Daily Rules, Proposed Rules, and Notices of the Federal Government
This Advance Notice of Proposed Rulemaking (ANPR) is organized into four Units. Unit I. contains “General Information” about the applicability of this ANPR, how to obtain additional information, how to submit comments in response to the request for comments, and certain other related matters. Unit II. provides background and historic information pertaining to human subject research. Unit III. describes the rulemaking process, identifies relevant statutory provisions, and requests public comments and suggestions on a broad range of issues related to the Agency's consideration of or reliance on research with human subjects. Unit IV. describes procedures followed in the development of this ANPR and certain statutes and Executive Orders that the public may wish to consider in preparing comments.
This action is directed to the public in general. This action may, however, be of particular interest to those who conduct testing of substances regulated by EPA. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under
An electronic version of the public docket is available through EPA's electronic public docket and comment system, EPA Dockets. You may use EPA Dockets at http://www.epa.gov/edocket to submit or view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Once in the system, select “search,” then key in the appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets. Information claimed as CBI and other information whose disclosure is restricted by statute, which is not included in the official public docket, will not be available for public viewing in EPA's electronic public docket. EPA's policy is that copyrighted material will not be placed in EPA's electronic public docket but will be available only in printed, paper form in the official public docket. To the extent feasible, publicly available docket materials will be made available in EPA's electronic public docket. When a document is selected from the index list in EPA Dockets, the system will identify whether the document is available for viewing in EPA's electronic public docket. Although not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I.B.1. EPA intends to work towards providing electronic access to all of the publicly available docket materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is that public comments, whether submitted electronically or on paper, will be made available for public viewing in EPA's electronic public docket as EPA receives them and without change, unless the comment contains copyrighted material, CBI, or other information whose disclosure is restricted by statute. When EPA identifies a comment containing copyrighted material, EPA will provide a reference to that material in the version of the comment that is placed in EPA's electronic public docket. The entire printed comment, including the copyrighted material, will be available in the public docket. Public comments submitted on computer disks that are mailed or delivered to the docket will be transferred to EPA's electronic public docket. Public comments that are mailed or delivered to the docket will be scanned and placed in EPA's electronic public docket. Where practical, physical objects will be photographed, and the photograph will be placed in EPA's electronic public docket along with a brief description written by the docket staff.
You may submit comments electronically, by mail, or through hand delivery/courier. To ensure proper receipt by EPA, identify the appropriate docket ID number in the subject line on the first page of your comment. Please ensure that your comments are submitted within the specified comment period. Comments received after the close of the comment period will be marked “late.” EPA is not required to consider these late comments. If you wish to submit CBI or information that is otherwise protected by statute, please follow the instructions in Unit I.D. Do not use EPA Dockets or e-mail to submit CBI or information protected by statute.
Do not submit information that you consider to be CBI electronically through EPA's electronic public docket or by e-mail. You may claim information that you submit to EPA as CBI by marking any part or all of that information as CBI (if you submit CBI on disk or CD ROM, mark the outside of the disk or CD ROM as CBI and then identify electronically within the disk or CD ROM the specific information that is CBI). Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket and EPA's electronic public docket. If you submit the copy that does not contain CBI on disk or CD ROM, mark the outside of the disk or CD ROM clearly that it does not contain CBI. Information not marked as CBI will be included in the public docket and EPA's electronic public docket without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under
You may find the following suggestions helpful for preparing your comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used that support your views.
4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this ANPR.
7. To ensure proper receipt by EPA, be sure to identify the docket control number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and
Over the years, scientific research with human subjects has provided much valuable information to help characterize and control risks to public health, but its use has also raised particular ethical concerns for the welfare of the human participants in such research as well as scientific issues related to the role of such research in assessing risks. Society has responded to these concerns by defining general standards for conducting human research. In the United States, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued in 1979 “The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research.” This document can be found on the web at http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm.
For most federal agencies in the United States, the principles of the Belmont Report are implemented through the Common Rule, which was developed cooperatively by some 17 departments and agencies, including EPA, and which guides all research with human subjects conducted or supported by these departments and agencies of the federal government. The Common Rule as promulgated by EPA (40 CFR part 26) has guided human research conducted or supported by EPA since it was put in place in 1991.
More broadly, the international medical research community has developed and maintains ethical standards documented in the Declaration of Helsinki, first issued by the World Medical Association in 1964 and revised several times since then. These standards apply to research on matters relating to the diagnosis and treatment of human disease, and to research that adds to understanding of the causes of disease and the biological mechanisms that explain the relationships between human exposures to environmental agents and disease.
In addition, many public and private research and academic institutions and private companies, both in the United States and in other countries, including non-federal U.S. and non-U.S. governmental organizations, have their own specific policies related to the protection of human participants in research.
Much of the scientific research supporting EPA's actions, including a significant portion of the research with human subjects submitted to the Agency or retrieved by the Agency from
Questions about the Agency's consideration of and reliance on third-party human research studies have arisen most notably, but not exclusively, in EPA's pesticides program. Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA may require pesticide companies to conduct studies with human subjects, for example, to measure potential exposure to pesticide users or to workers and others who re-enter areas treated with pesticides, and to evaluate the effectiveness of pesticide products intended to repel insects and other pests from human skin. In addition, EPA sometimes encourages other research with human subjects, including tests of the potential for some pesticides--generally those designed for prolonged contact with human skin--to irritate or sensitize human skin, and tests of the metabolic fate of pesticides in the human system. These latter studies typically precede monitoring studies of agricultural workers and others to protect them from exposure to potentially dangerous levels of pesticide residues.
In addition to these kinds of research which have been required or encouraged by EPA, other kinds of studies involving human subjects intentionally exposed to pesticides have occasionally been submitted to the agency voluntarily. Among these voluntarily submitted studies have been tests involving intentional dosing of human subjects to establish a No Observed Adverse Effect Level (NOAEL) or No Observed Effect Level (NOEL) for systemic toxicity of certain pesticides to humans. Before passage of the Food Quality Protection Act (FQPA) in 1996, submission of such studies was rare. EPA considered and relied on human NOAEL/NOEL studies in a few regulatory decisions on pesticides made prior to 1996. Since the passage of FQPA, submission of these types of studies to the Office of Pesticide Programs has increased; the Agency has received some 20 studies of this kind since 1996.
In response to concerns about human testing expressed in a report of a non-governmental advocacy organization, the Environmental Working Group, in July 1998, the Agency began a systematic review of its policy and practice. In a press statement on July 28, 1998, EPA noted that it had not relied on any such studies in any final decisions made under FQPA; this remains true today.
In further response to growing public concern over pesticide research with human subjects, EPA convened an advisory committee under the joint auspices of the EPA Science Advisory Board (SAB) and the FIFRA Scientific Advisory Panel (SAP) to address issues of the scientific and ethical acceptability of such research. This advisory committee, known as the Data from Testing of Human Subjects Subcommittee (DTHSS), met in December 1998 and November 1999, and completed its report in September 2000. Their report is available in the Docket cited above in this ANPR, and on the web at: http://www.epa.gov/science1/pdf/ec0017.pdf
The DTHSS advisory committee heard many comments at their two public meetings, and further comments have been submitted in response to their published report. No clear consensus emerged from the advisory committee process on the acceptability of NOAEL or NOEL studies of systemic toxicity of pesticides to human subjects, and significant differences of opinion remain on both their scientific merit and ethical acceptability. A vigorous public debate continues about the extent to which EPA should accept, consider, or rely on third-party intentional dosing human toxicity studies with pesticides.
EPA is now interested in addressing these issues more broadly, and in all Agency programs. In December 2001, EPA asked the advice of the National Academy of Sciences (NAS) on the many difficult scientific and ethical issues raised by this debate, and also stated the Agency's interim approach on third-party intentional dosing human subjects studies. The Agency's press release on this subject is on the web at http://yosemite.epa.gov/opa/ admpress.nsf/b1ab9f485b098972 852562e7004dc686/c232a45f5473 717085256b2200740ad4? OpenDocument. At that time the Agency committed that when it receives the NAS report, “EPA will engage in an open and participatory process involving federal partners, interested parties and the public during its policy development and/or rulemaking regarding future acceptance, consideration or regulatory reliance on such human studies.” Since making that commitment, EPA has decided to initiate a rulemaking process by issuing this ANPR.
In early 2002, various parties from the pesticide industry filed a petition with the U.S. Court of Appeals for the District of Columbia for review of EPA's December 2001 press release. These parties argued that the Agency's interim approach constituted a “rule” promulgated in violation of the procedural requirements of the Administrative Procedure Act and the Federal Food, Drug, and Cosmetic Act. The court has denied motions concerning emergency relief and other matters, briefs have been filed, and oral argument of the merits of the case occurred on March 17, 2003.
Under a contract with EPA, the NAS has convened a committee to provide the requested advice. The committee met in December 2002, and again in January and March 2003. The membership, meeting schedule, and other information about the work of this committee can be found on the NAS website at: http://www4.nas.edu/webcr.nsf/ 5c50571a75df494485256a95007 a091e/ 9303f725c15902f685256c44005d8931? OpenDocumentHighlight=0,EPA. The committee's final report is due in December 2003.
Notwithstanding these many recent developments concerning human studies, some things have not changed. EPA remains committed to full compliance with the Common Rule for all research with human subjects conducted or supported by the Agency. This body of research has provided many important insights and has contributed significantly to the protection of human health. The Agency will continue to conduct and support such research, and to consider and rely on its results in Agency actions. EPA also remains committed to scientifically sound assessments of the hazards of environmental agents, taking into consideration available, relevant, and appropriate scientific research.
EPA intends to undertake notice-and-comment rulemaking on the subject of its consideration of or reliance on research involving human subjects. The Agency will particularly focus on third-party intentional dosing human studies, but recognizes that the principles applicable to third-party studies may also be relevant to studies conducted or supported by the federal government. The first step in this process is this ANPR which calls for comments and suggestions from all interested parties. The next step the Agency would expect to undertake would be to issue a proposed rule for public comment. In developing any proposed rule, EPA will consider the advice in the National Academy of Sciences committee report, along with comments received in response to this ANPR. Comments received on any proposed rule would then be taken into consideration in developing a final rule or policy.
In general, the Agency expects that any rule or policy coming out of this process may do one or more of the following:
•Specify, if and to the extent determined by EPA to be appropriate, whether EPA would accept, consider, or rely on results from particular types of studies involving intentional dosing of human subjects or from human studies with particular characteristics.
•Establish minimum standards relating to the protection of human subjects which would be required to be met in the design and conduct of a study with human subjects, in order for EPA to accept, consider, or rely on the results of the study.
•Establish procedures for ensuring that any minimum standards for the conduct of third-party research with human subjects had been adhered to in the conduct of any such study that EPA intended to accept, consider, or rely on.
Section 25(a) of FIFRA gives the Administrator authority to “prescribe regulations to carry out the purposes of [FIFRA].” Such a rule would implement EPA's authority to require data in support of registration of pesticides (see, for example, FIFRA sections 3(c)(1)(F) and 3(c)(2)(B)) and to interpret the provision making it unlawful for any person “to use any pesticide in tests on human beings unless such human beings (i) are fully informed of the nature and purposes of the test and of any physical and mental health consequences which are reasonably foreseeable therefrom, and (ii) freely volunteer to participate in the test.” (FIFRA section 12(a)(2)(P)). In addition, section 408(e)(1)(C) of the FFDCA authorizes the Administrator to issue a regulation establishing “general procedures and requirements to implement this section.”
The Clean Air Act gives EPA general rulemaking authority in 42 U.S.C. 7601(a). The Clean Water Act, 33 U.S.C. 1361, authorizes the Administrator to promulgate regulations necessary to carry out the Agency's functions under that Act. Section 42 U.S.C. 9615 in the Comprehensive Environmental Response, Compensation, and Liability Act authorizes the President to establish regulations to implement the statute; this authority has been delegated to EPA by Executive Order 12580. The Emergency Planning and Community Right-to-Know Act also contains a general rulemaking provision, 42 U.S.C. 11048, authorizing the Administrator to promulgate rules necessary to carry out the Act. The Resource Conservation and Recovery Act specifically authorizes the Administrator to prescribe regulations necessary to carry out EPA's functions under the Act, 42 U.S.C. 6912. The Safe Drinking Water Act contains similar language, authorizing the Administrator to prescribe such regulations “as are necessary and appropriate” to carry out EPA's functions under the Act, 42 U.S.C. 300j-9. In addition, EPA has authority under 5 U.S.C. 301 and 42 U.S.C. 300v-1(b).
Neither this ANPR nor the specific questions presented below for public comment are intended to indicate that EPA now favors any particular policy approaches regarding the Agency's consideration of or reliance on third-party intentional dosing human studies. Similarly, neither this ANPR nor the specific questions presented below for public comment are intended to indicate that EPA has decided on a particular scope for any potential future rulemaking. Nor is this ANPR intended to impede or otherwise delay any Agency assessments or actions. Rather, this ANPR is designed to encourage public input from all interested parties on a broad range of issues that could help inform any rule or policy that EPA eventually promulgates or issues, respectively.
The Agency fully appreciates the number, the range, and the interconnectedness of the scientific and ethical concerns raised especially by intentional dosing human studies of the wide range of environmental agents addressed by EPA's programs. Reflecting the breadth of issues that have been raised, the Agency has identified specific questions on which it particularly invites comment. These questions are intended to help organize and focus the discussion, but not to constrain it. Commenters should feel free to address any other relevant topics as well.
b. Is it appropriate to use a standard intended to guide the conduct of therapeutic or diagnostic medical research or to clarify causes of disease, such as the Declaration of Helsinki, to assess the acceptability for review of other kinds of research without diagnostic or therapeutic intent, conducted with healthy subjects?
c. Should the Agency apply the same standard of acceptability independent of the type of substance tested (e.g., pharmaceutical, pesticide, pathogen, or environmental contaminant)? If not, how might differing standards be applied when a single substance has multiple uses, e.g., as both a pesticide and a drug?
d. Does it matter who maintains a standard, or by what process it is maintained? For example, would it be appropriate for EPA to accept and apply a standard maintained by a private, non-governmental organization, as is the Declaration of Helsinki?
e. Should the Agency extend the requirements of the Common Rule to the conduct of third-party research with human subjects intended for submission to EPA? What are the advantages and disadvantages of conducting a rulemaking or undertaking other Agency action for this purpose alone?
b. Should the Agency apply the same standard of acceptability independent of the level of exposure of the human subjects? For example, does it matter if the level of exposure to a chemical is below the Reference Dose or other established health standard designed to
c. Should the Agency apply the same standard of acceptability independent of the pathway of exposure? For example, should the same standard apply when exposure is oral, or dermal, or by inhalation?
d. Should the Agency apply the same standard of acceptability independent of the effects being evaluated? For example, should the same standard apply to a study measuring transitory changes in blood chemistry or levels of a substance in urine that applies to studies measuring longer-lasting changes? Should the same standard apply to a study of localized skin irritation that applies to a study of systemic dermal toxicity? Should the same standard apply to studies measuring organoleptic effects, such as taste or smell, that applies to studies of toxic effects? Should the same standard apply to measurements of toxic effects and to measurements through genomic or proteomic assessments?
e. Should conduct of research in compliance with the provisions of the Common Rule or another standard for the protection of human subjects be accepted as evidence of its ethical acceptability?
f. Should the Agency consider whether research has been performed consistent with an EPA guideline for data development in determining its acceptability? For example, EPA has published guidelines for certain kinds of human studies required for pesticide registration; should conduct of a required study in compliance with an EPA guideline be accepted as evidence of its acceptability?
g. Should the Agency apply the same standard of acceptability independent of a study's statistical power?
h. Should the Agency apply the same standard of acceptability whether or not a human study design is able to measure the same endpoints in humans that have been observed in animal testing of the same substance? For example, if the most sensitive adverse effects shown in animal studies have been detected through histopathological evaluation of brain tissue, is subsequent research involving intentional exposure of human subjects acceptable?
i. Should the Agency apply the same standard of acceptability to intentional dosing studies independent of whether there are alternative methods of obtaining data of comparable scientific merit that would not require deliberate exposure of humans? If not, to what extent, if any, should the cost of the alternate method be a factor?
j. What special considerations, if any, should the Agency apply in judging the acceptability of studies when some or all of the subjects are from populations likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons?
b. Should the Agency apply the same standard of acceptability independent of who or what organization conducts the research? For example, a research organization--public or private--holding a “Federal-Wide Assurance” from the Department of Health and Human Services's Office of Human Research Protections usually promises to comply with the Common Rule in all its human research. Should third-party work conducted by a research organization holding a Federal-Wide Assurance be assessed by the same standard that applies to other third-party human research?
c. Should the Agency apply the same standard of acceptability without regard to where the research was conducted? For example, does it matter whether research is conducted entirely in the United States or partially in the United States? If it is conducted outside the United States, does it matter in what country it is conducted? What are the advantages and disadvantages of judging the acceptability of human studies based on a single uniform standard versus prevailing local standards (e.g., in different countries)?
d. Should the Agency apply the same standard of acceptability without regard to the reasons the research was conducted? If not, how might the Agency determine intent?
e. Should the Agency apply the same standard of acceptability to submitted research without regard to who submitted it? For example, should the same standard apply to submissions from regulated industry, from public interest groups, from the public, or from other governments? Should the Agency apply the same standard of acceptability independent of whether the study was submitted voluntarily, or in response to a particular regulatory requirement of EPA?
f. Should the Agency apply the same standard of acceptability to human research which is not submitted, but which the Agency obtains at its own initiative from the scientific literature or other sources, independent of how or where EPA obtains it?
b. Should the Agency apply the same standard of acceptability without regard to how EPA intends to use the results, e.g., to reduce or remove the traditional tenfold interspecies uncertainty factor, to provide an endpoint for use in calculating a Reference Dose or Reference Concentration for the test substance, to provide a dose-response function for use in quantitative risk assessment, or for some other purpose?
b. Should the Agency independently assess the risks of the research to the subjects and the benefits of the research to the research subjects or to society, or should it defer to the judgment of Institutional Review Boards or similar oversight panels?
c. If EPA were to assess independently the risks and benefits of human research, on what range of information should it base its assessment? How might EPA obtain
b. How should the Agency determine compliance with an appropriate standard for human research data which is not submitted, but which it obtains from the scientific literature or other sources?
c. To what extent should new standards be applied to research which has already been conducted, or is underway? Should a different standard be applied to such research? Does fairness require a period of transition to any new rule or standards of acceptability, or do other considerations override that factor?
d. Should the Agency apply the same standard of acceptability to research already submitted to or obtained by EPA and to research newly submitted to or obtained by EPA? Does it matter if the submitted research was conducted for the specific regulatory purpose at hand or for other purposes (even though the study was conducted after EPA issued a policy on human testing)? Does fairness require a period of transition to any new rule or standards of acceptability, or do other considerations override that factor?
e. Is rulemaking needed at all? Would it be better to address the issues surrounding acceptance of human research, or some of them, by other means, such as policy statements or internal guidelines?
Under Executive Order 12866, entitled
Since this ANPR does not impose any requirements, and instead seeks comments and suggestions for the Agency to consider in developing a subsequent notice of proposed rulemaking, the various other review requirements that apply when an agency imposes requirements do not apply to this action.
As part of your comments on this ANPR you may include any comments or information that you have regarding these requirements. In particular, any comments or information that would help the Agency to assess the potential impact of a rule on small entities pursuant to the Regulatory Flexibility Act (RFA) (5 U.S.C. 601
Environmental protection, Protection of human research subjects.