to explain orimplement the provisions of the final rule.
The Agency thinks that one of the most important ways toencourage and monitor compliance is through the review ofproposals for new research before it is conducted, as required bythe final rule at § 26.1125. Once such studies areinitiated, EPA's Office of Enforcement and Compliance Assurance,through its laboratory audit program, can monitor facilities thatconduct human research covered by the rule.
EPA inspectors conduct inspections and audit studies underEPA's good laboratory practice (GLP) regulations. As stated inthe GLP regulations (40 CFR 160.15), EPA will not considerreliable for purposes of supporting an application for a researchor marketing permit any data developed by a testing facility orsponsor that refuses to permit such inspection. In addition, therecordkeeping provisions of FIFRA which cover records of anytests conducted on human beings and records containing researchdata relating to registered pesticides including all test reportssubmitted to the Agency in support of registration or in supportof a tolerance petition also apply to studies conducted underthis rule.
Finally, the close examination of reports on completedresearch represents another important part of the complianceprogram. EPA will train scientists who conduct, approve, orreview human research about the provisions of the final rule sothey can identify possible violations. Throughout all of theseefforts, the Agency hopes to work with the HHS Office for HumanResearch Protections and FDA, to ensure that sponsors,investigators, and IRBs understand and fulfill theirresponsibilities under the final rule.
XII. Subpart P-Review of Proposed and Completed HumanStudies
Summary : This subpart of the final ruleprovides that EPA will review all proposals by third parties toconduct research covered by subpart K, i.e., all researchinvolving the intentional exposure of human subjects, if theresearch is intended for submission to EPA under the pesticidelaws. The subpart also requires EPA to establish an independentgroup of experts, referred to as the Human Studies Review Board(HSRB), to assist EPA in evaluating such proposals. In addition,the subpart requires that EPA review reports submitted by thirdparties on completed human research and, if EPA decides to relyon information from such research in an action under thepesticide laws, to submit the results of its assessment of theresearch to the HSRB. The HSRB would perform science and ethicsreviews of proposals from third parties to conduct specifiedtypes of human research and of the results of specified types ofhuman research if EPA intended to rely on the information in itsdecision-making under the pesticide laws. Further, when HSRBreview is not required by the final rule, EPA would nonethelessretain discretion to ask the HSRB to review studies or to offeradvice on other issues.
Finally, although not required by the final rule, EPA hasdecided to establish the HSRB under the authority of the FederalAdvisory Committee Act. By operating as a federal advisorycommittee, the HSRB will be required to use procedures thatensure transparency in its operation and that affordopportunities for the public to express their views on issuesbeing considered by the HSRB.
A. The Proposed Rule
Proposed § 26.124 would have required third partiesto submit to EPA detailed information concerning any proposed newresearch covered by the new rule at least 90 days beforeinitiating of the research. The proposal would also haveestablished a HSRB to address in an integrated fashion thescientific and ethical issues raised by human research covered bythe proposal. Specifically, the Agency proposed to convene asmall group of appropriately qualified experts and to enlisttheir support in reviewing covered research proposals, i.e.,third-party research involving intentional exposure of humansubjects, when the results of such research are intended to besubmitted to EPA under the pesticide laws.
The same section also provided that EPA would review theresults of completed research covered by the rule. This sectionof the proposal also stated that, after completing its initialstaff assessment of a research proposal or a completed study ifEPA intended to rely on the results in its decision-making underthe pesticide laws, the Agency would send its review andsupporting materials concerning the study to the HSRB for furtherreview and comment.
EPA's proposal did not specify any details of how the HSRBwould function, other than to state that the members would not beEPA employees, would meet the conflict of interest standardsapplying to special government employees, and would haveexpertise appropriate for the review of human research. TheAgency invited public comment on whether the final rule shouldspecify the functions of the HSRB. The preamble also indicatedthat, as recommended by the NAS, EPA intended to reexamine thefunctions of the HSRB after 5 years.
B. Public Comment
EPA received a great many public comments on its proposal torequire submission of proposed protocols and other informationrelating to proposed new human research and to submit itsassessments of the proposed new human research to a new HSRB forfurther review. The Agency's Response to Comments document, inthe docket for this action, provides a full response to thesecomments. EPA agrees with comments that stressed the importanceof having the HSRB use the substantive standards contained inEPA's final rule when reviewing the ethics of proposed andcompleted human research. As an entity intended to help theAgency make ethical and scientific judgments, the HSRB will usethe provisions of this final rule in the formulation of theiradvice. The major issues raised by the comments are discussedbelow under three headings: HSRB procedures; HSRB membershipand qualifications; and the scope of research subject to HSRBreview.
1. HSRB procedures . The Agency notes thatmost, if not all, comments on the HSRB implicitly accepted EPA'sproposal that HSRB review of proposed new research would occurfollowing its review and approval by a local IRB and after EPAdeveloped its review.
Comment : Many comments addressed whether EPAshould charter the HSRB under the Federal Advisory Committee Act(FACA). Environmental and public health advocacy groups favoredthis approach because it would assure the use of procedures thatprovided opportunities for public comment and transparency.Others, primarily commenters affiliated with the pesticideindustry, objected on the grounds that a FACA-chartered HSRBwould be inefficient, and the ensuing delays would affect Agencydecision-making, particularly about new products. These commentsrecommended either staffing the HSRB only with EPA employees orrelying on the HHS Office for Human Research Protections (OHRP)for the kinds of reviews described in the proposed rule.Industry commenters also expressed concern that a FACA processmight lead to public disclosure of CBI.
Response : EPA has decided to charter the HSRBunder FACA. While operating under the requirements for advisorycommittees adds some procedural steps to the review process, itis not apparent, given the intensity of public concern about theuse of data from human research, that a FACA process wouldnecessarily take longer than a process involving internal EPAreview. More important, in EPA's view, the benefits of thetransparency and opportunities for public participation outweighany potential delays. Given the difficult nature of the issues,EPA sees significant advantages in ensuring that all theconsiderations influencing the Agency's final position have beenpublicly identified, carefully weighed, and commented on byindependent experts.
The Agency recognizes the need to manage aggressively toensure both the HSRB's and its own review processes operateefficiently. As part of its commitment to effective management,the Agency intends to acknowledge receipt of new researchproposals and to respond promptly with a projected timeline forcompleting EPA and HSRB review. In addition, upon completion ofits internal reviews, EPA will send copies to the submitter ofthe protocol and the schedule for HSRB review. EPA expects thatit will continue to meet the statutory deadlines for reachingdecisions on new applications for pesticide registrations, evenif HSRB review is required.
Finally, the Agency notes that under FIFRA and FACA, EPAfollows procedures designed to protect CBI from disclosure.Whenever EPA provides CBI to a federal advisory committee, thatinformation is not placed in a public docket or discussed in apublic meeting, and special steps are taken to maintain itsconfidentiality.
Comment : Many comments asked EPA to clarify inthe final rule the procedures that the HSRB would use. Inparticular, many suggested that the rule require that the HSRBmeetings afford an opportunity for public comment.
Response : The Agency believes that, at thisearly stage, the HSRB should have the flexibility to adoptprocedures which best allow it to meet its responsibilities.Since the HSRB will function as a federal advisory committee,FACA will dictate many of its procedures, including keyprocedures relating to transparency and public participation.Since these were the areas of greatest concern for mostcommenters, EPA believes that its decision to establish the HSRBunder FACA adequately addresses these comments.
Comment : Some comments complained that theproposed rule did not vest the HSRB with authority to disapproveproposed new research or EPA decisions to rely on the results ofcompleted human studies. Other comments supported giving theHSRB only an advisory role.
Response : EPA believes the HSRB should have anadvisory role. The decision to disapprove proposed new researchor to decide whether or not to rely on the results of completedstudies is inherently governmental. The Agency cannot legallyconfer authority to make such decisions on an advisory committee.The Agency notes, however, that it expects to give considerableweight to the advice of the HSRB.
2. HSRB membership and qualifications .
Comment : Many comments emphasized that the HSRBmust be independent, that its members must have no conflicts ofinterest, including any financial relationships with thepesticide industry.
Response : EPA agrees. Chartering the HSRB as afederal advisory committee to provide expert advice means thatall candidates for membership on the HSRB must meet the federalrequirements governing conflicts of interest. Although otherrequirements relating to the operation of the HSRB as an advisorycommittee are not specified in the final rule, EPA did retain inthe final rule a requirement that members have no conflicts ofinterest. Specifically, the final rule provides that HSRBmembers must "meet the ethics and other requirements forspecial government employees." See § 26.1603(a)of the regulatory text.
Comment : Several comments stressed theimportance of having HSRB members with sufficient expertise inthe substantive disciplines raised by the types of human researchcovered under the rule. They specifically identified thedisciplines of clinical toxicology, research ethics and theCommon Rule, and public health. Comments also noted that theAgency might need to supplement the HSRB to obtain expertise toaddress particular types of research covered by the rule.
Response : EPA generally agrees with the commentand on January 3, 2006, issued a Federal Register Notice inviting nominations of experts to serve on the HSRB (71FR 116). The Notice described the following areas of expertise:Bioethics, human toxicology, biostatistics, and human riskassessment. Under FACA, EPA has the authority to appointconsultants to the HSRB who can provide additional expertise whenneeded.
Comment : Several comments recommended that themembers of the HSRB include non-scientists who are members of thecommunity and who could represent the views of specialpopulations that could be the focus of proposed humanresearch.
Response : EPA does not believe that it isnecessary to include non-expert community members on the HSRB.However, under FACA, the public, including non-expert communityrepresentatives have opportunities to provide both written andoral public comment to the HSRB. In addition, the HSRB has theflexibility under FACA to ask representatives of community groupsto make presentations to the committee on specific topics.EPA also notes that, before a proposal reaches the HSRB, an IRBwill have reviewed and approved it. Such IRBs are required bythe new rules (§ 26.1107), to include people familiarwith the concerns arising in research with special populations.Thus, EPA expects in most cases that the concerns ofcommunity-based representatives will be a part of the informationbefore the HSRB.
3. Scope of research subject to HSRB review .
Comment : Some comments favored expanding thescope of studies reviewed by the HSRB to include all first-partyand second-party research, as well as third-party research; alltypes of human research, not only research involving intentionalexposure of human subjects; studies performed with any substanceregulated by EPA, not only studies with pesticides; and all humanresearch considered by EPA, not only the completed studies onwhich EPA intends to rely.
Response : EPA agrees that it may sometimes beappropriate to obtain HSRB review of some of these types ofstudies. The final rule gives EPA discretion to seek the adviceof the HSRB on additional types of studies beyond those for whichHSRB review is required. For the reasons explained earlier,however, the Agency has decided not to expand the scope ofsubpart K now, and therefore sees no reason to expand the scopeof required EPA or HSRB review of proposed new research.Similarly, the Agency has decided not to extend without furtheranalysis and public discussion the ethical framework in subpart Qto decisions made under statutory authorities other than FIFRA orFFDCA. It would make no sense to require the HSRB to reviewhuman research that fell outside the scope of the othersubstantive provisions of the rule. Finally, EPA has decidedthat it would not be an efficient use of resources to requireHSRB review of human research that the Agency had decided not torely on, typically because it falls short of contemporarystandards of scientific validity. The Agency does not anticipatethat the HSRB would often disagree with such conclusions, andtherefore EPA will use its discretion to determine whether suchscientific judgments warrant HSRB review.
Comment : Many comments generally supported theproposed review of new research and completed research reports byboth EPA staff and the HSRB, at least in some cases. A number ofcommenters, however, suggested ways to narrow the scope of thereviews performed by the HSRB, including: (1) By having the HSRBreview only studies intended to identify or measure toxiceffects, (2) by exempting from HSRB review consumer acceptancestudies, insect repellent efficacy tests, or other"product-in-use" studies; (3) by exempting from HSRBreview proposals to employ protocols for "routine"exposures or other studies that follow established EPAguidelines; and (4) by exempting from HSRB review the results ofresearch which the HSRB had previously reviewed and approved as aproposal, unless the investigator failed to follow the approvedprotocol. Finally, some comments recommended that the HSRB berestricted to considering ethical issues, but not scientificissues.
Response : EPA disagrees with the commentssuggesting a narrowed scope for HSRB review. EPA agrees thateach of the categories described above may contain at least somestudies that present no difficult scientific or ethical issues.To the extent EPA's review indicates that a study presents nodifficult science or ethics issues, the Agency would expect theHSRB to agree and quickly conclude its review. But any researchinvolving intentional exposure may present risks to individualhuman subjects greater than those they would receive in theirnormal activities, and therefore warrants careful examination,even if the purpose of the study is not to identify or measuretoxic effects. Similarly, while EPA anticipates that manyconsumer acceptance tests, insect repellent efficacy tests, andother "product-in-use" studies will raise nodifficult scientific or ethical issues, the Agency has relativelylittle experience with assessing explicitly the ethicalattributes of such research. Therefore the Agency thinks itwould be imprudent to exclude HSRB review of these studies. EPAlikewise recognizes that following established guidelines mayreduce the chances of scientific deficiencies in a study, butEPA's guidelines do not address the full range of potentialethical issues that should be considered on a case-by-case basis.Finally, EPA believes that even if a study follows an establishedprotocol, unanticipated scientific and ethical issues may arisethat will warrant expert advice.
C. The Final Rule
As a result of the reorganization of the final rule, allprovisions relating to EPA and HSRB review of proposals for new,third-party research or reports of completed studies, or to theestablishment of the HSRB, now appear in subpart P.
The final rule reflects one significant change from theproposal. Under the final rule, the HSRB will review allresearch involving intentional exposure conducted after theeffective date of the final rule, as well as all researchinvolving intentional exposure performed before the rule takeseffect, if the purpose of the research was to identify or measurea toxic effect. But the final rule grants to the Agencydiscretion to decide whether studies performed before theeffective date of the final rule that do not measure toxicityshould undergo HSRB review.
After publishing the proposal, EPA examined how the proposalwould affect its plans to complete tolerance reassessment byAugust 2006, as required by the 1996 FQPA amendments to FFDCA.The Agency reviewed the existing toxicity and exposure databasesfor upcoming tolerance reassessment decisions and determined thatas many as several hundred studies relevant to the riskassessments for these actions appeared to meet the definition of"research involving intentional exposure of humansubjects." Only a relative few of these intentionalexposure studies measure the toxicity of a pesticide; the greatmajority of them measure the levels of potential human exposureresulting from pesticide use, the efficacy of insect repellents,or the absorption, distribution, metabolism, and excretion ofpesticides.
Since the enactment of the Food Quality Protection Act in 1996EPA has relied on many of these non-toxicity,intentional-exposure human studies in its registration andreregistration decisions. Moreover, the Agency has affordedmultiple opportunities for public comment on several hundreddraft and final Reregistration Eligibility Decision (RED)documents and Interim RED (IRED) documents, but has neverreceived any public comment on a RED or IRED concerning theethics of intentional-exposure human studies other than atoxicity study. Taking all of these non-toxicity,intentional-exposure studies to the HSRB would significantlyincrease its workload and expand the number of pending regulatorydecisions affected. Accordingly, EPA has decided that while thefinal rule should require the Agency to send to the HSRB allcompleted toxicity studies on which it intends to rely, it neednot require all non-toxicity studies in its existing databases toundergo HSRB review. Thus, under the final rule, the Agency willretain the discretion to submit additional types of old studiesto the HSRB, and will consider public comments on its upcomingpesticide actions for tolerance reassessment in deciding which ofthe non-toxicity studies raise significant ethical or scientificissues warranting HSRB review.
In addition, subpart P in the final rule reflects a few otherminor revisions to the proposal. The provisions governing Agencyreview of proposals for new third-party research were placed insubpart P in preference to subpart K, so that subpart P wouldapply only to EPA, and subpart K would apply only to regulatedthird parties.
To help ensure effective implementation of the final rule, EPAhas made several administrative decisions affecting the HSRB.Most important, the Agency has decided to establish the HSRB as aseparately chartered advisory committee under the FederalAdvisory Committees Act (FACA). FACA requires the HSRB, as afederal advisory committee, to follow certain basic proceduresdesigned to promote transparency and to ensure publicparticipation. These include timely public notice of meetings,public access to meetings, and opportunity for the public tocomment; public availability of documents considered by the HSRBand meeting minutes; and a Federal officer or employee attendingeach meeting. Of course, the HSRB will be required to protectmaterials designated as confidential from public disclosure.Finally, EPA is also committing to aggressive management of theprocess to promote efficient use of resources and timelydecisions, and to ensure affected stakeholders have completeinformation about the status of ongoing reviews.
XIII. Subpart Q-Ethical Standards for AssessingWhether to Rely on the Results of Human Research in EPARegulatory Decisions
This unit discusses the ethical standards EPA will use toguide its decisions whether to rely in its actions under thepesticide laws on the results from completed human research.Unit XIII.A. summarizes EPA's proposal, Unit XIII.B. discussespublic comment, and Unit XIII.C. describes the positions taken inthe final rule.
Summary : The final rule is substantivelyunchanged from the proposal, although the provisions have beenrevised to make them clearer. One new section(§ 26.1701) clarifies the applicability of thissubpart to EPA decisions to rely on relevant, scientificallyvalid "data from research involving intentional exposure ofhuman subjects to a pesticide" in its actions under thepesticide laws, FIFRA and FFDCA. A second new section(§ 26.1702) provides needed definitions of terms. Theremaining four sections in the final rule together delineate theframework within which EPA will decide whether to rely on theresults of certain types of human research.
This framework rests on the basic principle that EPA will notrely in its actions on data derived from unethical research.Section 26.1703 forbids EPA to rely on data from any studyinvolving intentional exposure of pregnant women, fetuses, orchildren. Section 26.1704 forbids EPA to rely on data from"old" research-i.e., covered studies initiatedbefore the effective date of the final rule-concluded to befundamentally unethical or significantly deficient with respectto the ethical standards prevailing when it was conducted.Section 26.1705 forbids EPA to rely on data from any"new" research-i.e., research initiated afterthe effective date of the final rule-unless EPA finds thatthe research complied with the new requirements. Finally,§ 26.1706 creates a very narrow exception to theAgency's general refusal to rely on unethical data, one thatallows reliance on unethical data when it is crucial tosupporting more stringent regulatory measures to protect publichealth.
A. The Proposed Rule
In proposed subpart F of 40 CFR part 26, EPA set out ethicalstandards for its decisions to rely on or not to rely in itsregulatory decisions under FIFRA or FFDCA on reports of completedintentional-dosing research with human subjects. For coveredresearch initiated after the effective date of the rule, EPA proposed to refuse to rely on data from scientifically sound andrelevant human research unless EPA had adequate informationdemonstrating that the research complied with the Common Rule.For covered research initiated before the effective date of therule, EPA proposed to rely on data from scientifically sound andrelevant human research unless there was clear evidence to showthe conduct of the research was fundamentally unethical or wassignificantly deficient relative to the ethical standardsprevailing when it was conducted. EPA also proposed a formalexception to these standards when to rely on scientifically soundbut ethically deficient research would give crucial support to aregulatory action more protective of public health than could bejustified without relying on the ethically deficientresearch.
B. Public Comments
EPA received many public comments on proposed subpart F. Themajor issues raised by the comments are grouped and summarizedbelow under these four headings:
• Comments advocating a broader or narrower scopefor this subpart-a change to the kinds of research and therange of EPA decisions the framework should cover.
• Comments questioning the proposed frameworkitself, including arguments to include standards for scientificvalidity of human research, and arguments that EPA should neverreject scientifically sound data for ethical reasons.
• Comments on the substantive ethical standard tobe applied to "old" research initiated before thisfinal rule takes effect.
• Comments on the proposed "public healthexception" to the general refusal to rely on unethicalresearch.
The Agency notes that, although some comments favored morespecificity in EPA's final rule, many comments expressed supportfor EPA's proposal to rely on the Common Rule as the ethicalbenchmark for judging the acceptability of research conductedafter the effective date of the final rule.
1. The scope of application of EPA's ethicalframework.
Comment : Some comments advocated expanding theapplication of the ethical framework beyond research involvingintentional exposure of human subjects to cover all types ofhuman subjects research considered by the Agency, or to embraceconsideration of human subjects research conducted withpesticides under EPA statutes other than the pesticide laws, orto cover research involving intentional exposure of humansubjects to any environmental substance, not only topesticides.
Response : The Agency has decided not to expandthe application of the ethical standards in this subpart toencompass all types of human subjects research relied on by EPA,to research involving substances other than pesticides, or toactions taken under authorities other than the pesticide laws.In the future, the Agency will consider further actions toaddress these and other issues beyond the scope of this finalrule.
The Agency believes an initial focus on research involvingintentional exposure is warranted in that potential risks toresearch subjects are generally greater when exposure isintentional than in other types of studies. It is reasonable toscrutinize such research closely to ensure that research subjectsare fully protected and the research is ethical. EPA has notfully considered, and public comments have not thoughtfullyaddressed, what protective measures would be appropriate forresearch that does not involve intentional exposure. Thus, theAgency thinks it premature to conclude that all of the provisionsapplying to research involving intentional exposure should applymore widely.
EPA thinks there has also been inadequate consideration of theconsequences of expanding the scope of the ethical framework toembrace research with substances other than pesticides. Most ofthe comments favoring expansion of the rule beyond pesticidescame primarily from stakeholders affiliated with the pesticideindustry, and EPA received essentially no meaningful response toits requests for comment from other stakeholder interests,including those likely to be affected by such an expansion.Given the mandate of the 2006 Appropriations Act to addressresearch "for pesticides," the final rule retains theproposed focus on human research for pesticides.
Finally, the Agency has decided to retain the proposedapplicability of the framework to actions taken under thepesticide laws. Although EPA recognizes the theoreticalpossibility that human research with a pesticide may beconsidered under other statutes, the Agency notes that the 2006Appropriation Act does not require the adoption of a broaderscope than decisions under FIFRA and FFDCA. Also, the Agency hasnot received meaningful public comment on whether its authoritiesunder other statutes permit it to refuse to rely on relevant,scientifically sound data which were derived from an unethicalstudy. Because of the questions about the Agency's legalauthorities and the absence of a clear mandate, EPA has decidednot to require the application of the ethical framework toactions taken under its other laws.
Comment : Other comments argued for restrictingthe application of the ethical framework to only certain kinds ofhuman research-to research intended to identify or measuretoxic effects, to research conducted in a laboratory or clinicalsetting, or to exclude research involving only exposures that EPAhad already approved (e.g., studies of registered pesticides usedin accordance with their approved labeling). Two general reasonswere offered for these recommendations: (i) Public controversyhas focused exclusively on a narrower set of studies than thosefalling within the scope of proposed subpart F, and (ii) there isso little risk from the types of studies suggested for exclusionthat no additional measures would be needed to protectsubjects.
Response : Because EPA finds these reasonsunpersuasive, the Agency has decided to retain, at this time, thescope of the proposal for its final rule. Thus, EPA is notnarrowing the scope of its framework in any of the waysrecommended above.
Although recent controversy has focused on "intentionaldosing, human toxicity testing for pesticides" (see theAppropriations Act discussed in Unit XIV.A.), there has also beenpublic debate about other kinds of human research, includingproduct-in-use studies using registered pesticides, studiesperformed outside the laboratory setting, and studies which donot measure toxicity. To promote public confidence in itsoperations and judgments EPA must address this larger universe ofresearch. Second, EPA thinks that it is important to examine therisks of studies involving intentional exposure of researchsubjects-even when comparable exposures have already beenapproved for the general public under a pesticide registration.While the risks experienced by the research subjects and thegeneral public may not differ, the risks experienced by theparticular subjects may exceed what they would otherwise receive,and therefore researchers must provide each potential subject afull explanation of the potential for any additional risk theymight assume by volunteering for a study. For its part, EPAshould ensure that, in their interactions with subjects, thesponsors and investigators have acted ethically.
2. The adequacy of the ethical standards .
Comment : Although nearly all comments supportedEPA's application of an explicit ethical standard in decidingwhether or not to rely on data from completed human research, onesignificant line of comment argued that EPA should never refuseto rely on relevant, scientifically sound research even if itwere conducted unethically. This conclusion rested on threearguments: (i) Rejecting scientifically sound data would deprivedecision-makers of information that would serve the mission ofprotecting public health; (ii) applying a new standard of ethicalacceptability retroactively to completed research would beunfair; and (iii) refusing to rely on data from unethicalresearch could do nothing to remedy any harm done to the subjectsin the research.
Response : While EPA sees some merit in each ofthese arguments, the Agency disagrees with the conclusion. EPAbelieves that rejecting unethical data is an appropriate andpowerful means of promoting compliance with ethical standards,and that rejecting unethical data generally meets publicexpectations about conduct of the government.
First, EPA agrees that it is important to consider allavailable information in carrying out its mission to protectpublic health. This is especially important when reliable datashow humans to be more sensitive than animals. Sometimes,however, data from human research will show that humans are lesssensitive-or no more sensitive-than animals, andthat a less restrictive regulatory measure may provide adequateprotection for public health. This is important to know becausethe Agency is interested in cost-efficient regulations. Finally,human research often confirms a risk assessment based on animaltoxicity data. Such confirmation increases confidence in theAgency's decisions. Therefore, the Agency agrees that it isalways important to assess data from available humanresearch.
The Agency also agrees that it is generally inappropriate toapply current ethical standards to judge the acceptability ofresearch completed before such standards were articulated. Notonly could that lead to declaring unethical much completedresearch which was considered ethical when it was conducted, itwould also set a standard for ethical conduct-adherence tostandards not yet articulated-that even the most ethicallyconcerned investigators and sponsors could never meet. To avoidsuch an outcome EPA will generally judge the ethicalacceptability of research initiated before the effective data ofthis rule in terms of the ethical standards prevailing when itwas performed.
The Agency also agrees that no actions taken after research iscompleted can undo any harm experienced by the human subjects inthe research. But this point ignores the deterrent value ofgovernment actions that "punish" unacceptableconduct. EPA believes that by refusing to rely on unethical datait creates a strong incentive for the scientific community toconduct future research ethically. If investigators and sponsorsunderstand that EPA will not rely on the results of theirresearch unless it is performed ethically, they will not wish torisk losing either their direct investment in the research or anybenefit its use might bring to them.
Finally, EPA believes that the public expects its governmentto apply a clear standard of ethical acceptability in decidingwhether to rely on the results of completed research. Such anexpectation, evident in thousands of public comments on theproposed rule, provides additional reason for establishing anexplicit ethical framework for making these decisions, and forrefusing to rely on unethically obtained data. (As discussedbelow, EPA believes that in certain very limited circumstancesthe ethical course of conduct may require reliance on ethicallydeficient research when to do so is crucial to supporting morestringent regulatory measures to protect public health.)
Comment : Some comments, noting thatscientifically unsound research is always unethical, argued thatthe proposed framework should articulate explicit standards ofscientific validity.
Response : EPA agrees that its ethical frameworkshould exclude data which are not scientifically sound, and thusthe final rule clarifies that subpart Q applies only to"scientifically valid and relevant data." The Agencyhas not, however, attempted to define a standard for scientificvalidity and relevance, because this is necessarily acase-by-case judgment. EPA has long had in place policies andprocedures to ensure rigorous scientific review of research it isconsidering, including procedures for formal peer review ofresearch and assessments critical to Agency actions. Inaddition, § 26.1603(b) of the final rule provides thatthe HSRB "shall review and comment on the scientific andethical aspects of research proposals and reports of completedintentional exposure research. . . ." Over time theresults of HSRB review of the scientific aspects of both proposedand completed human research will support articulation of generalprinciples for the scientifically sound and ethical conduct ofdifferent types of human research.
3. The ethical standard for accepting"old" research . Opinions about researchconducted before the final rule varied widely, and are summarizedbelow under these headings:
• The proposed standard is too weak; the CommonRule should be applied to all research, regardless of when it wasconducted;
• The rule should define such terms as"standards prevailing when research was conducted";"fundamentally unethical"; and "significantlydeficient."
• Rejection of any research involving intentionalexposure of pregnant women, fetuses, or children is inconsistentwith "standards prevailing when research wasconducted."
• The standard of "clear evidence"should be different;
Comment : Many comments favored application ofthe Common Rule to all research, regardless of when it wasperformed. These comments argued that the standard in proposed§ 26.601 was unacceptably weak because it failed toreflect contemporary ethical standards.
Response : EPA believes it would be unreasonableto apply to completed research ethical standards articulatedafter the research was conducted. Thus, the final rule retainsthe proposed standard for judging the acceptability of completed"old" research-i.e., research initiated beforethe final rule becomes effective.
First, for many years the prevailing ethical standard in theU.S. has been the Common Rule, and with respect to biomedicalresearch, the earlier DHHS rules that form the basis for theCommon Rule. Consequently, as a practical matter, the samestandard of ethical acceptability-the Common Rule or itsforeign equivalent-would apply to research conducted sinceits promulgation in 1991.
Thus, reference to ethical standards prevailing at the time ofthe research makes a practical difference only when consideringthe acceptability of research which meets today's standards ofscientific validity but which was conducted before today'sethical standards were articulated. Codes of ethical researchconduct require investigators to do certain things in certainways before and during the research. It is reasonable to expectinvestigators to follow ethical codes that prevail when they dotheir work; it is unreasonable to expect them to anticipate andfollow standards developed after their work is done. EPAbelieves that scientifically meritorious research which adheredto accepted ethical norms when it was conducted should not be setaside because ethical standards have subsequently changed. EPAalso believes that ethical standards are likely to continue tochange in the future and that if and when they do, such a changeshould not invalidate or make unacceptable otherwise meritoriousresearch conducted now, in conformity with the ethical standardsof today.
It is sometimes argued that to accept "old"research falling short of today's standards would encourageothers to conduct unethical research in the future. EPAdisagrees. With respect to new research, the principal incentiveto conduct research ethically is the prospect that the Agencymight refuse to rely on research that doesn't comply withcontemporary ethical standards. A refusal by EPA to rely on newhuman research would carry serious economic consequences for theinvestigator and sponsor. Much third-party research is conductedby private, for-profit organizations in the hope that the resultswill lead to financial benefits, often through changes ingovernment regulation. For example, the current controversy overpesticide studies centers on research conducted by pesticidecompanies who hoped to demonstrate through human studies thattheir products were safer than was indicated by available animalstudies, and thus that their market could expand-or atleast need not shrink-because of concerns about risk. AnAgency refusal to rely on data would deprive the investigator andsponsor of such potential financial benefits. Importantly, under§ 26.1705 of the final rule, the Common Rule'sprovisions will guide EPA's decisions about reliance on theresults of new research, i.e., studies conductedafter the rule takes effect. The fact that EPA may apply adifferent standard to "old" studies is irrelevant.An investigator conducting a new, covered study after these finalrules take effect would be very foolish to think that the Agencywill judge its ethical acceptability by any standard other thanthe Common Rule.
Comment : A number of comments called for therule to specify that certain documents-the Nuremberg Code,various editions of the Declaration of Helsinki, the BelmontReport, and the Common Rule, among others-would serve asthe point of reference in identifying the "standardsprevailing at the time the research was conducted." Othercomments asked that the Agency explain and give examples of thetypes of ethical deficiencies that it would deem"fundamentally unethical" or "significantlydeficient" in the provision codified as§ 26.1704 of the final rule.
Response : In recent years, EPA has reviewednumerous reports of completed research on pesticides involvingintentional exposure of human subjects. These studies have beenconducted over many years, in many places, under a variety ofethical policies and regulatory schemes; they have addressed awide range of research questions, and they have presented a widespectrum of ethical shortcomings, from minor flaws to moreserious deficiencies. Given these variations, the Agencybelieves that its ethical framework must retain sufficientflexibility to judge each situation on its merits, in the contextof the time and place the research was conducted. While thehistorical documents cited in the comments reflected widelyshared views about what constitutes ethical conduct, they werenot necessarily universal or comprehensive in their coverage.Certainly they are among the standards which may have prevailedwhen specific research was conducted, and EPA will rely on themwhen they are appropriate to the evaluation of a particularstudy. But it adds nothing to list them in the final rule.
EPA also thinks it unnecessary to elaborate on the meaning ofthe narrative standards "fundamentally unethical,""significantly deficient" or "substantialcompliance." The gravity of a particular ethical lapsedepends not only on the details of the deficiency, but also onthe circumstances in which it occurred. EPA agrees with the NASthat each study requires case-by-case evaluation. EPA expectsthese terms to acquire greater clarity over time, through HSRBand public review of Agency decisions concerning reliance oncompleted human research.
Comment : Some comments objected to the proposedprohibition of EPA's reliance in its pesticide decisions on datafrom human subjects research involving intentional exposure ofpregnant women, fetuses, or children. These comments argued thatif such research was not considered unethical under the standardsprevailing when it was conducted EPA should accept and considerit, and that exclusion of such research could deprive EPA ofpotentially valuable information.
Response : EPA agrees that existing researchinvolving intentional exposure of pregnant women, fetuses, orchildren may have been considered ethical according to thestandards prevailing when the studies were conducted.Nonetheless, in light of the provisions of the 2006Appropriations Act and the thousands of public comments on theproposal condemning research of this kind, the Agency believes itmust generally refuse to rely on such research. The Agency knowsof only a very few existing studies involving intentionalexposure of pregnant women or children. If it were determinedthat reliance on any of them were crucial to a decision thatwould impose a more stringent regulatory restriction to protectpublic health than could otherwise be justified, the exceptionprocedure defined in § 26.1706 in the final rule couldbe invoked.
Comment : Several comments recommended revisingthe evidentiary standard for accepting "old" studies.Some suggested a change from "clear evidence" to aless demanding test, such as "any evidence." Othersrecommended adoption of the exact wording of the NASrecommendation on which EPA based the proposal, changing"clear evidence" to "clear and convincingevidence."
Response : It is conceivable that the standardrequiring "clear evidence" could lead the Agency toaccept data from research which it suspected but could not provehad serious ethical flaws. The Agency agrees this would beunfortunate, but believes a change to a standard of "anyevidence" would likely lead to even more unfortunateoutcomes. Because reliable information about its conduct isoften very limited, in many cases it is difficult or impossibleto prove that older research was ethical. An unsupportedaccusation of unethical conduct should thus not in itself besufficient to force rejection of completed research. Rejectionof research on the basis of weak or suggestive evidence ofunethical conduct could deprive the Agency of informationimportant to sound decisions. Because EPA can see no benefitthat would flow from changing the standard to "anyevidence," EPA is not accepting this recommendation.
On the other hand EPA agrees with the comments urging a returnto the exact wording of the evidentiary test in NASRecommendation 5-7. Since the Agency did not intend toalter the standard, and since "clear and convincingevidence" has an accepted meaning under administrative law,EPA has changed the final rule to read, in pertinent part:
. . . EPA shall not rely on data from any research initiatedbeforeApril 7, 2006 if there is clear and convincingevidence that the conduct of that the research was fundamentallyunethical . . .
4. The exception allowing use of unethical data tojustify more stringent regulatory restrictions to protect publichealth .
Comment : One group of comments argued that theAgency should, without exception, never rely on data derived fromunethical research because to do otherwise would condoneunethical research. Many of these commenters also misunderstoodthe proposed exception as authorizing the conduct of unethicalfuture research.
Response : Although EPA thinks there willrarely, if ever, be situations requiring the use of thisexception, EPA can easily imagine a circumstance in which ethicalbehavior could require Agency decision-makers to rely onunethical data. (See Unit II.) The exception would be used whenscientifically sound but ethically flawed data show that theAgency needs to take a more protective action than could bejustified without considering the human research. Invoking theexception would allow EPA to protect the health of manypeople-perhaps millions; a greater public good than anybenefits that would flow from refusing to rely on the data. InEPA's moral calculus, the greater good should and will guide thechoice whether to use unacceptable data.
The Agency disagrees with the argument that the final ruleshould contain no exceptions to the basic principle of refusingto rely on unethical research, because an exception wouldencourage the conduct of unethical research. A public refusal byEPA to rely on unethical data brings shame to the investigatorwho acted unethically, and in most cases also directly affectsthe financial interests of the investigator, sponsor, or both.Such a refusal serves as an important deterrent to otherinvestigators, discouraging unethical research in the future.
To further ensure that EPA's exceptional use of ethicallyflawed data does not encourage unethical research conduct,§ 26.1706 expressly requires the Agency to publish"a full explanation of its decision to rely on otherwiseunacceptable data, including a thorough discussion of the ethicaldeficiencies of the study . . . ." In addition, the Agencywill have recourse to any of the other measures identified insubpart O to promote compliance with standards of ethicalresearch. EPA believes the exception as defined in the finalrule, allowing for EPA consideration of unethical research underwell defined and narrow conditions and requiring a full publicdiscussion of its ethical deficiencies, will not in any wayencourage other investigators to conduct unethical research.
Comment : Some comments argued for a broadinterpretation of the concept of "protection of publichealth," such that it would not be limited to casesinvolving imposition of more stringent regulatory restrictions.Some comments suggested, for example, that a more accurateassessment of risks to humans should be interpreted as"protection of public health." Other comments calledupon EPA to clarify in the final rule that "protection ofpublic health" does not encompass the ability of Americanagriculture to produce more crops at a lower cost.
Response : EPA does not agree that the publichealth exception should be interpreted to permit reliance onunethical research to support more accurate risk assessments ormore efficient or lower cost agricultural production. EPA'sethical framework is built on the principle that unethicalresearch should not be relied on in Agency actions except in themost extraordinary circumstances; such interpretations wouldamount to abandoning this principle altogether, and couldseverely undermine incentives for compliance with the newrequirements.
The Agency does agree, however, that the proposal was unclearwith respect to what would constitute a "publichealth" benefit justifying invocation of the exception.EPA has thus revised the final rule to clarify that invoking thepublic health exception would only permit the Agency to"impose a more stringent regulatory restriction that wouldimprove protection of public health . . . ." See§ 26.1706 of the regulatory text.
C. The Final Rule
Subpart Q of the final rule corresponds in substance tosubpart F of the proposal. In this final rule EPA has moved therule text to a new subpart, and has rewritten the proposedprovisions to express the standards more clearly.
Section 26.1701 of the final rule describes the scope ofsubpart Q; it applies to:
. . . EPA's decisions whether to rely in its actions underthe Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C.136 et seq. ) or section 408 of the Federal Food, Drug,and Cosmetic Act (21 U.S.C. 346a) on scientifically valid andrelevant data from research involving intentional exposure ofhuman subjects.
The Agency has chosen to retain the scope of the proposed rulebecause it believes that the 2006 Appropriations Act does notrequire this rule to address a broader scope of issues, andbecause there has not been adequate consideration of theconsequences of adopting a more expansive scope.
Section 26.1703 prohibits EPA's reliance on data from researchinvolving intentional exposures of pregnant women, fetuses, orchildren. Derived from proposed §§ 26.221 and26.421, this section states:
Except as provided in § 26.1706, in actions withinthe scope of § 26.1701, EPA shall not rely on datafrom any research involving intentional exposure of any humansubjects who is a pregnant woman (and therefore her fetus) orchild.
This provision makes clear that the Agency will not rely inits actions on the results of research that EPA and third partiesare prohibited from conducting under subparts B and L, exceptunder the narrow exception provided by § 26.1706. Toclarify that this prohibition applies to EPA's non-regulatoryactions (such as issuance of a risk assessment or a healthadvisory level) as well as to its regulatory decisions, EPA haschanged the phrase "regulatory decision-making" inthe proposal to "actions" in the final rule.
Section 26.1704 defines the ethical standard EPA will use todecide whether to rely on the results of research conducted withnon-pregnant adults before the effective date of the rule. Itprovides:
Except as provided in § 26.1706, in actions withinthe scope of § 26.1701, EPA shall not rely on datafrom any research initiated before April 7, 2006, if there is clear and convincing evidence that theconduct of the research was fundamentally unethical (e.g., theresearch was intended to seriously harm participants or failed toobtain informed consent), or was significantly deficient relativeto the ethical standards prevailing at the time the research wasconducted. This prohibition is in addition to the prohibition in§ 26.1703.
The above rule text is derived from proposed§ 26.601, and follows the language of the NASrecommendation 5-7. In response to public comment, theevidentiary standard for concluding research was unethical hasbeen changed from "clear evidence" to "clearand convincing evidence." The Agency made this change tominimize confusion, to conform to the wording of the NASrecommendation, and to use a formulation of the evidentiarystandard that has an accepted legal meaning in administrativelaw. For purposes of clarity, the section also reaffirms thatthe prohibition in § 26.1703 against relying onresearch involving pregnant women and children is unaffected bythis provision.
Section 26.1705 describes the ethical standard EPA will use todecide whether to rely on the results of human subjects researchconducted with non-pregnant adults after the effective date ofthe rule. It provides that the Agency will not rely on data fromsuch research:
Except as provided in § 26.1706, in actions withinthe scope of § 26.1701, EPA shall not rely on datafrom any research initiated after April 7, 2006, unless EPA has adequate information to determinethat the research was conducted in substantial compliance withsubparts A through M of this part, or if conducted in a foreigncountry, under procedures at least as protective as those insubparts A through L. This prohibition is in addition to theprohibition in § 26.1703.
This rule text is based on proposed § 26.602. Ithas been revised to make clear that EPA may accept and rely ondata from human research conducted in a foreign country if EPAhas adequate information to determine the research was"conducted . . . under procedures at least as protective asthose in subparts A through L." Allowing the use offoreign research provided the research meets ethical normsequivalent to those of the Common Rule is consistent with theCommon Rule at § 26.101(h). Like§ 26.1704, § 26.1705 reaffirms, for thesake of clarity, that the prohibition in § 26.1703against relying on research involving pregnant women and childrenis unaffected by this provision.
Finally § 26.1706 provides for an exception to thegeneral refusal to rely on the results of unethical research.This section defines the specific circumstance in which theAgency will use data from research judged unacceptable under§ 26.1703, § 26.1704, or§ 26.1705, and the procedures EPA must follow inreaching that decision, as follows:
EPA may rely on such data only if all the conditions inparagraphs (a) through (d) of this section are satisfied:
(a) EPA has obtained the views of the Human Studies ReviewBoard concerning the proposal to rely on the otherwiseunacceptable data,
(b) EPA has provided an opportunity for public comment on theproposal to rely on the otherwise unacceptable data,
(c) EPA has determined that relying on the data is crucial toa decision that would impose a more stringent regulatoryrestriction that would improve protection of public health thancould be justified without relying on the data, and
(d) EPA publishes a full explanation of its decision to relyon the otherwise unacceptable data, including a thoroughdiscussion of the ethical deficiencies of the study and the fullrationale for finding that the standard in paragraph (c) of thissection was met.
The text of this section of the final rule contains a numberof minor revisions to clarify the substantive and proceduralrequirements. Most notably, EPA changed the wording for thesubstantive standard for using the exception from "crucialto the protection of public health" in the proposal to"crucial to a decision that would impose a more stringentregulatory restriction that would improve protection of publichealth" in the final rule. This change reflects theAgency's intent to limit the exception to a very narrowcircumstance and to prevent use of the exception in a way thatcould benefit a person responsible for the unethical conduct.
XIV. EPA's 2006 Appropriations Act and the Final Rule
This unit discusses how today's final rule meets therequirements of the Department of the Interior, Environment, andRelated Agencies Appropriations Act, 2006, Public Law No.109-54 (Appropriations Act), which required EPA topromulgate a final rule relating to intentional dosing humantoxicity studies for pesticides within 180 days of enactment ofthe Act, and included various mandates concerning the promulgatedfinal rule.
A. Section 201 of EPA's FY 2006 Appropriations Act
On August 2, 2005, the President signed into law theDepartment of the Interior, Environment, and Related AgenciesAppropriations Act, 2006, Public Law No. 109-54(Appropriations Act), which provides appropriated funds for EPAand other federal departments and agencies. Section 201 of theAppropriations Act addressesEPA activities regarding intentional dosing human toxicitystudies for pesticides as follows:
None of the funds made available by this Act may be used bythe Administrator of the Environmental Protection Agency toaccept, consider or rely on third-party intentional dosing humantoxicity studies for pesticides, or to conduct intentional dosinghuman toxicity studies for pesticides until the Administratorissues a final rulemaking on this subject. The Administratorshall allow for a period of not less than 90 days for publiccomment on the Agency's proposed rule before issuing a finalrule. Such rule shall not permit the use of pregnant women,infants or children as subjects; shall be consistent with theprinciples proposed in the 2004 report of the National Academy ofSciences on intentional human dosing and the principles of theNuremberg Code with respect to human experimentation; and shallestablish an independent Human Subjects Review Board. The finalrule shall be issued no later than 180 days after enactment ofthis Act.
B. Compliance of the Final Rule with the AppropriationsAct
The first requirement of the Appropriations Act is that EPAnot "accept, consider or rely on third-party intentionaldosing human toxicity studies for pesticides, or . . . conductintentional dosing human toxicity studies for pesticides untilthe Administrator issues a final rulemaking on thissubject." EPA has not accepted, considered, or relied onany third-party intentional dosing human toxicity studies in itsactions under FIFRA and FFDCA since September 2005. EPA hasfurther neither conducted nor supported any intentional dosinghuman toxicity study for pesticides during this rulemakingperiod.
The second requirement of the Appropriations Act is to"allow for a period of not less than 90 days for publiccomment on the Agency's proposed rule before issuing a finalrule." A notice of proposed rulemaking addressing boththird-party intentional dosing human toxicity studies forpesticides and EPA's conduct of intentional dosing human studieswas published in the Federal Register on September12, 2005 (70 FR 53838); the public comment period ended onDecember 12, 2005.
EPA's proposed rule addressed first-, second-, and third-partyhuman subjects testing for pesticides. In particular, theproposal defined the scope of third-party human research coveredby the proposal as:
[A]ll research involving intentional exposure of a humansubject if, at any time prior to initiating such research, anyperson who conducted or supported such research intended:
(1) To submit results of the research to EPA for considerationin connection with any regulatory action that may be performed byEPA under the Federal Insecticide, Fungicide, and Rodenticide Act(7 U.S.C. 136 et seq. ) or section 408 of theFederal Food, Drug, and Cosmetic Act (21 U.S.C. 346a); or
(2) To hold the results of the research for later inspectionby EPA under the Federal Insecticide, Fungicide, and RodenticideAct (7 U.S.C. 136 et seq. ) or section 408 of theFederal Food, Drug, and Cosmetic Act (21 U.S.C. 346a).
EPA used the act of submitting, or the intent to submit, tothe Agency under FIFRA or FFDCA as a surrogate for theAppropriations Act's requirement that EPA promulgate a ruleaddressing "third-party intentional dosing human toxicitystudies for pesticides ." The use, sale, anddistribution of pesticides are exclusively regulated by EPA underFIFRA and FFDCA. Moreover, as discussed above, the ongoingcontroversy over EPA's use of human research data in its riskassessments has focused almost exclusively on the use of suchdata in risk assessments under FIFRA and FFDCA. Indeed, theCongressional debate that resulted in the passage of section 201of the Appropriations Act focused entirely on human subjectsresearch related to Agency actions under FIFRA and FFDCA.Therefore, EPA believes that interpreting the phrase"third-party intentional dosing human toxicity studies forpesticides" to require either submission or intent tosubmit under FIFRA or FFDCA reflects the intent of the Congressas expressed in section 201 of the Appropriations Act.
The third requirement of the Appropriations Act is that thefinal rule "not permit the use of pregnant women, infantsor children as subjects." Today's final rule effectuatesthis mandate by: (1) Categorically prohibiting EPA fromconducting or supporting research involving intentional exposureto any substance of human subjects who are pregnant women orchildren (subpart B of the final rule, § 26.203); and(2) prohibiting third-party research for pesticides involvingintentional exposure of human subjects who are pregnant women orchildren (subpart L of the final rule,§ 26.1203).
The fourth requirement of the Appropriations Act is that thefinal rule "shall be consistent with the principlesproposed in the 2004 report of the National Academy of Scienceson intentional human dosing." Based on a careful review ofthe NAS report, EPA concludes that the underlying principlesintended by the NAS committee to be reflected in itsrecommendations are the three "fundamental ethicalprinciples" identified by the National Commission for theProtection of Human Subjects of Biomedical and BehavioralResearch (National Commission) in its report, Ethical Principlesand Guidelines for the Protection of Human Subjects of Research(the "Belmont Report"). These three fundamentalprinciples are respect for persons, beneficence, and justice.See NAS Report at pp. 49-50, 98, and 113-14.
The NAS committee makes the point clearly that they did notpropose new principles:
[T]he committee was not required to invent the basicstandards that govern human research in the United States. Thesestandards are already embodied in the Federal Policy for theProtection of Human Subjects (the Common Rule.) NAS Report pp.4, 33.
The NAS committee further stated that the fundamentalprinciples articulated in the Belmont Report both undergird andare made operational by the procedural requirements of the CommonRule. The following quotations express this view:
Federal regulations incorporate the obligation of beneficenceby requiring IRBs to ensure that risks are minimized to theextent possible, given the research question, and are reasonablein relation to potential benefits to the participant or to theimportance of the knowledge to be gained through the research (40CFR 26.111(a)(1)-(2)). NAS Report at 56.
[D]etermining whether the principle of beneficence has beensatisfied requires balancing the anticipated risks to studyparticipants against the anticipated benefits of the study tosociety. The risks to participants must be reasonable inrelation to the societal benefit. In the words of the CommonRule, the risks must be reasonable in relation to the importanceof the knowledge that may reasonably be expected to result (40CFR 26.111 (a)(2)). NAS Report at 107.
According to the Common Rule, IRBs should not approve aresearch protocol involving humans unless "selection ofsubjects is equitable" (40 CFR 26.111(3)). Thisrequirement derives from the principle of justice identified inthe Belmont Report. NAS Report at 114.
Voluntary, informed consent by research participants . . . isa major element in the system of protection of researchparticipants. The consent requirement expresses the principle ofrespect for persons, including respect for and promotion ofautonomous choices. The Common Rule stresses this requirement,as do other codes of research ethics, including the NurembergCode (1949), the Declaration of Helsinki, and the Good ClinicalPractice guidelines. NAS Report at 120.
Accordingly, EPA concludes that the "principles proposedin the 2004 report of the National Academy of Sciences onintentional human dosing" are, in fact, the threefundamental principles of respect for persons, beneficence, andjustice articulated in the Belmont Report, and that the CommonRule rests on the foundation of those principles. Today's finalrule extending the substantive requirements of EPA's Common Ruleto additional categories of regulated third-party research isthus consistent with those principles, as required by theAppropriations Act.
The fifth requirement of the Appropriations Act is that thefinal rule "shall be consistent with the principles . . .of the Nuremberg Code with respect to humanexperimentation."
The NAS report (p. 47) explains the history of the NurembergCode as follows:
Public policies regarding the ethical treatment of humans inresearch began forming in the late 1940's, largely in response tothe atrocities committed by Nazi investigators who were triedbefore the Nuremberg Military Tribunal ( UnitedStates v. Karl Brandt , et al .)In 1946, the American Medical Association adopted its first codeof research ethics, which ultimately influenced the NurembergTribunal's standards for ethical research, embodied in the ten"basic principles" for human research now known asthe Nuremberg Code. [Footnotes and references omitted]
Before publishing the NPRM, EPA carefully assessed whether theproposed provisions were consistent with the 10 principles of theNuremberg Code as a guide, and concluded that it was consistentwith such principles. EPA believes this final rule remainsconsistent with the principles of the Nuremberg Code. Ananalysis explaining this conclusion is in the docket for thisaction, and comments on this issue have been addressed in ourResponse to Comments document.
The sixth requirement of the Appropriations Act is that thefinal rule "shall establish an independent Human SubjectsReview Board." EPA believes that the entity required bythe Appropriations Act is intended to be substantially identicalto the "Human Studies Review Board" recommended byChapter 6 of the NAS Report. Consistent with both therequirement of the Appropriations Act and the recommendations ofthe NAS, this final rule establishes an independent HSRB. TheHSRB will review proposed human subjects research after review bya local IRB and EPA staff. This sequence is consistent both withEPA's current practice for reviewing first- and second-partyhuman research proposals and with the practice of FDA forreviewing human research proposals. Although the NAS Reportrecommended that the EPA and HSRB reviews come before the IRBreview, EPA believes that HSRB review after local IRB and EPAreview will better serve the purposes for which HSRB review ofproposed research is intended.
The final requirement of the Appropriations Act is that thefinal rule "shall be issued no later than 180 days afterenactment of this Act." This requirement was met when EPAAdministrator Stephen L. Johnson signed the final rule beforeJanuary 29, 2006, and it was made publicly available.
XV. Effective Date of the Final Rule
EPA noted in the preamble to the proposed rule that itconsidered the expeditious application of the new protections inthe final rule to be in the public interest. Accordingly theAgency explained that it would provide no longer period than isessential between publication of the final rule and its effectivedate. Since the final rule is being promulgated under theauthority of FIFRA, EPA is subject to FIFRA section 25(a)(4), 7U.S.C. 136w(a)(4), which provides that:
Simultaneously with the promulgation of any rule or regulationunder this Act, the Administrator shall transmit a copy thereofto the Secretary of the Senate and the Clerk of the House ofRepresentatives. The rule or regulation shall not becomeeffective until the passage of 60 calendar days after the rule orregulation is so transmitted.
Therefore, EPA proposed that the final rule would be effective60 days after its promulgation and transmittal to Congress.
EPA received only one comment on the effective date, arguingthat the requirements of the rule should not apply retroactively.EPA agrees that the provisions of the final rule should not applyretroactively, and the final rule contains no retroactiverequirements. Specifically, the final rule establishes standardsfor the conduct by EPA and by third parties, in the future, ofcertain types of research. The Agency notes that the actions topromote compliance identified in subpart O of the final rulewould only be applied to those whose actions, following theeffective date of the final rule, did not comply with applicablerequirements. Actions occurring before the final rule takeseffect would not be subject to direct sanctions under subpart O,such as civil penalties or debarment. In addition, the finalrule establishes standards to guide future Agency decisions aboutthe ethical acceptability of completed research. While some ofthe research that EPA will evaluate under the new standards forethical acceptability was conducted prior to the effective dateof the final rule, such studies will be judged by the ethicalstandards prevailing when the research was performed. Thus, eventhe standard of acceptability is not "retroactive" inthe sense that conduct would be judged using a standard createdafter the conduct occurred.
The Agency has decided to make the final rule effective 60days after the date of publication of its Notice of FinalRulemaking in the Federal Register . As required byFIFRA section 25(a)(4), the Agency has previously transmittedcopies of the signed final rule to the Secretary of the Senateand the Clerk of the House of Representatives. Althoughtechnically the rule could take effect a few days earlier, EPAconcluded that allowing 60 days from the date of publication ofthis Federal Register document was appropriate.Accordingly, this rule takes effect on April 7, 2006.
The Agency notes that a number of the provisions of the ruleapply to research "initiated" after the effectivedate of this rule. For purposes of research conducted orsupported by EPA, the Agency will consider that an investigatorhas initiated a study once the Agency's HSRRO has approved theprotocol for the study. For purposes of research that is coveredby subparts K or L or by § 26.1705, a study was"initiated" when the first subject was enrolled. Ifthat date cannot be determined, EPA will consider the earliestdate on which experimental activity involved a subject to be thedate of initiation of the research.
XVI. FIFRA Review Procedures for the Final Rule
FIFRA section 25(a)(2)(B) provides: "[a]t least 30 daysprior to signing any regulation in final form for publication inthe Federal Register , the Administrator shallprovide the Secretary of Agriculture a copy of suchregulation." This section also authorizes the Secretary towaive the opportunity to review and comment on final regulations.FIFRA section 25(d)(1) states that "[t]he Administratorshall submit to an advisory panel for comment [the] final formof regulations issued under section 25(a) within the same timeperiods as provided for the comments of the Secretary ofAgriculture . . . ." This section also authorizes theFIFRA Scientific Advisory Panel to waive the opportunity forreview. Both, the FIFRA Scientific Advisory Panel (SAP) and theU.S. Department of Agriculture (USDA) have waived the opportunityunder FIFRA to review the final rule.
In addition, FIFRA section 25(a)(3) states that "[a]tsuch time as the Administrator is required under paragraph (2) toprovide the Secretary of Agriculture with . . . a copy of thefinal form of regulations, the Administrator shall also furnish acopy of such regulations to the Committee on Agriculture in theHouse of Representatives, and the Committee on Agriculture,Nutrition, and Forestry in the United States Senate."Because USDA waived review under FIRFA section 25(a)(2)(B), EPAis not required to furnish a copy of the final regulations to thespecified committees 30 days prior to signature of the finalrule. The Agency, nonetheless, provided copies of the final ruleto the Congressional committees prior to its publication.
XVII. Statutory and Executive Order Reviews
A. Executive Order 12866
Under Executive Order 12866, entitled RegulatoryPlanning and Review (58 FR 51735, October 4, 1993), theOffice of Management and Budget (OMB) has determined that thisfinal rule is a "significant regulatory action" undersection 3(f) of the Executive Order because this action mightraise novel legal or policy issues. Accordingly, this action wassubmitted to OMB for review under Executive Order 12866 and anychanges made based on OMB recommendations have been documented inthe docket for this rulemaking as required by section 6(a)(3)(E)of the Executive Order.
In addition, EPA prepared an economic analysis of thepotential costs and benefits associated with this action. Thisanalysis is contained in a document entitled "EconomicAnalysis of the Human Studies Final Rule" (EconomicAnalysis). A copy of the Economic Analysis is available in thedocket for this rulemaking and is briefly summarized here.
The Economic Analysis describes the benefits of the rulemakingin qualitative terms. These benefits include greater protectionsfor test subjects, and a corresponding reduction in their risks,to the extent that affected third-party researchers are notalready following the Common Rule. The benefits to sponsors ofthird-party human research include a better understanding of thestandards that EPA will apply in determining whether to rely onthe results of their studies, and thus, the opportunity to designand perform studies that are more likely to meet EPA standards,leading to more efficient Agency reviews. The Agency believes thegeneral public will also benefit from this action because therule will strengthen the protections for human subjects andreinforce the Agency's strong commitment to base its decisions onscientifically sound information.
The Economic Analysis also estimates the costs of the finalrule by focusing on the costs to third parties of complying withthe new requirements and the costs to EPA of implementing the newrequirements. In general, EPA believes that most, if not all,recent third-party research intended for submission to EPA thatinvolves intentional exposure of human subjects already complieswith the Common Rule or an equivalent foreign standard. Forpurposes of this analysis, EPA assumed that current practice wasin full compliance with the Common Rule.
After reviewing the history of EPA's consideration of researchinvolving human subjects in its various program offices, EPAestimates that this action will affect only a limited number ofthird-party studies involving human subjects each year. EPA alsocollected data on the cost per study of compliance with theCommon Rule. These costs include preparing documents to supportreview by an IRB and the expense associated with the IRB review.These costs are very minor relative to the overall cost ofconducting the studies. For EPA, the costs are associated withthe review of protocols and the review of completed human studiesby EPA staff and the Human Studies Review Board.
As detailed in the Economic Analysis prepared for this finalrule, this action is estimated to result in a total annualincremental cost to third parties of approximately $39,000, andan estimated annual cost to EPA of approximately $808,000.
B. Paperwork Reduction Act
The information collection requirements contained in thisfinal rule have been approved by the Office of Management andBudget (OMB) under the Paperwork Reduction Act (PRA), 44 U.S.C.3501 et seq. , under OMB control number2070-0169. In accordance with the procedures at 5 CFR1320.11, EPA sought comment on the Information Collection Request(ICR) document that was submitted to OMB in conjunction with theproposed rule (identified under EPA ICR No. 2195.01). Revised toreflect the provisions in this final rule, the ICR document(identified under EPA ICR No. 2195.02) was prepared and submittedto OMB and serves as the basis for OMB's approval. A copy ofthis ICR document has been placed in the docket for thisrulemaking.
Under the PRA, an agency may not conduct or sponsor, and aperson is not required to respond to an information collectionrequest unless it displays a currently valid OMB control number.The OMB control numbers for the EPA regulations codified inChapter 40 of the CFR, after appearing in the preamble of thefinal rule, are listed in 40 CFR part 9, displayed either bypublication in the Federal Register or by otherappropriate means, such as on the related collection instrumentor form, if applicable. The display of OMB control numbers incertain EPA regulations is consolidated in 40 CFR part 9. Forthis ICR activity, in addition to displaying the applicable OMBcontrol number in this unit, the Agency is amending the table in40 CFR 9.1 to list the OMB control number assigned to this ICRactivity. Due to the technical nature of the table, EPA findsthat further notice and comment about amending the table isunnecessary. As a result, EPA finds that there is "goodcause" under section 553(b)(B) of the AdministrativeProcedures Act (APA), 5 U.S.C. 553(b)(B), to amend this tablewithout further notice and comment.
EPA estimates that respondents may submit to the Agency eachyear under FIFRA or FFDCA, approximately 33 reports of researchinvolving intentional exposure of human subjects. The Agencyexpects extremely limited submission of toxicity studies per year(i.e., 0-4 studies), with the bulk of the 33 studies beingcomposed of efficacy and skin sensitization studies. (See alsothe response to comment on this topic that appears in Unit III.)EPA estimates that it may receive approximately 29 reports eachyear of other types of pesticide research involving humansubjects. EPA estimates that preparation of the requiredinformation will require about 32 hours per study, for a totalestimated annual burden for affected entities of 1,984 hours, atan estimated cost of $1,927 per study, or a total estimatedannual paperwork cost to respondents of $84,647. This totalannual paperwork burden and cost estimate includes activitiesrelated to initial rule familiarization, as well as activitiesthat researchers already perform and would continue to performeven without the Agency's rulemaking in this area (i.e.,developing a protocol and maintaining records). The averageannual burden on EPA for reviewing this information for eachstudy submission is estimated to be 80 hours per study (in total4,960 hours), representing a paperwork related labor cost ofabout $14,672 per response and a total annual cost of$909,664.
In the context of the PRA, "burden" means thetotal time, effort, or financial resources expended by persons togenerate, maintain, retain, or disclose or provide information toor for a Federal agency. This includes the time needed to reviewinstructions; develop, acquire, install, and utilize technologyand systems for the purposes of collecting, validating, andverifying information, processing and maintaining information,and disclosing and providing information; adjust the existingways to comply with any previously applicable instructions andrequirements; train personnel to be able to respond to acollection of information; search data sources; complete andreview the collection of information; and transmit or otherwisedisclose the information.
The information collection activity imposed by this final ruleis planned to ensure that sound and appropriate scientific dataare available to EPA when making regulatory decisions, and toprotect the interests, rights and safety of those individuals whoare participants in the type of research activity that is thesubject of this rule. Specifically, this new informationcollection activity consists of reporting and recordkeepingrequirements. Whenever respondents intend to conduct researchfor submission to EPA under the pesticide laws that involvesintentional dosing of human subjects, they will be required tosubmit study protocols to EPA and a cognizant local IRB beforesuch research is initiated so that the scientific design andethical standards that will be employed during the proposed studymay be reviewed and approved. Respondents will also be requiredto submit information about the ethical conduct of completedresearch that involved intentional dosing of human subjects whensuch research is submitted to EPA.
FIFRA sections 3(c)(1)(F) and 3(c)(2)(B) authorize EPA torequire various data in support of a pesticide's continuedregistration or an application for a new or amended pesticideregistration. FIFRA section 12(a)(2)(P) forbids any person"to use any pesticide in tests on human beings unless suchhuman beings (i) are fully informed of the nature and purposes ofthe test and of any physical and mental health consequences whichare reasonably foreseeable therefrom, and (ii) freely volunteerto participate in the test."
C. Regulatory Flexibility Act
Pursuant to section 605(b) of the Regulatory Flexibility Act(RFA), 5 U.S.C. 601 et seq. , after considering thepotential economic impacts of today's rule on small entities, theAgency hereby certifies that this final rule will not have asignificant adverse economic impact on a substantial number ofsmall entities. This determination is based on the Agency'seconomic analysis performed for this rulemaking, summarized inUnit XVI.A., and a copy of which is available in the docket forthis rulemaking. The following is a brief summary of the factualbasis for this certification.
Small entities include small businesses, small organizations,and small governmental jurisdictions. For purposes of assessingthe impacts of today's rule on small entities, small entity isdefined in accordance with the RFA as: (1) A small business asdefined by the Small Business Administration's (SBA) regulationsat 13 CFR 121.201; (2) a small governmental jurisdiction that isa government of a city, county, town, school district, or specialdistrict with a population of less than 50,000; and (3) a smallorganization that is any not-for-profit enterprise which isindependently owned and operated and is not dominant in itsfield.
Although we cannot predict whether or how many small entitiesmight engage in the subject matter research in the future, asestimated in the Economic Analysis, the cost to researcherscovered by this rule is estimated to be $5,200 per study. Thisis a trivially small portion of the overall cost of performingsuch studies, each of which is estimated to cost from $125,000 to$500,000. After reviewing the history of EPA's consideration onhuman research in its various program offices, EPA estimates thatthis rule would affect only a limited number of third-party humanstudies each year. Because both the number of affected studiesis relatively small and the estimated current costs of compliancewith the Common Rule are low, the potential overall costs fromthis rule to third parties are also estimated to be small.
D. Unfunded Mandates Reform Act
Under Title II of the Unfunded Mandates Reform Act of 1995(UMRA) (Public Law 104-4), EPA has determined that thisaction does not contain a Federal mandate that may result inexpenditures of $100 million or more for State, local, and tribalgovernments, in the aggregate, or the private sector in any oneyear. As described in Unit XVI.A. the estimated total costsassociated with this action are approximately $38,837 per year.This cost represents the incremental cost to researchersattributed to the additional procedural requirements contained inthis final rule. Based on historical submissions, EPA hasdetermined that State, local, and tribal governments rarelyperform human research intended for submission to EPA under FIFRAor FFDCA. In addition, the final rule is not expected tosignificantly or uniquely affect small governments. Accordingly,this action is not subject to the requirements of sections 202and 205 of UMRA.
E. Executive Order 13132
Pursuant to Executive Order 13132, entitled Federalism (64 FR 43255, August 10, 1999), EPA hasdetermined that this rule does not have "federalismimplications," because it will not have substantial directeffects on the states, on the relationship between the nationalgovernment and the states, or on the distribution of power andresponsibilities among the various levels of government, asspecified in the Order. As indicated earlier, instances where astate performs human research intended for submission to EPAunder FIFRA or FFDCA are rare. Therefore, this final rule mayseldom affect a state government. Thus, Executive Order 13132does not apply to this rule.
F. Executive Order 13175
As required by Executive Order 13175, entitled Consultation and Coordination with Indian TribalGovernments (59 FR 22951, November 6, 2000), EPA hasdetermined that this final rule does not have tribal implicationsbecause it will not have substantial direct effects on tribalgovernments, on the relationship between the Federal governmentand the Indian tribes, or on the distribution of power andresponsibilities between the Federal government and Indiantribes, as specified in the Order. As indicated previously,instances where a tribal government performs human researchintended for submission to EPA under FIFRA or FFDCA are extremelyrare. Thus, Executive Order 13175 does not apply to thisrule.
G. Executive Order 13045
Executive Order 13045, entitled Protection ofChildren from Environmental Health Risks and Safety Risks (62FR 19885, April 23, 1997) does not apply to this rule becausethis action is not designated as an "economicallysignificant" regulatory action as defined by ExecutiveOrder 12866. Furthermore, this final rule does not establish anenvironmental standard that is intended to have a negativelydisproportionate effect on children. To the contrary, this actionwill provide added protections for children with regard to theresearch covered by the rule.
H. Executive Order 13211
This final rule is not subject to Executive Order 13211,entitled Actions Concerning Regulations that SignificantlyAffect Energy Supply, Distribution, or Use (66 FR 28355, May22, 2001) because this rule does not have any significant adverseeffect on the supply, distribution, or use of energy.
I. National Technology Transfer and Advancement Act
Section 12(d) of the National Technology Transfer andAdvancement Act of 1995 (NTTAA), 15 U.S.C. 272 note) directs EPAto use voluntary consensus standards in its regulatory activitiesunless to do so would be inconsistent with applicable law orimpractical. Voluntary consensus standards are technicalstandards (e.g., materials specifications, test methods, samplingprocedures) that are developed or adopted by voluntary consensusstandards bodies. NTTAA directs EPA to provide Congress, throughOMB, with explanations when the Agency decides not to useavailable and applicable voluntary consensus standards. Thisaction does not require specific methods or standards to generatedata. Therefore, this final rule does not impose any technicalstandards that would require Agency consideration of voluntaryconsensus standards.
J. Executive Order 12898
This final rule does not have an adverse impact on theenvironmental and health conditions in low-income and minoritycommunities. Therefore, under Executive Order 12898, entitled Federal Actions to Address Environmental Justice inMinority Populations and Low-Income Populations (59 FR 7629,February 16, 1994), the Agency is not required to considerenvironmental justice-related issues. Although not directlyimpacting environmental justice-related concerns, the provisionsof this rule will require researchers to use procedures to ensureequitable selection of test subjects in covered humanresearch.
XVIII. Congressional Review Act
The Congressional Review Act, 5 U.S.C. 801 etseq. , generally provides that before a rule may take effect,the Agency promulgating the rule must submit a rule report thatincludes a copy of the rule to each House of the Congress and theComptroller General of the United States. EPA will submit areport containing this rule and other required information to theU.S. Senate, the U.S. House of Representatives, and theComptroller General of the United States prior to publication ofthe rule in the Federal Register . This rule is nota "major rule" as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 9
Environmental protection, Reporting and recordkeepingrequirements.
List of Subjects in 40 CFR Part 26
Environmental protection, Human research subjects, Reportingand recordkeeping requirements.
Dated: January 26, 2006.
Stephen L. Johnson,
Administrator.
Therefore, 40 CFR chapter I is amended as follows:
1. Part 9 is amended as follows:
PART 9-[AMENDED]
a. The authority citation for part 9 continues to readas follows:
Authority:
7 U.S.C. 135 et seq. ,136-136y; 15 U.S.C. 2001, 2003, 2005, 2006,2601-2671, 21 U.S.C. 331j, 346a, 348; 31 U.S.C. 9701; 33U.S.C. 1251 et seq. , 1311, 1313d, 1314, 1318, 1321,1326, 1330, 1342, 1344, 1345 (d) and (e), 1361; E.O. 11735, 38 FR21243, 3 CFR, 1971-1975 Comp. p. 973; 42 U.S.C. 241, 242b,243, 246, 300f, 300g, 300g-1, 300g-2, 300g-3,300g-4, 300g-5, 300g-6, 300j-1,300j-2, 300j-3, 300j-4, 300j-9, 1857 et seq. , 6901-6992k, 7401-7671q, 7542,9601-9657, 11023, 11048.
b. In § 9.1 the table is amended by adding thefollowing new entries under the new heading "Protection ofHuman Subjects" to read as follows:
§ 9.1 OMB approvals under thePaperwork Reduction Act.
| 40 CFR citation | OMB Control No. |
|---|---|
| ***** | |
| Protection of Human Subjects | |
| 26.1125 26.1303 | 2070-0169 2070-0169 |
| ***** | |
PART 26-[AMENDED]
2. Part 26 is amended as follows:
a. By revising the authority citation for part 26 to readas follows:
Authority:
5 U.S.C. 301; 7 U.S.C. 136w(a)(1); 21U.S.C. 346a(e)(1)(C); section 201 of Public Law No. 109-54;and 42 U.S.C. 300v-1(b).
b. By redesignating §§ 26.101 through26.124 as subpart A and adding a new subpart heading to read asfollows:
Subpart A-Basic EPA Policy for Protection ofSubjects in Human Research Conducted or Supported by EPA
c. By adding new subparts B through Q as follows:
Subpart B-Prohibition of Research Conductedor Supported by EPA Involving Intentional Exposure of HumanSubjects who are Pregnant Women or Children
Sec. 26.201 To what does this subpart apply?26.202 Definitions.26.203 Prohibition of research conducted orsupported by EPA involving intentional exposure of any humansubject who is a pregnant woman (and therefore her fetus) orchild.
Subpart C-Observational Research: AdditionalProtections for Pregnant Women and Fetuses Involved as Subjectsin Observational Research Conducted or Supported by EPA
26.301 To what does this subpart apply?26.302 Definitions.26.303 Duties of IRBs in connection withobservational research involving pregnant women and fetuses.26.304 Additional protections for pregnant womenand fetuses involved in observational research.26.305 Protections applicable, after delivery,to the placenta, the dead fetus, or fetal material.
Subpart D-Observational Research: AdditionalProtections for Children Involved as Subjects in ObservationalResearch Conducted or Supported by EPA
26.401 To what does this subpart apply?26.402 Definitions.26.403 IRB duties.26.404 Observational research not involvinggreater than minimal risk.26.405 Observational research involving greaterthan minimal risk but presenting the prospect of direct benefitto the individual subjects.26.406 Requirements for permission by parents orguardians and for assent by children.
Subpart E-[Reserved]
Subpart F-[Reserved]
Subpart G-[Reserved]
Subpart H-[Reserved]
Subpart I-[Reserved]
Subpart J-[Reserved]
Subpart K-Basic Ethical Requirements forThird-Party Human Research for Pesticides Involving IntentionalExposure of Non-pregnant Adults
26.1101 To what does this subpart apply?26.1102 Definitions.26.1103-26.1106 [Reserved]26.1107 IRB membership.26.1108 IRB functions and operations.26.1109 IRB review of research.26.1110 Expedited review procedures for certainkinds of research involving no more than minimal risk, and forminor changes in approved research.26.1111 Criteria for IRB approval of research.26.1112 Review by institution.26.1113 Suspension or termination of IRBapproval of research.26.1114 Cooperative research.26.1115 IRB records.26.1116 General requirements for informedconsent.26.1117 Documentation of informed consent.26.1118-26.1122 [Reserved]26.1123 Early termination of research.26.1124 [Reserved]26.1125 Prior submission of proposed humanresearch for EPA review.
Subpart L-Prohibition of Third-Party Researchfor Pesticides Involving Intentional Exposure of Human Subjectswho are Pregnant Women or Children
26.1201 To what does this subpart apply?26.1202 Definitions.26.1203 Prohibition of research involvingintentional exposure of any pregnant woman, fetus, or child.
Subpart M-Requirements for Submission ofInformation on the Ethical Conduct of Completed Human Research
26.1301 To what does this subpart apply?26.1302 Definitions.26.1303 Submission of information pertaining toethical conduct of completed human research.
Subpart N-[Reserved]
Subpart O-Administrative Actions forNoncompliance
26.1501 To what does this subpart apply?26.1502 Lesser administrative actions.26.1503 Disqualification of an IRB or aninstitution.26.1504 Public disclosure of informationregarding revocation.26.1505 Reinstatement of an IRB or aninstitution.26.1506 Debarment.26.1507 Actions alternative or additional todisqualification.
Subpart P-Review of Proposed and CompletedHuman Research
26.1601 EPA review of proposed human research.26.1602 EPA review of completed human research.26.1603 Operation of the Human Studies ReviewBoard.
Subpart Q-Ethical Standards for AssessingWhether to Rely on the Results of Human Research in EPA Actions
26.1701 To what does this subpart apply?26.1702 Definitions.26.1703 Prohibition of reliance on researchinvolving intentional exposure of human subjects who are pregnantwomen (and therefore their fetuses) or children.26.1704 Prohibition of reliance on unethicalhuman research with non-pregnant adults conducted before April 7, 2006.26.1705 Prohibition of reliance on unethicalhuman research with non-pregnant adults conducted after April 7, 2006.26.1706 Criteria and procedure for decisions toprotect public health by relying on otherwise unacceptableresearch.
Subpart B-Prohibition of Research Conductedor Supported by EPA Involving Intentional Exposure of HumanSubjects who are Pregnant Women or Children.
§ 26.201 To what does thissubpart apply?
(a) This subpart applies to all research involving intentionalexposure of any human subject who is a pregnant woman (and herfetus) or a child conducted or supported by the EnvironmentalProtection Agency (EPA). This includes research conducted in EPAfacilities by any person and research conducted in any facilityby EPA employees.
(b) The requirements of this subpart are in addition to thoseimposed under the other subparts of this part.
§ 26.202 Definitions.
The definitions in § 26.102 shall be applicableto this subpart as well. In addition, the definitions at 45 CFR 46.202(a) through (f) and at 45 CFR 46.202(h) are applicable tothis subpart.
(a) Research involving intentional exposure of ahuman subject means a study of a substance in which theexposure to the substance experienced by a human subjectparticipating in the study would not have occurred but for thehuman subject's participation in the study.
(b) A child is a person who has not attainedthe age of 18 years.
§ 26.203 Prohibition ofresearch conducted or supported by EPA involving intentionalexposure of any human subject who is a pregnant woman (andtherefore her fetus) or child.
Notwithstanding any other provision of this part, under nocircumstances shall EPA conduct or support research involvingintentional exposure of any human subject who is a pregnant woman(and therefore her fetus) or child.
Subpart C-Observational Research: AdditionalProtections for Pregnant Women and Fetuses Involved as Subjectsin Observational Research Conducted or Supported by EPA
§ 26.301 To what does thissubpart apply?
(a) Except as provided in paragraph (b) of this section, thissubpart applies to all observational research involving humansubjects who are pregnant women (and therefore their fetuses)conducted or supported by the Environmental Protection Agency(EPA). This includes research conducted in EPA facilities by anyperson and research conducted in any facility by EPAemployees.
(b) The exemptions at § 26.101(b)(1)through (b)(6) are applicable to this subpart.
(c) The provisions of § 26.101(c) through (i) areapplicable to this subpart. References to State or local laws inthis subpart and in § 26.101(f) are intended toinclude the laws of federally recognized American Indian andAlaska Native Tribal Governments.
(d) The requirements of this subpart are in addition to thoseimposed under the other subparts of this part.
§ 26.302 Definitions.
The definitions in §§ 26.102 and 26.202 shallbe applicable to this subpart as well. In addition, observational research means any human research thatdoes not meet the definition of research involvingintentional exposure of a human subject in§ 26.202(a).
§ 26.303 Duties of IRBs inconnection with observational research involving pregnant womenand fetuses.
The provisions of 45 CFR 46.203 are applicable to thissection.
§ 26.304 Additionalprotections for pregnant women and fetuses involved inobservational research.
The provisions of 45 CFR 46.204 are applicable to thissection.
§ 26.305 Protectionsapplicable, after delivery, to the placenta, the dead fetus, orfetal material.
The provisions of 45 CFR 46.206 are applicable to thissection.
Subpart D-Observational Research: AdditionalProtections for Children Involved as Subjects in ObservationalResearch Conducted or Supported by EPA
§ 26.401 To what does thissubpart apply?
(a) This subpart applies to all observational researchinvolving children as subjects, conducted or supported by EPA.References to State or local laws in this subpart and in§ 26.101(f) are intended to include the laws offederally recognized American Indian and Alaska Native TribalGovernments. This includes research conducted in EPA facilitiesby any person and research conducted in any facility by EPAemployees.
(b) Exemptions at § 26.101(b)(1) and (b)(3) through(b)(6) are applicable to this subpart. The exemption at§ 26.101(b)(2) regarding educational tests is alsoapplicable to this subpart. However, the exemption at§ 26.101(b)(2) for research involving survey orinterview procedures or observations of public behavior does notapply to research covered by this subpart, except for researchinvolving observation of public behavior when the investigator(s)do not participate in the activities being observed.
(c) The exceptions, additions, and provisions for waiver asthey appear in § 26.101(c) through (i) are applicableto this subpart.
§ 26.402 Definitions.
The definitions in § 26.102 shall be applicable tothis subpart as well. In addition, the following terms aredefined:
(a) For purposes of this subpart, Administrator means the Administrator of the Environmental Protection Agencyand any other officer or employee of the Environmental ProtectionAgency to whom authority has been delegated by theAdministrator.
(b) Assent means a child's affirmative agreementto participate in research. Mere failure to object should not,absent affirmative agreement, be construed as assent.
(c) Permission means the agreement of parent(s)or guardian to the participation of their child or ward inresearch.
(d) Parent means a child's biological oradoptive parent.
(e) Guardian means an individual who isauthorized under applicable State, Tribal, or local law toconsent on behalf of a child to general medical care.
(f) Observational research means any researchwith human subjects that does not meet the definition of researchinvolving intentional exposure of a human subject in§ 26.202(a).
(g) Minimal risk means that the probability andmagnitude of harm or discomfort anticipated in the research arenot greater in and of themselves than those ordinarilyencountered in daily life or during the performance of routinephysical or psychological examinations or tests.
§ 26.403 IRB duties.
In addition to other responsibilities assigned to IRBs underthis part, each IRB shall review observational research coveredby this subpart and approve only research that satisfies theconditions of all applicable sections of this subpart.
§ 26.404 Observationalresearch not involving greater than minimal risk.
EPA will conduct or fund observational research in which theIRB finds that no greater than minimal risk to children ispresented, only if the IRB finds that adequate provisions aremade for soliciting the assent of the children and the permissionof their parents or guardians, as set forth in§ 26.406.
§ 26.405 Observationalresearch involving greater than minimal risk but presenting theprospect of direct benefit to the individual subjects.
If the IRB finds that an intervention or procedure presentsmore than minimal risk to children, EPA will not conduct or fundobservational research that includes such an intervention orprocedure unless the IRB finds and documents that:
(a) The intervention or procedure holds out the prospect ofdirect benefit to the individual subject or is likely tocontribute to the subject's well-being;
(b) The risk is justified by the anticipated benefit to thesubjects;
(c) The relation of the anticipated benefit to the risk is atleast as favorable to the subjects as that presented by availablealternative approaches; and
(d) Adequate provisions are made for soliciting the assent ofthe children and permission of their parents or guardians, as setforth in § 26.406.
§ 26.406 Requirements forpermission by parents or guardians and for assent by children.
(a) In addition to the determinations required under otherapplicable sections of this subpart, the IRB shall determine thatadequate provisions are made for soliciting the assent of thechildren, when in the judgment of the IRB the children arecapable of providing assent. In determining whether children arecapable of assenting, the IRB shall take into account the ages,maturity, and psychological state of the children involved. Thisjudgment may be made for all children to be involved in researchunder a particular protocol, or for each child, as the IRB deemsappropriate. If the IRB determines that the capability of some orall of the children is so limited that they cannot reasonably beconsulted or that the intervention or procedure involved in theobservational research holds out a prospect of direct benefitthat is important to the health or well-being of the children andis available only in the context of the research, the assent ofthe children is not a necessary condition for proceeding with theobservational research. Even where the IRB determines that thesubjects are capable of assenting, the IRB may still waive theassent requirement under circumstances in which consent may bewaived in accord with § 26.116(d).
(b) In addition to the determinations required under otherapplicable sections of this subpart, the IRB shall determine, inaccordance with and to the extent that consent is required by§ 26.116, that adequate provisions are made forsoliciting the permission of each child's parents or guardian.Where parental permission is to be obtained, the IRB may findthat the permission of one parent is sufficient for research tobe conducted under § 26.404 or§ 26.405.
(c) In addition to the provisions for waiver contained in§ 26.116, if the IRB determines that a researchprotocol is designed for conditions or for a subject populationfor which parental or guardian permission is not a reasonablerequirement to protect the subjects (for example, neglected orabused children), it may replace the consent requirements insubpart A of this part and paragraph (b) of this section withprovided an appropriate, equivalent mechanism for protecting thechildren who will participate as subjects in the research issubstituted, and provided further that the waiver is notinconsistent with Federal, State, or local law. The choice of anappropriate, equivalent mechanism would depend upon the natureand purpose of the activities described in the protocol, the riskand anticipated benefit to the research subjects, and their age,maturity, status, and condition.
(d) Permission by parents or guardians shall be documented inaccordance with and to the extent required by§ 26.117.
(e) When the IRB determines that assent is required, it shallalso determine whether and how assent must be documented.
Subpart E-[Reserved]
Subpart F-[Reserved]
Subpart G-[Reserved]
Subpart H-[Reserved]
Subpart I-[Reserved]
Subpart J-[Reserved]
Subpart K-Basic Ethical Requirements forThird-Party Human Research for Pesticides Involving IntentionalExposure of Non-pregnant Adults
§ 26.1101 To what does thissubpart apply?
(a) Except as provided in paragraph (b) of this section,subpart K of this part applies to all research initiated afterApril 7, 2006 involving intentionalexposure of a human subject if, at any time prior to initiatingsuch research, any person who conducted or supported suchresearch intended:
(1) To submit results of the research to EPA for considerationin connection with any action that may be performed by EPA underthe Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C.136 et seq. ) or section 408 of the Federal Food,Drug, and Cosmetic Act (21 U.S.C. 346a); or
(2) To hold the results of the research for later inspectionby EPA under the Federal Insecticide, Fungicide, and RodenticideAct (7 U.S.C. 136 et seq. ) or section 408 of theFederal Food, Drug, and Cosmetic Act 21 U.S.C. 346a).
(b) Unless otherwise required by the Administrator, researchis exempt from this subpart if it involves only the collection orstudy of existing data, documents, records, pathologicalspecimens, or diagnostic specimens from previously conductedstudies, and if these sources are publicly available or if theinformation is recorded by the investigator in such a manner thatsubjects cannot be identified, directly or through identifierslinked to the subjects.
(c) The Administrator retains final judgment as to whether aparticular activity within the scope of paragraphs (a) and (b) ofthis section is covered by this subpart.
(d) Compliance with this subpart requires compliance withpertinent Federal laws or regulations which provide additionalprotections for human subjects.
(e) This subpart does not affect any State or local laws orregulations which may otherwise be applicable and which provideadditional protections for human subjects. Reference to State orlocal laws in this subpart is intended to include the laws offederally recognized American Indian and Alaska Native TribalGovernments.
(f) This subpart does not affect any foreign laws orregulations which may otherwise be applicable and which provideadditional protections to human subjects of research.
(g) For purposes of determining a person's intent underparagraph (a) of this section, EPA may consider any availableinformation relevant to determining the intent of a person whoconducts or supports research with human subjects after theeffective date of the rule. EPA shall rebuttably presume suchintent existed if:
(1) The person or the person's agent has submitted or madeavailable for inspection the results of such research to EPA;or
(2) The person is a member of a class of people who, or whoseproducts or activities, are regulated by EPA under FIFRA or theFFDCA and, at the time the research was initiated, the results ofthe research would be relevant to EPA's exercise of its authorityunder FIFRA or the FFDCA with respect to that class of people,products, or activities.
§ 26.1102 Definitions.
(a) For purposes of this subpart, Administrator means the Administrator of the Environmental Protection Agency(EPA) and any other officer or employee of EPA to whom authorityhas been delegated.
(b) Institution means any public or privateentity or agency (including Federal, State, and otheragencies).
(c) Legally authorized representative means anindividual or judicial or other body authorized under applicablelaw to consent on behalf of a prospective subject to thesubject's participation in the procedure(s) involved in theresearch.
(d) Research means a systematic investigation,including research, development, testing and evaluation, designedto develop or contribute to generalizable knowledge. Activitieswhich meet this definition constitute research for purposes ofthis subpart, whether or not they are considered research forother purposes. For example, some demonstration and serviceprograms may include research activities.
(e) Human subject means a living individualabout whom an investigator (whether professional or student)conducting research obtains:
(1) Data through intervention or interaction with theindividual, or
(2) Identifiable private information.
(3) "Intervention" includes both physicalprocedures by which data are gathered (for example, venipuncture)and manipulations of the subject or the subject's environmentthat are performed for research purposes. Interaction includescommunication or interpersonal contact between investigator andsubject. "Private information" includes informationabout behavior that occurs in a context in which an individualcan reasonably expect that no observation or recording is takingplace, and information which has been provided for specificpurposes by an individual and which the individual can reasonablyexpect will not be made public (for example, a medical record).Private information must be individually identifiable (i.e., theidentity of the subject is or may readily be ascertained by theinvestigator or associated with the information) in order forobtaining the information to constitute research involving humansubjects.
(f) IRB means an institutional review boardestablished in accord with and for the purposes expressed in thispart.
(g) IRB approval means the determination of theIRB that the research has been reviewed and may be conducted atan institution within the constraints set forth by the IRB and byother institutional and Federal requirements.
(h) Minimal risk means that the probability andmagnitude of harm or discomfort anticipated in the research arenot greater in and of themselves than those ordinarilyencountered in daily life or during the performance of routinephysical or psychological examinations or tests.
(i) Research involving intentional exposure of ahuman subject means a study of a substance in which theexposure to the substance experienced by a human subjectparticipating in the study would not have occurred but for thehuman subject's participation in the study.
(j) Person means any person, as that term isdefined in FIFRA section 2(s) (7 U.S.C. 136), except:
(1) A federal agency that is subject to the provisions of theFederal Policy for the Protection of Human Subjects of Research,and
(2) A person when performing human research supported by afederal agency covered by paragraph (j)(1) of this section.
§§ 26.1103 through 26.1106[Reserved]
§ 26.1107 IRB membership.
(a) Each IRB shall have at least five members, with varyingbackgrounds to promote complete and adequate review of researchactivities which are presented for its approval. The IRB shall besufficiently qualified through the experience and expertise ofits members, and the diversity of the members, includingconsideration of race, gender, and cultural backgrounds andsensitivity to such issues as community attitudes, to promoterespect for its advice and counsel in safeguarding the rights andwelfare of human subjects. In addition to possessing theprofessional competence necessary to review specific researchactivities, the IRB shall be able to ascertain the acceptabilityof proposed research in terms of institutional commitments andregulations, applicable law, and standards of professionalconduct and practice. The IRB shall therefore include personsknowledgeable in these areas. If an IRB regularly reviewsresearch that involves a vulnerable category of subjects, such asprisoners or handicapped or mentally disabled persons,consideration shall be given to the inclusion of one or moreindividuals who are knowledgeable about and experienced inworking with these subjects.
(b) Every nondiscriminatory effort will be made to ensure thatno IRB consists entirely of men or entirely of women, includingthe institution's consideration of qualified persons of bothsexes, so long as no selection is made to the IRB on the basis ofgender. No IRB may consist entirely of members of oneprofession.
(c) Each IRB shall include at least one member whose primaryconcerns are in scientific areas and at least one member whoseprimary concerns are in nonscientific areas.
(d) Each IRB shall include at least one member who is nototherwise affiliated with the institution and who is not part ofthe immediate family of a person who is affiliated with theinstitution.
(e) No IRB may have a member participate in the IRB's initialor continuing review of any project in which the member has aconflicting interest, except to provide information requested bythe IRB.
(f) An IRB may, in its discretion, invite individuals withcompetence in special areas to assist in the review of issueswhich require expertise beyond or in addition to that availableon the IRB. These individuals may not vote with the IRB.
§ 26.1108 IRB functions andoperations.
In order to fulfill the requirements of this subpart each IRBshall:
(a) Follow written procedures:
(1) For conducting its initial and continuing review ofresearch and for reporting its findings and actions to theinvestigator and the institution;
(2) For determining which projects require review more oftenthan annually and which projects need verification from sourcesother than the investigator that no material changes haveoccurred since previous IRB review;
(3) For ensuring prompt reporting to the IRB of proposedchanges in research activity; and
(4) For ensuring that changes in approved research, during theperiod for which IRB approval has already been given, may not beinitiated without IRB review and approval except where necessaryto eliminate apparent immediate hazards to the humansubjects.
(b) Follow written procedures for ensuring prompt reporting tothe IRB, appropriate institutional officials, and theEnvironmental Protection Agency of:
(1) Any unanticipated problems involving risks to humansubjects or others;
(2) Any instance of serious or continuing noncompliance withthis subpart of the requirements or determinations of the IRB;or
(3) Any suspension or termination of IRB approval.
(c) Except when an expedited review procedure is used (see§ 26.1110), review proposed research at convenedmeetings at which a majority of the members of the IRB arepresent, including at least one member whose primary concerns arein nonscientific areas. In order for the research to be approved,it shall receive the approval of a majority of those memberspresent at the meeting.
§ 26.1109 IRB review ofresearch.
(a) An IRB shall review and have authority to approve, requiremodifications in (to secure approval), or disapprove all researchactivities covered by this subpart.
(b) An IRB shall require that information given to subjects aspart of informed consent is in accordance with§ 26.1116. The IRB may require that information, inaddition to that specifically mentioned in § 26.1116be given to the subjects when, in the IRB's judgment, theinformation would meaningfully add to the protection of therights and welfare of subjects.
(c) An IRB shall require documentation of informed consent inaccordance with § 26.1117.
(d) An IRB shall notify investigators and the institution inwriting of its decision to approve or disapprove the proposedresearch activity, or of modifications required to secure IRBapproval of the research activity. If the IRB decides todisapprove a research activity, it shall include in its writtennotification a statement of the reasons for its decision and givethe investigator an opportunity to respond in person or inwriting.
(e) An IRB shall conduct continuing review of research coveredby this subpart at intervals appropriate to the degree of risk,but not less than once per year, and shall have authority toobserve or have a third party observe the consent process and theresearch.
§ 26.1110 Expedited reviewprocedures for certain kinds of research involving no more thanminimal risk, and for minor changes in approved research.
(a) The Secretary, HHS, has established, and published as aNotice in the Federal Register , a list ofcategories of research that may be reviewed by the IRB through anexpedited review procedure. The list will be amended, asappropriate after consultation with other departments andagencies, through periodic republication by the Secretary, HHS,in the Federal Register . A copy of the list isavailable from the Office for Human Research Protections, HHS, orany successor office.
(b)(1) An IRB may use the expeditedreview procedure to review either or both of the following:
(i) Some or all of the research appearing on the list andfound by the reviewer(s) to involve no more than minimalrisk,
(ii) Minor changes in previously approved research during theperiod (of 1 year or less) for which approval is authorized.
(2) Under an expedited review procedure, the review may becarried out by the IRB chairperson or by one or more experiencedreviewers designated by the chairperson from among members of theIRB. In reviewing the research, the reviewers may exercise all ofthe authorities of the IRB except that the reviewers may notdisapprove the research. A research activity may be disapprovedonly after review in accordance with the non-expedited procedureset forth in § 26.1108(b).
(c) Each IRB which uses an expedited review procedure shalladopt a method for keeping all members advised of researchproposals which have been approved under the procedure.
(d) The Administrator may restrict, suspend, or terminate, aninstitution's or IRB's use of the expedited review procedure forresearch covered by this subpart.
§ 26.1111 Criteria for IRBapproval of research.
(a) In order to approve research covered by this subpart theIRB shall determine that all of the following requirements aresatisfied:
(1) Risks to subjects are minimized:
(i) By using procedures which are consistent with soundresearch design and which do not unnecessarily expose subjects torisk, and
(ii) Whenever appropriate, by using procedures already beingperformed on the subjects for diagnostic or treatmentpurposes.
(2) Risks to subjects are reasonable in relation toanticipated benefits, if any, to subjects, and the importance ofthe knowledge that may reasonably be expected to result. Inevaluating risks and benefits, the IRB should consider only thoserisks and benefits that may result from the research (asdistinguished from risks and benefits subjects would receive evenif not participating in the research). The IRB should notconsider possible long-range effects of applying knowledge gainedin the research (for example, the possible effects of theresearch on public policy) as among those research risks thatfall within the purview of its responsibility.
(3) Selection of subjects is equitable. In making thisassessment the IRB should take into account the purposes of theresearch and the setting in which the research will be conductedand should be particularly cognizant of the special problems ofresearch involving vulnerable populations, such as prisoners,mentally disabled persons, or economically or educationallydisadvantaged persons.
(4) Informed consent will be sought from each prospectivesubject or the subject's legally authorized representative, inaccordance with, and to the extent required by§ 26.1116.
(5) Informed consent will be appropriately documented, inaccordance with, and to the extent required by§ 26.1117.
(6) When appropriate, the research plan makes adequateprovision for monitoring the data collected to ensure the safetyof subjects.
(7) When appropriate, there are adequate provisions to protectthe privacy of subjects and to maintain the confidentiality ofdata.
(b) When some or all of the subjects are likely to bevulnerable to coercion or undue influence, such as prisoners,mentally disabled persons, or economically or educationallydisadvantaged persons, additional safeguards have been includedin the study to protect the rights and welfare of thesesubjects.
§ 26.1112 Review byinstitution.
Research covered by this subpart that has been approved by anIRB may be subject to further appropriate review and approval ordisapproval by officials of the institution. However, thoseofficials may not approve the research if it has not beenapproved by an IRB.
§ 26.1113 Suspension or terminationof IRB approval of research.
An IRB shall have authority to suspend or terminate approvalof research that is not being conducted in accordance with theIRB's requirements or that has been associated with unexpectedserious harm to subjects. Any suspension or termination ofapproval shall include a statement of the reasons for the IRB'saction and shall be reported promptly to the investigator,appropriate institutional officials, and the Administrator ofEPA.
§ 26.1114 Cooperativeresearch.
In complying with this subpart, sponsors, investigators, orinstitutions involved in multi-institutional studies may usejoint review, reliance upon the review of another qualified IRB,or similar arrangements aimed at avoidance of duplication ofeffort.
§ 26.1115 IRB records.
(a) An IRB shall prepare and maintain adequate documentationof IRB activities, including the following:
(1) Copies of all research proposals reviewed, scientificevaluations, if any, that accompany the proposals, approvedsample consent documents, progress reports submitted byinvestigators, and reports of injuries to subjects.
(2) Minutes of IRB meetings which shall be in sufficientdetail to show attendance at the meetings; actions taken by theIRB; the vote on these actions including the number of membersvoting for, against, and abstaining; the basis for requiringchanges in or disapproving research; and a written summary of the discussion of controverted issues and their resolution.
(3) Records of continuing review activities.
(4) Copies of all correspondence between the IRB and theinvestigators.
(5) A list of IRB members identified by name; earned degrees;representative capacity; indications of experience such as boardcertifications, licenses, etc., sufficient to describe eachmember's chief anticipated contributions to IRB deliberations;and any employment or other relationship between each member andthe institution, for example, full-time employee, a member ofgoverning panel or board, stockholder, paid or unpaidconsultant.
(6) Written procedures for the IRB in the same detail asdescribed in § 26.1108(a) and§ 26.1108(b).
(7) Statements of significant new findings provided tosubjects, as required by § 26.1116(b)(5).
(b) The records required by this subpart shall be retained forat least 3 years, and records relating to research which isconducted shall be retained for at least 3 years after completionof the research. All records shall be accessible for inspectionand copying by authorized representatives of EPA at reasonabletimes and in a reasonable manner.
§ 26.1116 Generalrequirements for informed consent.
No investigator may involve a human being as a subject inresearch covered by this subpart unless the investigator hasobtained the legally effective informed consent of the subject orthe subject's legally authorized representative. An investigatorshall seek such consent only under circumstances that provide theprospective subject or the representative sufficient opportunityto consider whether or not to participate and that minimize thepossibility of coercion or undue influence. The information thatis given to the subject or the representative shall be inlanguage understandable to the subject or the representative. Noinformed consent, whether oral or written, may include anyexculpatory language through which the subject or therepresentative is made to waive or appear to waive any of thesubject's legal rights, or releases or appears to release theinvestigator, the sponsor, the institution or its agents fromliability for negligence.
(a) Basic elements of informed consent. In seeking informedconsent the following information shall be provided to eachsubject:
(1) A statement that the study involves research, anexplanation of the purposes of the research and the expectedduration of the subject's participation, a description of theprocedures to be followed, and identification of any procedureswhich are experimental;
(2) A description of any reasonably foreseeable risks ordiscomforts to the subject;
(3) A description of any benefits to the subject or to otherswhich may reasonably be expected from the research;
(4) A disclosure of appropriate alternative procedures orcourses of treatment, if any, that might be advantageous to thesubject;
(5) A statement describing the extent, if any, to whichconfidentiality of records identifying the subject will bemaintained;
(6) For research involving more than minimal risk, anexplanation as to whether any compensation and an explanation asto whether any medical treatments are available if injury occursand, if so, what they consist of, or where further informationmay be obtained;
(7) An explanation of whom to contact for answers to pertinentquestions about the research and research subjects' rights, andwhom to contact in the event of a research-related injury to thesubject; and
(8) A statement that participation is voluntary, refusal toparticipate will involve no penalty or loss of benefits to whichthe subject is otherwise entitled, and the subject maydiscontinue participation at any time without penalty or loss ofbenefits to which the subject is otherwise entitled.
(b) Additional elements of informed consent. When appropriate,one or more of the following elements of information shall alsobe provided to each subject:
(1) A statement that the particular treatment or procedure mayinvolve risks to the subject (or to the embryo or fetus, if thesubject may become pregnant) which are currentlyunforeseeable;
(2) Anticipated circumstances under which the subject'sparticipation may be terminated by the investigator withoutregard to the subject's consent;
(3) Any additional costs to the subject that may result fromparticipation in the research;
(4) The consequences of a subject's decision to withdraw fromthe research and procedures for orderly termination ofparticipation by the subject;
(5) A statement that significant new findings developed duringthe course of the research which may relate to the subject'swillingness to continue participation will be provided to thesubject; and
(6) The approximate number of subjects involved in thestudy.
(c) The informed consent requirements in this subpart are notintended to preempt any applicable Federal, State, or local lawswhich require additional information to be disclosed in order forinformed consent to be legally effective.
(d) Nothing in this subpart is intended to limit the authorityof a physician to provide emergency medical care, to the extentthe physician is permitted to do so under applicable Federal,State, or local law.
(e) If the research involves intentional exposure of subjectsto a pesticide, the subjects of the research must be informed ofthe identity of the pesticide and the nature of its pesticidalfunction.
§ 26.1117 Documentation ofinformed consent.
(a) Informed consent shall be documented by the use of awritten consent form approved by the IRB and signed by thesubject or the subject's legally authorized representative. Acopy shall be given to the person signing the form.
(b) The consent form may be either of the following:
(1) A written consent document that embodies the elements ofinformed consent required by § 26.1116. This form maybe read to the subject or the subject's legally authorizedrepresentative, but in any event, the investigator shall giveeither the subject or the representative adequate opportunity toread it before it is signed; or
(2) A short form written consent document stating that theelements of informed consent required by § 26.1116have been presented orally to the subject or the subject'slegally authorized representative. When this method is used,there shall be a witness to the oral presentation. Also, the IRBshall approve a written summary of what is to be said to thesubject or the representative. Only the short form itself is tobe signed by the subject or the representative. However, thewitness shall sign both the short form and a copy of the summary,and the person actually obtaining consent shall sign a copy ofthe summary. A copy of the summary shall be given to the subjector the representative, in addition to a copy of the shortform.
§§ 26.1118 through 26.1122[Reserved]
§ 26.1123 Early terminationof research.
The Administrator may require that any project covered by thissubpart be terminated or suspended when the Administrator findsthat an IRB, investigator, sponsor, or institution has materiallyfailed to comply with the terms of this subpart.
§ 26.1124 [Reserved]
§ 26.1125 Prior submission ofproposed human research for EPA review.
Any person or institution who intends to conduct or sponsorhuman research covered by § 26.1101(a) shall, afterreceiving approval from all appropriate IRBs, submit to EPA priorto initiating such research all information relevant to theproposed research specified by § 26.1115(a), and thefollowing additional information, to the extent not alreadyincluded:
(a) A discussion of:
(1) The potential risks to human subjects;
(2) The measures proposed to minimize risks to the humansubjects;
(3) The nature and magnitude of all expected benefits of suchresearch, and to whom they would accrue;
(4) Alternative means of obtaining information comparable towhat would be collected through the proposed research; and
(5) The balance of risks and benefits of the proposedresearch.
(b) All information for subjects and written informed consentagreements as originally provided to the IRB, and as approved bythe IRB.
(c) Information about how subjects will be recruited,including any advertisements proposed to be used.
(d) A description of the circumstances and methods proposedfor presenting information to potential human subjects for thepurpose of obtaining their informed consent.
(e) All correspondence between the IRB and the investigatorsor sponsors.
(f) Official notification to the sponsor or investigator, inaccordance with the requirements of this subpart, that researchinvolving human subjects has been reviewed and approved by anIRB.
Subpart L-Prohibition of Third-Party Researchfor Pesticides Involving Intentional Exposure of Human Subjectswho are Pregnant Women or Children
§ 26.1201 To what does thissubpart apply?
Subpart L applies to any person who, after April 7, 2006, conducts or supports research witha human subject intended:
(1) For submission to EPA for consideration in connection withany action that may be performed by EPA under the FederalInsecticide, Fungicide, and Rodenticide Act (7 U.S.C. 136 et seq. ) or section 408 of the Federal Food, Drug, andCosmetic Act (21 U.S.C. 346a); or
(2) To be held for later inspection by EPA under the FederalInsecticide, Fungicide, and Rodenticide Act (7 U.S.C. 136 et seq. ) or section 408 of the Federal Food, Drug, andCosmetic Act 21 U.S.C. 346a).
(b) For purposes of determining a person's intent underparagraph (a) of this section, EPA may consider any availableinformation relevant to determining the intent of a person whoconducts or supports research with human subjects after theeffective date of the rule. EPA shall rebuttably presume suchintent existed if:
(1) The person or the person's agent has submitted or madeavailable for inspection the results of such research to EPA;or
(2) The person is a member of a class of people who, or whoseproducts or activities, are regulated by EPA under FIFRA or theFFDCA and, at the time the research was initiated, the results ofthe research would be relevant to EPA's exercise of its authorityunder FIFRA or the FFDCA with respect to that class of people,products, or activities.
§ 26.1202 Definitions.
The definitions in § 26.1102 shall be applicable tothis subpart as well. In addition, the definitions at 45 CFR46.202(a) through (f) and at 45 CFR 46.202(h) are applicable tothis subpart. In addition, a child is a person who has notattained the age of 18 years.
§ § 26.1203 Prohibitionof research involving intentional exposure of any pregnant woman,fetus, or child.
Notwithstanding any other provision of this part, under nocircumstances shall a person conduct or sponsor research coveredby § 26.1201 that involves intentional exposure of anyhuman subject who is a pregnant woman (and therefore her fetus)or child.
Subpart M-Requirements for Submission ofInformation on the Ethical Conduct of Completed Human Research
§ 26.1301 To what does thissubpart apply?
This subpart applies to any person who submits a reportcontaining the results of any human research if:
(a) The report is submitted after April 7, 2006, and
(b) The report is submitted for consideration in connectionwith any action that may be performed by EPA under the FederalInsecticide, Fungicide, and Rodenticide Act (7 U.S.C. 136 et seq. ) or section 408 of the Federal Food, Drug, andCosmetic Act (21 U.S.C. 346a).
§ 26.1302 Definitions.
The definitions in § 26.102 shall apply to thissubpart as well.
§ 26.1303 Submission ofinformation pertaining to ethical conduct of completed humanresearch.
Any person who submits to EPA data derived from human researchcovered by this subpart shall provide at the time of submissioninformation concerning the ethical conduct of such research. Tothe extent available to the submitter and not previously providedto EPA, such information should include:
(a) Copies of all of the records relevant to the researchspecified by § 26.1115(a) to be prepared andmaintained by an IRB.
(b) Copies of all of the records relevant to the informationidentified in § 26.1125(a) through (f).
(c) Copies of sample records used to document informed consentas specified by § 26.1117, but not identifying anysubjects of the research.
(d) If any of the information listed in paragraphs (a)through (c) of this section is not provided, the person shalldescribe the efforts made to obtain the information.
Subpart N-[Reserved]
Subpart O-Administrative Actions forNoncompliance
§ 26.1501 To what does thissubpart apply?
This subpart applies to any human research subject to subpartsA through L of this part. References to State or local laws inthis subpart are intended to include the laws of federallyrecognized American Indian and Alaska Native TribalGovernments.
§ 26.1502 Lesseradministrative actions.
(a) If apparent noncompliance with the applicable regulationsin subparts A through L of this part concerning the operation ofan IRB is observed by an officer or employee of EPA or of anyState duly designated by the Administrator during an inspection.EPA may send a letter describing the noncompliance to the IRBand to the parent institution. The agency will require that theIRB or the parent institution respond to this letter within areasonable time period specified by EPA and describe thecorrective actions that will be taken by the IRB, theinstitution, or both to achieve compliance with theseregulations.
(b) On the basis of the IRB's or the institution's response,EPA may schedule a reinspection to confirm the adequacy ofcorrective actions. In addition, until the IRB or the parentinstitution takes appropriate corrective action, the Agencymay:
(1) Withhold approval of new studies subject to therequirements of this part that are conducted at the institutionor reviewed by the IRB;
(2) Direct that no new subjects be added to ongoing studiessubject to this part;
(3) Terminate ongoing studies subject to this part when doingso would not endanger the subjects; or
(4) When the apparent noncompliance creates a significantthreat to the rights and welfare of human subjects, notifyrelevant State and Federal regulatory agencies and other partieswith a direct interest of the deficiencies in the operation ofthe IRB.
(c) The parent institution is presumed to be responsible forthe operation of an IRB, and EPA will ordinarily direct anyadministrative action under this subpart against the institution.However, depending on the evidence of responsibility fordeficiencies, determined during the investigation, EPA mayrestrict its administrative actions to the IRB or to a componentof the parent institution determined to be responsible for formaldesignation of the IRB.
§ 26.1503 Disqualification ofan IRB or an institution.
(a) Whenever the IRB or the institution has failed to takeadequate steps to correct the noncompliance stated in the lettersent by the Agency under § 26.1502(a) and the EPAAdministrator determines that this noncompliance may justify thedisqualification of the IRB or of the parent institution, theAdministrator may institute appropriate proceedings.
(b) The Administrator may disqualify an IRB or the parentinstitution from studies subject to this part if theAdministrator determines that:
(1) The IRB has refused or repeatedly failed to comply withany of the regulations set forth in this part, and
(2) The noncompliance adversely affects the rights or welfareof the human subjects of research.
(c) If the Administrator determines that disqualification isappropriate, the Administrator will issue an order that explainsthe basis for the determination and that prescribes any actionsto be taken with regard to ongoing human research, covered bysubparts A through L of this part, conducted under the review ofthe IRB. EPA will send notice of the disqualification to the IRBand the parent institution. Other parties with a direct interest,such as sponsors and investigators, may also be sent a notice ofthe disqualification. In addition, the agency may elect topublish a notice of its action in the FederalRegister .
(d) EPA may refuse to consider in support of a regulatorydecision the data from human research, covered by subparts Athrough L of this part, that was reviewed by an IRB or conductedat an institution during the period of disqualification, unlessthe IRB or the parent institution is reinstated as provided in§ 26.1505, or unless such research is deemedscientifically sound and crucial to the protection of publichealth, under the procedure defined in § 26.1706.
§ 26.1504 Public disclosureof information regarding revocation.
A determination that EPA has disqualified an institution fromstudies subject to this part and the administrative recordregarding that determination are disclosable to the public under40 CFR part 2.
§ 26.1505 Reinstatement of anIRB or an institution.
An IRB or an institution may be reinstated to conduct studiessubject to this part if the Administrator determines, upon anevaluation of a written submission from the IRB or institutionthat explains the corrective action that the institution or IRBhas taken or plans to take, that the IRB or institution hasprovided adequate assurance that it will operate in compliancewith the standards set forth in this part. Notification ofreinstatement shall be provided to all persons notified under§ 26.1502(c).
§ 26.1506 Debarment.
If EPA determines that an institution or investigatorrepeatedly has not complied with or has committed an egregiousviolation of the applicable regulations in subparts A through Lof this part, EPA may recommend that institution or investigatorbe declared ineligible to participate in EPA-supported research(debarment). Debarment will be initiated in accordance withprocedures specified at 40 CFR part 32.
§ 26.1507 Actions alternativeor additional to disqualification.
Disqualification of an IRB or of an institution is independentof, and neither in lieu of nor a precondition to, otherstatutorily authorized proceedings or actions. EPA may, at anytime, on its own initiative or through the Department of Justice,institute any appropriate judicial proceedings (civil orcriminal) and any other appropriate regulatory action, inaddition to or in lieu of, and before, at the time of, or after,disqualification. The Agency may also refer pertinent matters toanother Federal, State, or local government agency for any actionthat that agency determines to be appropriate.
Subpart P-Review of Proposed and CompletedHuman Research
§ 26.1601 EPA review ofproposed human research.
(a) EPA shall review all protocols submitted under§ 26.1125 in a timely manner. With respect to anyresearch or any class of research, the Administrator mayrecommend additional conditions which, in the judgment of theAdministrator, are necessary for the protection of humansubjects.
(b) In reviewing proposals covered by this subpart, theAdministrator may take into account factors such as whether theapplicant has been subject to a termination or suspension under§ 26.123(a) or § 26.1123 and whether theapplicant or the person or persons who would direct or has/havedirected the scientific and technical aspects of an activityhas/have, in the judgment of the Administrator, materially failedto discharge responsibility for the protection of the rights andwelfare of human subjects (whether or not the research wassubject to Federal regulation).
(c) When research covered by subpart K takes place in foreigncountries, procedures normally followed in the foreign countriesto protect human subjects may differ from those set forth insubpart K. (An example is a foreign institution which complieswith guidelines consistent with the World Medical AssemblyDeclaration of Helsinki, issued either by sovereign states or byan organization whose function for the protection of humanresearch subjects is internationally recognized.) In thesecircumstances, if the Administrator determines that theprocedures prescribed by the institution afford protections thatare at least equivalent to those provided in subpart K, theAdministrator may approve the substitution of the foreignprocedures in lieu of the procedural requirements provided insubpart K.
(d) Following initial evaluation of the protocol by Agencystaff, EPA shall submit the protocol and all supportingmaterials, together with the staff evaluation, to the HumanStudies Review Board.
(e) EPA shall notify the submitter of the proposal of theresults of the EPA and Human Studies Review Board reviews.
§ 26.1602 EPA review ofcompleted human research.
(a) When considering data under FIFRA or FFDCA from researchinvolving intentional exposure of humans, EPA shall review thematerial submitted under § 26.1303 and otheravailable, relevant information and document its conclusionsregarding the scientific and ethical conduct of the research.
(b) EPA shall submit its review of data from human researchcovered by subpart Q, together with the available supportingmaterials, to the Human Studies Review Board if EPA decides torely on the data and:
(1) The data are derived from research initiated afterApril 7, 2006, or
(2) The data are derived from research initiated beforeApril 7, 2006, and the research was conductedfor the purpose of identifying or measuring a toxic effect.
(c) In its discretion, EPA may submit data from research notcovered by paragraph (b) of this section to the Human StudiesReview Board for their review.
(d) EPA shall notify the submitter of the research of theresults of the EPA and Human Studies Review Board reviews.
§ 26.1603 Operation of theHuman Studies Review Board.
EPA shall establish and operate a Human Studies Review Boardas follows:
(a) Membership . The Human Studies Review Boardshall consist of members who are not employed by EPA, who meetthe ethics and other requirements for special governmentemployees, and who have expertise in fields appropriate for thescientific and ethical review of human research, includingresearch ethics, biostatistics, and human toxicology.
(b) Responsibilities . The Human Studies ReviewBoard shall comment on the scientific and ethical aspects ofresearch proposals and reports of completed research with humansubjects submitted by EPA for its review and, on request, adviseEPA on ways to strengthen its programs for protection of humansubjects of research.
Subpart Q-Ethical Standards for AssessingWhether to Rely on the Results of Human Research in EPA Actions
§ 26.1701 To what does thissubpart apply?
This subpart applies to EPA's decisions whether to rely in itsactions taken under the Federal Insecticide, Fungicide, andRodenticide Act (7 U.S.C. 136 et seq. ) or section408 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 346a)on scientifically valid and relevant data from research involvingintentional exposure of human subjects.
§ 26.1702 Definitions.
The definitions in § 26.1102 and§ 26.1202 shall apply to this subpart as well.
§ 26.1703 Prohibition ofreliance on research involving intentional exposure of humansubjects who are pregnant women (and therefore their fetuses) orchildren.
Except as provided in § 26.1706, in actions withinthe scope of § 26.1701, EPA shall not rely on datafrom any research involving intentional exposure of any humansubject who is a pregnant woman (and therefore her fetus) orchild.
§ 26.1704 Prohibition ofreliance on unethical human research with non-pregnant adultsconducted beforeApril 7, 2006.
Except as provided in § 26.1706, in actions withinthe scope of § 26.1701, EPA shall not rely on datafrom any research initiated before April 7, 2006, if there is clear and convincing evidence that theconduct of the research was fundamentally unethical ( e.g. , the research was intended to seriously harmparticipants or failed to obtain informed consent), or wassignificantly deficient relative to the ethical standardsprevailing at the time the research was conducted. Thisprohibition is in addition to the prohibition in§ 26.1703.
§ 26.1705 Prohibition ofreliance on unethical human research with non-pregnant adultsconducted afterApril 7, 2006.
Except as provided in § 26.1706, in actions withinthe scope of § 26.1701, EPA shall not rely on datafrom any research initiated after April 7, 2006, unless EPA has adequate information to determinethat the research was conducted in substantial compliance withsubparts A through L of this part, or if conducted in a foreigncountry, under procedures at least as protective as those insubparts A through L of this part. This prohibition is inaddition to the prohibition in § 26.1703.
§ 26.1706 Criteria andprocedure for decisions to protect public health by relying onotherwise unacceptable research.
This section establishes the exclusive criteria and procedureby which EPA may decide to rely on data from research that is notacceptable under the standards in §§ 26.1703through 26.1705. EPA may rely on such data only if all theconditions in paragraphs (a) through (d) of this section aresatisfied:
(a) EPA has obtained the views of the Human Studies ReviewBoard concerning the proposal to rely on the otherwiseunacceptable data,
(b) EPA has provided an opportunity for public comment on theproposal to rely on the otherwise unacceptable data,
(c) EPA has determined that relying on the data is crucial toa decision that would impose a more stringent regulatoryrestriction that would improve protection of public health, suchas a limitation on the use of a pesticide, than could bejustified without relying on the data, and
(d) EPA publishes a full explanation of its decision to relyon the otherwise unacceptable data, including a thoroughdiscussion of the ethical deficiencies of the underlying researchand the full rationale for finding that the standard in paragraph(c) of this section was met.
[FR Doc. 06-1045 Filed 2-3-06; 8:45am]
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