oEPA
United States
Environmental Protection
Agency
EPA600/R-10/175 | June 2009 | www.epa.gov/ord
Guidance for Human Subjects
Research in the National
Exposure Research Laboratory
Office of
Research and Development
National Exposure Research
Laboratory
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v>EPA
United States
Environmental Protection
Agency
GUIDANCE FOR HUMAN SUBJECTS
RESEARCH IN THE NATIONAL
EXPOSURE RESEARCH LABORATORY
NATIONAL EXPOSURE RESEARCH LABORATORY
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
First Edition
June 2009
Director, ORD Human Research Protocol Office
(919)966-6217
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DISCLAIMER
This document has been subjected to the Agency's peer and
administrative review and has been approved for publication
as an EPA document.
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TABLE OF CONTENTS
Disclaimer ii
1.0 Introduction 1
1.1 Purpose 1
1.2 HRPO 1
2.0 Historical Overview of Policies Regulating Human Subjects Research 3
2.1 Nuremburg Code (1947) 3
2.2 The World Medical Association Declaration of Helsinki (1964) 3
2.3 The Belmont Report (1979) 3
2.4 The Federal Policy for the Protection of Human Subjects or the "Common Rule" 3
2.5 EPA Order 1000.17 Change A1 (1999) 3
2.6 Health Insurance Portability and Accountability Act (HIPAA-2003) 4
2.7 Scientific and Ethical Approaches for Observational Exposure Studies 4
3.0 Title 40 CFR Part 26: Protection of Human Subjects or the EPA Common Rule, including
Subparts for Additional Protection of Vulnerable Populations 5
3.1 Subpart B 5
3.2 Subpart C 5
3.3 Subpart D 5
3.4 Subparts K, L, M, 0, P, and Q 5
3.5 Section 26.101: To What Research Does 40 CFR 26 Apply? 5
3.6 Section 26.102: Definitions 6
3.7 Section 26.103: Assuring Compliance with 40 CFR 26 6
4.0 Development, Review, and Approval of Human Subjects Research Protocols 7
4.1 Elements of the Human Subjects Research Protocol Package 8
4.1.1 NERL Study Design 8
4.1.2 Consent Form/Informed Consent Process 10
4.1.3 Surveys and Questionnaires 10
4.1.4 Advertising, Brochures, and Other Required Items 11
4.1.5 Ethics Training Requirements 11
4.1.6 IRB Research Protocol 11
4.1.7 IRB Approval Letters 11
4.1.8 External Scientific Reviews (Peer Review) 11
4.1.9 Fact Sheet 12
4.1.10 NERL Sign-Off Sheet 12
4.1.11 Cover Memorandum 12
4.2 Process for Review and Approval of a Typical NERL Study Design and Human Subjects
Research Protocol Package 12
4.3 Protocol Review Procedures for Special Cases 13
4.3.1 Studies Not Meeting the Definition of Human Subjects Research 13
4.3.2 Exempt Human Subject Research 14
4.3.3 Waiver of Informed Consent 14
4.4 Collaboration and Consultation on Research Primarily Conducted Outside NERL 14
5.0 Observational Human Exposure Studies 15
6.0 Intentional Exposure Studies 17
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TABLE OF CONTENTS CONTINUED
7.0 Study Of Human Data, Human Tissues, And Environmental Samples Collected
In Human Subjects Research 19
7.1 Purpose 19
7.2 Definitions 19
7.3 Genetic Studies 19
7.4 Stored Specimens 19
7.5 Specimens Obtained from Other Researchers or Commercial Tissue Banks 19
8.0 Adverse Events And Unexpected Events 21
8.1 Definitions 21
8.2 Serious Adverse Events and Unanticipated Problems Occurring at Sites or Which a
UNC-Chapel Hill IRB Has Direct Oversight Responsibility 21
8.3 Adverse Event Written Report 21
8.4 IRB Responsibilities Following Receipt of Serious Adverse Event/Unanticipated
Problem Report 22
References: 22
9.0 NERL Employees As Research Subjects 23
9.1 Purpose 23
9.2 Requirements for Participation of an EPA Employee as a Research Subject 23
9.3 EPA Employees in Non-Human Subjects Research Activities 23
9.4 Survey Questionnaires 24
List Of Acronyms And Abbreviations 25
Appendix A: Templates For Memorandums For Human Subjects Research Requests 27
Appendix B: Flow Diagram For The Nerl Review Process 29
Appendix C: Guidance For Preparation Of The Section Or Appendix On "Considerations For
Protection Of Human Subjects In The Study" 31
Appendix D: NERL Human Research Sign-Off Sheet 33
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1.0
INTRODUCTION
1.1 Purpose
This document provides guidance to investigators and
managers associated with the U.S. Environmental Protection
Agency (EPA) Office of Research and Development (ORD)'s
National Exposure Research Laboratory (NERL) on the
ethical conduct, regulatory review, and approval of all human
research activities. The focus of this document is twofold:
first, on the methods for ensuring the safety and rights of
human research subjects, and. second, on how to conduct such
research in a manner consistent with EPA and NERL policy.
Principal investigators (Pis) are responsible for obtaining
approval for human subjects research. If a PI does not have
significant experience in the approval process for human
subjects research, he or she should rely on an experienced
colleague or co-investigator (Co-I) or contact the Office of
the Director of the Human Research Protocol Office (HRPO)
located at the National Health and Environmental Effects
Research Laboratory Human Studies Facility in Chapel Hill.
NC. The mission of the HRPO is to assist investigators in all
aspects of the ethical and regulatory review of human subjects
research. Pis with questions about the process are encouraged
to contact the office early in protocol development. The phone
number of the HRPO is (919)966-6217.
1.2 HRPO
The Office of the Director of the HRPO will be responsible
for the ethical oversight and coordination of the process by
which human subjects research activities are developed,
reviewed, and approved in NERL, in addition to all intramural
research w ithin ORD. Some specific duties include
• ensuring the safety and rights of all human research
subjects are respected and protected;
• assisting investigators in the preparation of human
subjects research protocols that are consistent with
EPA policy:
• maintaining records, including approved protocols,
amendments, renewals, adverse events, and
protocol deviations (The office of the HRPO should
be provided copies of all Institutional Review Board
(IRB) correspondence and approvals for the duration
of a human subjects research project or protocol.); and
• ensuring that human subjects research in NERL is
consistent with principles set forth in the Scientific
and Ethical Approaches for Observational Exposure
Studies (SEAOES) document (EPA 600/R-08/062,
available at www.epa.gov/nerl/sots).
The HRPO welcomes any questions regarding the ethics
or regulatory compliance of any human subjects research
protocol. Past experience has shown that involvement of the
HRPO early in protocol development saves time and reduces
confusion in the EPA approval process.
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2.0
HISTORICAL OVERVIEW OF POLICIES
REGULATING HUMAN SUBJECTS RESEARCH
The conduct of human research carries special responsibilities
with regard to ethical, medical, and scientific issues. Society,
although generally accepting research on humans as necessary
to advance scientific knowledge, has imposed special
requirements on investigators because of concern of potential
maltreatment of human research subjects, based in part, on the
historical legacy of improper human studies.
The following sections summarize key documents tracing the
changes in human research ethics that took place beginning
immediately after World War 11 and continuing to the present.
This is followed by a description of the additional policy
documents that currently govern the conduct of human
subjects research within EPA. These are covered in more
depth in the following chapters.
2.1 Nuremburg Code (1947)
The Nuremburg Code was a direct result of the proceedings
of the military tribunal trials after World War 11 of Na/.i
physicians who committed atrocities on prisoners of war
under the guise of medical research. The code contains 10
principles; among them are the need for voluntary consent,
that research yield fruitful results for the good of society,
and the degree of risk to be taken should never exceed that
determined by the humanitarian importance of the problem to
be solved by the experiment.
2.2 The World Medical Association Declaration
of Helsinki (1964)
The World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research Involving Human
Subjects initially was adopted in 1964 and has been amended
and clarified eight times, most recently in 2008 in Seoul. That
document represents the first significant effort of the medical
community to regulate medical research and combined the
Nuremburg Code with the Declaration of Geneva (1948), a
statement of the ethical duties of physicians.
In the case of EPA involvement in foreign countries,
adherence to the Declaration of Helsinki is the strongest
assurance that investigators will accept the international norm
for protection of human research subjects.
2.3 The Belmont Report (1979)
The Belmont Report is the foundation of research ethics in
the United States and was the basis for the "Common Rule."
The report was a result of the 1974 National Research Act.
which created the National Commission for the Protection
of Human Subjects of Biomedical and Behavioral Research.
The commission's charge was to identify the basic ethical
principles that should underlie the conduct of biomedical
and beliavioral research involving human subjects and to
develop guidelines that should be followed to ensure that such
research is conducted in accordance with those principles.
The report was the product of a 4-day conference held in
1976 at the Smithsonian Institute's Belmont Conference
Center and monthly discussions over 4 years by the
commission's 11 members.
The report promoted three principles:
(1) respect for persons.
(2) beneficence, and
(3) justice.
2.4 The Federal Policy for the Protection
of Human Subjects or the "Common Rule"
Since 1991, 14 Federal agencies have agreed to adopt an
identical basic set of regulations governing human subjects
research. The name "Common Rule" refers to these basic
regulations being identical in all 14 agencies. Specifically, the
Common Rule pertains to subpart A of 45 Code of Federal
Regulations (CFR) 46. The Common Rule has brought
uniformity to a patchwork of existing Federal research
protections and embodies the principles of the Belmont
Report. It establishes standards for the conduct of human
subjects research funded by the Federal government.
Some agencies, including EPA and Department of Health and
Human Services (DHHS). have adopted subparts tliat provide
additional protections to special populations. EPA codified the
Common Rule at 40 CFR 26 in 1991, and redesignated it as
40 CFR 26 subpart A when additional subparts were added
in 2006.
2.5 EPA Order 1000.17 Change A1 (1999)
This order superseded the 1977 EPA Order 1000.17, Policy
and Procedures on Protection of Human Subjects. The order
applies to all research covered by 40 CFR 26, including
exemptions from the Common Rule. The policy establishes
that all human subjects research studies supported by the
EPA must either be approved or be determined to be exempt
research by the EPA Human Subjects Research Review
Official (HSRRO) before any contract, grant, cooperative
agreement. Cooperative Research and Development
Agreement (CR AD A). interagency agreement, or any formal
agreement involving EPA support of such studies is awarded
or entered into. The order also requires the HSRRO to review
all foreign research not subject to the Common Rule prior to
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commencement.
Note that the Agency HSRRO approves all EPA research
and is an entity distinct from the Director of the HRPO. The
HRPO Director helps the PI assemble the needed documents
for review by the Agency HSRRO and helps to ensure timely
approval and avoid unnecessary delays.
2.6 Health Insurance Portability and
Accountability Act (HIPAA-2003)
Effective in April 2003, the HI PA A included both the
portability of employees' health insurance as employees
change jobs and defined accountability for individuals'
protected health information (PHI).
HI PA A recognizes three covered entities. (1) health care
providers. (2) health care information clearinghouses, and
(3) health care payers, that must have authorization from
individual patients or research subjects before individual
PHI can be shared or used in research. Because EPA is not
a covered entity, it ordinarily does not have to comply with
HI PA A. However, if joint human studies are conducted
between EPA and a covered entity, HI PA A authorization may
be required from each of the study subjects, but many studies
qualify for a limited waiver to review PHI. The IRES of record
for the study is a good source of information on whether
HI PA A regulations for PHI apply.
HI PA A regulations do not apply to studies on existing
databases, research in foreign countries, and studies on
deceased individuals.
2.7 Scientific and Ethical Approaches
for Observational Exposure Studies
In 2008, EPA published the SEAOES document, which
provides information and guidance for NERL researchers as
they design and implement observational human exposure
measurement studies. The document identifies issues that
need to be considered in these studies and provides state-
of-the-science information on ethical considerations. It
includes extensive references to sources of information
relevant to ethical considerations in human subjects research
studies. The document includes the following sections: (1)
Elements to be Considered in Study Conceptualization and
Planning; (2) Ensuring Protection of Vulnerable Groups;
(3) Privacy. Confidentiality, and Other Concerns Related
to Observational Human Exposure Studies; (4) Creating
an Appropriate Relationship Between the Participant and
Researcher; (5) Building and Maintaining Appropriate
Community and Stakeholder Relationships; and (6) Designing
and Implementing Strategies for Effective Communication.
SEAOES addresses issues related to activities such as
selecting and enrolling study participants, informed consent
procedures, participant compensation, participant retention,
reporting unanticipated observations, the communication of
study results, and similar activities. The document adds to
existing EPA policies and guidelines. In a single document,
it brings together information on approaches and procedures
that researchers can use in design and performance of
observational studies. NERL researchers are to use the
guidance and recommendations provided in SEAOES in the
design and implementation of observational studies. The
document recommendations also are to be used by second-
party researchers funded by NERL.
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3.0
TITLE 40 CFR PART 26:
PROTECTION OF HUMAN SUBJECTS OR THE EPA COMMON
RULE, INCLUDING SUBPARTS FOR ADDITIONAL PROTECTION
OF VULNERABLE POPULATIONS
As described in section 2.4, the EPA Common Rule is codified
at subpart A of 40 CFR 26, and this identical regulation is
recognized by 14 Federal agencies. As of 2006, EPA has
added subparts B, C, and D for the purpose of affording
additional protections to special populations. In addition, it
added subparts K, L, M, O, P, and Q containing regulations
for third-party human research for pesticides and rules for
data use. compliance oversight, and other matters. Subparts B.
C, and D cover protections for nursing women (B). pregnant
women and fetuses (B and C), and children less than 18 years
of age (B and D). in research conducted or supported by EPA.
3.1 Subpart B
Subpart B prohibits research conducted or supported by
EPA involving intentional exposure of human subjects
who are children or pregnant or nursing women. Research
involving intentional exposure of a human subject is defined
by a "study of a substance in which the exposure to the
substance experienced by a human subject participating in
the study would not have occurred but for the human subject's
participation in the study. "
This policy does not distinguish between toxic substances
and any other types of substances, including therapeutic
substances.
If you have questions regarding whether a proposed research
project includes intentional exposure research, contact the
HRPO or the Agency HSRRO.
3.2 Subpart C
Subpart C provides additional protections for pregnant women
and fetuses involved in observational research conducted or
supported by EPA. Observational research is defined as "any
human research that does not meet the definition of research
involving intentional exposure of a human subject. "
Subpart C also adds the additional protections of subpart
B of the DHHS rule (45 CFR 46) but does not include a
provision for research not otherwise approvable that presents
an opportunity to understand, prevent, or alleviate a serious
problem in pregnant women, fetuses, or neonates
(45 CFR 46.207).
3.3 Subpart D
Subpart D provides for additional protections for children
involved as subjects in observational research conducted or
supported by EPA. The subpart adopts the language of subpart
D of DHHS regulations with respect to research not involving
greater than minimal risk and research involving greater than
minimal risk but preserving the prospect of direct benefit to
the individual subject.
EPA did not adopt, hence does not allow for. research
involving greater than minimal risk without prospect of direct
benefit but likely to yield generalizable knowledge about the
subject's condition or research not otherw ise approvable that
presents an opportunity to understand, prevent, or alleviate a
serious problem affecting the health or welfare of children.
3.4 Subparts K, L, M, O, P, and Q
Subparts K, L, M, O. P. and Q (N is reserved) pertain to a
variety of issues not typically of concern for EPA researchers.
Below is a list of each subpart with a brief description of it.
• Subpart K: Basic Ethical Requirements for Third-
Party Research for Pesticides Involving Intentional
Exposure of Non-pregnant. Non-nursing Adults
• Subpart L: Prohibition of Third Party Research for
Pesticides Involving Intentional Exposure of Human
Subjects Who Are Children or Pregnant or Nursing
Women
• Subpart M: Requirements for Submission of
Information on the Ethical Conduct of Completed
Human Research (applies to outside research
submitted under the Federal Insecticide. Fungicide,
and Rodenticide Act [ FIFR A | or section 408 of the
Food. Drug, and Cosmetic Act)
• Subpart O: Administrative Actions for Non-
Compliance (with Any Subpart A-L)
• Subpart P: EPA Review of Proposed and Completed
Research (This subpart establishes the EPA Human
Studies Review Board [HSRB], defines its functions,
and requires it to review certain submitted
non-EPA research.)
• Subpart Q: Ethical Standards for Assessing Whether
To Rely on the Results of Human Research
in EPA actions
3.5 Section 26.101: To What Research
Does 40 CFR 26 Apply?
Section 26.101 states that the regulations apply to all research
involving human subjects conducted, supported, or otherw ise
subject to regulation by EPA or other Federal agencies that
have adopted the Common Rule.
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Section 26.101(b)(l-6) covers exemptions from this policy.
Section 26.101(b)(4) is likely to be the exemption most
applicable to much of the research at NERL.
Section 26.101(b)(4) states. "Research involving the
collection or study of existing data, documents, records,
pathological specimens, or diagnostic specimens, if these
sources arc publicly available or if the information is recorded
by the investigator in such a manner that subjects cannot
be identified, directly or through identifiers linked to the
subjects." However, only the Agency HSRRO can make the
determination of whether the human subjects research in
question is exempt, with or without the support of the IRB of
record. The PI and the HRPO Director cannot make
this determination.
The HRPO can guide the researcher through the language
and appropriate documentation to prepare a request for
classification as exempt human subjects research.
3.6 Section 26.102: Definitions
Section 26.102 provides a number of important and useful
regulatory definitions. The two that are most relevant and
impact all NERL research are those of research and human
subjects that follow.
• "Research means a systematic investigation,
including research development, testing, and
evaluation, designed to develop or contribute to
generalizable knowledge. Activities which meet
this definition constitute research for purpose of this
policy, whether or not they are conducted or
supported under a program that is considered
research for other purposes. "
• "Human subject means a living individual about
whom an investigator (whether professional or
student) conducting research obtains:
(1) data through intervention or interaction with
the individual, or
(2) identifiable private information. "
Sections 26.101 and 26.102 establish which studies are
governed by 40 CFR 26. Currently, most studies involving
human data or tissues clearly fall within the definition
of human subjects research because the studies meet the
definition of research, involve intervention or interaction with
a subject, or clearly involve analysis of data with personal
identifiers. There are other situations, however, where it is not
immediately apparent that a study constitutes human
subjects research.
Often, the issue is whether personally identifiable private
information is available to the investigator. Clearly, analysis
of existing data that is publicly available and cannot under
any circumstances be linked to individuals is not human
subjects research. However, there are numerous studies
involving existing data or tissues that do not contain readily
identifiable private information but that can be linked
to individual subjects through coded identifiers. These
codes could conceivably be used to identify individuals.
A determination of whether such studies constitute human
subjects research or not often depends on the individual
circumstance surrounding access to the data or to keys to
any existing codes. The HRPO Director is the individual in
ORD who is most fully trained and qualified to make human
subjects research/non-human subjects research determination,
and research projects that use data from or about humans
generally should be referred to the HRPO for such a
determination. In difficult or ambiguous cases, the HRPO
director may consult with the Agency HSRRO before making
a final determination.
3.7 Section 26.103: Assuring Compliance
with 40 CFR 26
Section 26.103 requires that any research conducted or
supported by a Federal agency or department must be
reviewed by an appropriate IRB. and that any organization
engaged in such research must have a written assurance
in place indicating its compliance with the regulatory
requirements of that agency. For most U.S. institutions
that engage in human research, including EPA, this written
assurance is provided in the form of a Federal Wide
Assurance (FWA) issued by DHHS. EPA's FWA number
is FWA00012755, and NERL specifically is identified as a
component on that assurance. In addition. EPA has a contract
with the University of North Carolina (UNC) IRB system to
serve as the IRB of record on EPA studies conducted under
the Agency's FWA. Investigators who develop research
studies within ORD. therefore, usually will use the UNC IRB
system as the IRB of record. Use of an alternate IRB can be
considered under certain circumstances but requires an IRB
Authorization Agreement signed by the Agency HSRRO. The
HRPO Director will initiate this action in the occasional cases
in which it is required.
EPA-funded research performed by outside researchers
without EPA involvement will use the outside researcher's
FWA and IRB of record. When EPA investigators collaborate
with outside institutions such as the Centers for Disease
Control and Prevention (CDC), the National Institutes of
Health (NIH), or a research university, review by the IRB
of each of the engaged institutions is required unless there
are signed IRB Authori/ation Agreements in place allow ing
one IRB to serve as the IRB of record for more than one of
the institutions engaged in the study, thus simplifying the
review process by eliminating redundant IRB review. Again,
the HRPO Director will initiate an action with the Agency
HSRRO when EPA investigators are involved in a study in
which this kind of agreement is required.
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4.0
DEVELOPMENT, REVIEW, AND APPROVAL
OF HUMAN SUBJECTS RESEARCH PROTOCOLS
EPA scientists and their management take the protection
of human subjects who participate in their human subjects
research studies very seriously and want to ensure that
the procedures used in their studies meet the most up-to-
date scientific and ethical standards. To address this goal,
researchers in NERL have published the SE AOES document,
which identifies key scientific and ethical issues in the design
and implementation of observational human exposure studies
and provides information and resources that will be useful to
researchers conducting these studies.
The document was developed with input from a panel of
external experts, released for public comment, and reviewed
by the Agency's HSRB. The document, available at www.
eDa.gov/nerl/sots. is to be used by NERL researchers as they
develop the technical study design and the human subjects
research protocols. Information in the document will be used
in preparing the required paperw ork, as described below.
The purpose of this chapter is to serve as a "how to" manual
for the preparation and review of a human subjects research
protocol package. It should be noted that ethical concerns
must be incorporated into the scientific effort from the onset
of study conceptualization and throughout the study design
and implementation. Therefore, the study design and human
subjects research protocol should be developed concurrently
and fully integrate scientific and ethical concerns. The
following discussion outlines the steps, required paperwork,
review s, and necessary EPA management approvals before
any human subjects research can begin.
No, second-party research Yes, first-party research
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r
Lead investigator prepares Human Subjects Research
protocol and obtains approval; EPA contact obtains
concurrence following Appendix B flow diagram.
EPA staff prepares Human Subjects
Research protocol and obtains approval
following Appendix B flow diagram.
Figure 4-1. Decision process for determining if a study is human subjects research
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The PI and his/her management team first must
determine whether the proposed research study is human
subjects research. This is done during the initial study
conceptualization and planning, as described in SEAOES.
It involves defining the study objectives, general approach,
and involvement of human subjects. Figure 4-1 depicts the
decision making process, which is described below.
Step 1: Determine whether the research
is human subjects research.
The first decision to be made for getting approval of any
research activity is to determine whether the proposed study
meets the regulatory definition of human subjects research.
The regulatory definition of human subjects research is found
in section 26.102 of 40 CFR 26 and in section 3.6 of this
document. If a researcher is planning to conduct research that
might meet the regulatory definition of research involving
human subjects, the HRPO should be contacted for guidance.
If the proposed research docs not meet the regulatory
definition of human subjects research, the Director of
the HRPO is empowered to make an official Agency
determination of non-human subjects research for the study
and will provide a letter to the PI and to the Agency HSRRO
allowing the research to proceed. When research is non-
human subjects research, it is not subject to the requirements
of 40 CFR 26. See section 4.3.1 "Studies Not Meeting
the Definition of Human Subjects Research" for more
information.
Appendix A contains a sample memo to request research be
declared as non-human subjects research.
If the research is human subjects research, proceed to step 2.
Step 2: Determine whether the research
is exempt human subjects research.
If the study is determined to be human subjects research but
qualifies as exempt human subjects research under one of
the exemption categories of 26.101(b)(l-6) as mentioned in
section 3.5, an exemption from the requirements of 40 CFR
26 may be granted by the Agency HSRRO.
The HRPO should be contacted and will assist with this
request. See section 4.3.2 "Exempt Human Subject Research"
for more information.
Appendix A contains a sample memo to request research be
declared as exempt human subjects research.
If the study is nonexempt human subjects research. 40 CFR
26 applies, and a human subjects research protocol package
will need to be created and approved by an IRB and the
Agency HSRRO. The process for receiving approval will
vary depending on whether the research is first- or second-
party research. NERL is not involved in third-party research.
Proceed to step 3.
Step 3: Determine the role of EPA personnel
in the proposed study.
The final decision to be made is whether the proposed
research will involve EPA personnel, such as investigators.
project officers (POs). collaborators, or Co-Is. with another
entity outside of EPA.
EPA personnel may be involved as investigators in first-
party research (conducted in-house by EPA stall) or as Co-Is
in second-party research (e.g., in contracts or cooperative
agreements with entities outside of EPA). First-party research
is designed and led by EPA stall as the Pl(s). First-party
research in NERL requires approval by an IRB listed on
EPA's FWA. Except in unusual circumstances, this will be the
UNC IRB. and the protocol package will be created using the
UNC IRB forms. Following approval by the UNC IRB. the
protocol package will be submitted to the HRPO. who will
submit it to the Agency HSRRO for review and approval.
The first-party human subjects research review procedure is
detailed in section 4.2 "Process for Review and Approval of
a Typical NERL Study Design and Human Subjects Research
Protocol Package" and is summarized in Appendix B.
Second-party research is designed and led by an entity
outside of the Agency, such as a contractor or cooperative
agreement partner. Regardless of whether EPA is involved as
a Co-I. the second party will be responsible for preparation
of the research protocol and obtaining approval from the
contractor's IRB. The second party should use forms required
by their organization's IRB. which likely will be consistent
with the UNC IRB forms, but not the same. If EPA personnel
will also be engaged in the research, the HRPO should
be consulted about whether to seek an IRB Authorization
Agreement with the awardee institution or whether the
research also will have to be reviewed by the UNC IRB. If
the UNC IRB will be review ing the research in addition to the
second-party-institution's IRB. the EPA contact (PO, Work
Assignment Contracting Office Representative, or PI) will
prepare a protocol package to be submitted to the UNC IRB.
using the UNC forms and the protocol package approved by
the second-party-institution"s IRB. The EPA investigator w ill
submit the approved protocol package to the EPA HRPO. who
will submit it to the Agency HSRRO for review and approval.
See section 4.4, "Collaboration and Consultation on Research
Primarily Conducted Outside NERL," for further information.
If there are questions at any point in the process, contact the
EPA HRPO for assistance. A PO. collaborator, or one unsure
of the classification of one's role should contact the Agency
HRPO.
It is likely that research by second parties will continue in
NERL, thus requiring a meshing of second-party IRB human
subjects research requirements with those of NERL. The
PI. Branch Chief and Division Director are responsible for
ensuring that IRB protocols developed by second parties for
NERL meet all EPA requirements.
In addition, remember that all human subjects research studies
supported by EPA must either be approved or be determined
to be exempt research by the EPA HSRRO before any
contract, grant, cooperative agreement. CR AD A. interagency
agreement, or any formal agreement can be completed. Please
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contact the Agency HRPO or HSRRO for assistance with
approval of any of the above agreements, contracts, or grants.
Requests for applications and requests for proposals do not
need HSRRO approval until after the contract is awarded, but
approval is needed prior to the awarding of a contract and.
again, prior to the beginning of the research.
4.1 Elements of the Human Subjects Research
Protocol Package
The final human subjects research protocol package submitted
to the Agency HSRRO will include the following items.
• NERL study design, including a section on
"Considerations for Protection of Human Subjects
in the Study"
• Consent forms approved and stamped by the IRB
• Questionnaires and advertising approved and stamped
by the IRB
• Ethics training reports required by the IRB
• RB-approved research protocol
• IRB-approval letter!s)
• Copies of extramural scientific reviews and responses
• NERL fact sheet
• NERL sign-off sheet with signatures
• Cover memo from the PI to the HRPO requesting
review of the protocol
The following subsections describe the individual elements of
the protocol package. Section 4.2 subsequently describes the
process for preparing, reviewing, and approving the package.
4.1.1 NERL Study Design
The foundational document for a human subjects research
study is the NERL study design. The study design document
should contain sufficient detail to enable independent review
and assessment of the scientific soundness of the study and
the approaches that will be followed to ensure that the study
meets the highest scientific and ethical standards. Elements
recommended for inclusion in the study design of an
observational exposure study are presented in section 2 of the
NERL SEAOES document, available at
www.epa. aov/nerl/sots).
The following elements may be included in a study design.
• Introduction and background, including the purpose and
scope of the study
• The desired outputs and outcomes of the study, including
the objectives and the hypotheses to be tested
• A brief description or overview of the study
• The technical approach and conceptual model that
accounts for
- sources of the chemicals being studied;
- potential routes and pathways of exposure;
- factors that may impact exposure and other
relevant stressors;
- selection and cliaracteristics of the study
participants.eligibility criteria, recruitment, retention,
and payment approaches;
- justification for sample si/c. the methodology
for selecting participants, and the sampling methods;
- characteristics of the community in which the study
will be performed;
- environmental conditions, factors, or end points
to be measured, including sampling and analysis
approaches and methods (with description
of expected performance);
- survey design and questionnaires and other survey
instruments, as applicable (with description of prior
use and validation in similar studies);
- pilot studies that may be undertaken;
- quality assurance (QA) project plan and
quality control;
- time frame for the study;
- exposure scenarios to be considered;
- burden of the study on the participants;
- resources available; and
- feasibility.
• Discussion of alternative study designs and approaches
considered and reasons for rejecting other approaches
and selecting the one proposed
• An analysis plan that considers
- information and data needs, including data storage,
security, access, and release;
- nature of the measurement data
(e.g., variability. QA);
- how the collected data will be used, and how
the proposed analyses will address objectives
of the study; and
- hypotheses to be tested and statistical power
and sample si/e required to test the hypotheses.
• Resources required or available
• Project organization and management, including team
members and their roles and responsibilities
• Communications plan
• Schedule
Investigators should follow the recommendations presented
in SE AOES during study design and preparation of the
design document. The format and content of the study design
document will be prescribed by the policies of the Pi's
division. The document will contain a section or appendix
titled "Considerations for Protection of Human Subjects
in the Study." This section or appendix will address the
recommendations of SE AOES with respect to scientific and
ethical considerations in the design and implementation of
studies involving human subjects and provide documentation
that the elements of SEAOES have been addressed. For
example, this section will include the justification for the
study, justification for including human subjects, the basis
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for participant payment plans, approach for community
involvement, plans for technician training on collateral
hazards, etc. The format for this section or appendix and
elements to be addressed in this section or appendix of the
study design document are summarized in Appendix C
of this document.
4.1.2 Consent Form/Informed Consent Process
As described in the SEAOES document, informed consent is
a process, not a form. Information must be presented to enable
potential subjects to decide voluntarily whether to participate
as research subjects. Informed consent is the fundamental
mechanism to ensure respect for persons through provision of
thoughtful consent for a voluntary act. The procedures used
to obtain informed consent should be designed to educate the
potential research subjects using language they understand.
Informed consent language and documentation, especially
the explanations of the study purpose, duration, experimental
procedures, alternatives, risks, and benefits, must be written
in "lay language." Current recommendations suggest that
informed consent language be understood by individuals
with an 8th- to loth-grade reading level, although researchers
should be aware that many individuals read below this level.
The process of obtaining informed consent, the required
elements of a consent form, and the documentation of
informed consent must be consistent with 40 CFR 26 sections
116 and 117. In most cases, the IRB of record will provide
a template or suggestions for a consent form consistent with
the Common Rule. The UNC IRB has a variety of sample
consent forms at http://ohrc.unc.cdu/fornis.php. Additional
information about the informed consent process is included in
SEAOES at www.epa.gov/nerl/sots.
More detailed information and guidance can be found at the
website of the DHHS Office for Human Research Protection
at www.hhs.gov/ohrp/policv/index.html#informed. In
addition to the requirements of the IRB of record, the EPA
has requirements and language to be included in the informed
consent document.
In the consent form, under the section regarding, "What
will happen if you are injured by this research?" insert the
following language.
All forms of medical research, diagnosis, and treatment
involve some risk of injury or illness. Despite our high
level of precaution, you may develop an injury or illness
due to participating in this study. The US EPA has not set
aside funds to pay you for any such illness or injuries,
or for medical care related to such injuries or illness. If
you believe your injury or illness was due to a lack of
reasonable care or other negligent action, you have the
right to pursue legal remedy. The Federal Tort Claims
Act, 28 U.S.C. 2671 et seq.. provides for money damages
against the United States when personal injury or
property loss results from the negligent or wrongful act or
omission of any employee of the EPA while acting within
the scope of his or her employment. Signing this consent
form docs not waive any of your legal rights or release
the investigator, the sponsor, the institution, or its agents
from liability for negligence. If a research related injury
or illness occurs, you should contact the Director of the
EPA HRPO at 919.966.6217.
For first-party research approved by the UNC IRB. under the
section. "What if you have questions about your rights as a
research participant?" the last sentence must be amended as
follows.
All research on human volunteers is reviewed by a
committee that works to protect your rights and welfare.
If you have questions or concerns about your rights as
a research subject you may contact, anonymously if you
wish, the Institutional Review Board at 919.966.3113 or by
email to IRB_subjects@unc.edu. and/or the Director of the
EPA HRPO at 919.966.6217.
4.1.3 Surveys and Questionnaires
The Paperwork Reduction Act of 1995 (44 U.S.C. 3501)
requires tliat agencies receive Office of Management and
Budget (OMB) clearance before requesting most types of
information from the public ("information collections"),
including surveys and questionnaires, from more than nine
study participants. EPA maintains an Information Collection
Request (ICR) Center within the Office of Environmental
Information to assist EPA employees in preparing an
ICR. More information about the process and necessary
documentation can be found at http://intranet.epa.gov/
icrintra/. Experience with the system suggests the process
takes between 6 to 9 months for OMB clearance.
The Paperwork Reduction Act defines a collection of
information as follows.
"Collection of information means, except as provided
in Sec. 1320.4, the obtaining, causing to be obtained,
soliciting, or requiring the disclosure to an agency, third
parties or the public of information by or for an agency
by means of identical questions posed to, or identical
reporting, recordkeeping, or disclosure requirements
imposed on, ten or more persons, whether such collection
of information is mandatory, voluntary, or required to
obtain or retain a benefit. "
Note that for it to be necessary for an OMB review, the survey
or questionnaire needs to include more than 9 individuals
in a 12-mo period. Most studies will reach this threshold.
However, some small-scale pilot studies or research on
collection and validation of methodologies may not require
more than nine individuals.
The Paperwork Reduction Act does allow for exceptions.
These exceptions can be found at 5 CFR 1320.3(h).
Two exceptions that apply to some research within ORD are
shown below.
(1) CFR 1320.3(h)(5): Facts or opinions obtained
initially or in follow-on requests, from individuals
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(including individuals in control groups) under
treatment or clinical examination in connection with
research on or prophylaxis to prevent a clinical
disorder, direct treatment of that disorder, or the
interpretation of biological analyses of body fluids,
tissues, or other specimens, or the identification or
classification of such specimens.
(2) CFR 1320.3(h)(7): Examinations designed to test
the aptitude, abilities, or knowledge of the persons
tested and the collection of information for
identification or classification in connection with
such examinations.
For further guidance on the need for information collection
clearance for EPA research, contact the Director of the HRPO
or the EPA ICR Center (http://www.epa. gov/icr).
4.1.4 Advertising, Brochures, and Other
Required Items
Complex research studies often require a wide range of
additional items that must be reviewed and approved by the
IRES and EPA. Some common examples include recruitment
brochures, advertising (both print and online), clinic
recruitment letters, and surveys. Include all IRB approved
additional documents in the protocol package.
4.1.5 Ethics Training Requirements
All EPA investigators conducting human subjects research
must have formal human research ethics training. UNC-
Chapel Hill has joined the Collaborative IRB Training
Initiative (CITI), and this is now the default for satisfying
basic educational requirements. CITI is a Web-based program
on issues relating to human subjects research. The CITI
Web site is maintained by the University of Miami, with
content developed by a national consortium. More than 400
institutions are using CITI for their mandatory training, with
more than 140,000 individual registrants.
CITI contains modules on topics including ethical principles.
IRB regulations, informed consent, and vulnerable
populations. Each module has a short qui/ at the end to
assess understanding. The modules have been grouped for (1)
Biomedical Research. (2) Social and Behavioral Research,
and (3) Research Involving Data and Specimens Only. Users
select the grouping that best reflects their area of research, and
the other modules are available options. For more detailed
information and links to the CITI Web site, please visit www.
ohre.unc.edu/educ.php.
All personnel involved with a human research project
submitted for UNC IRB review must have completed the
CITI Basic Course.
EPA and contractor personnel should choose UNC as their
institution when registering for the training. The EPA HRPO
and the CITI Web site can offer additional guidance or help
with CITI training issues.
Annual Continuing Education. Following completion
of the basic education requirement, all personnel who
remain engaged in human subjects research are required to
complete continuing education on an annual basis, with the
schedule determined by the date on which basic training
was completed. New IRB approvals will not be granted,
and active protocols may be suspended if the continuing
education requirement has not been completed on time. The
annual continuing education requirement may be satisfied by
one of the following methods, each requiring approximately
1 h to complete.
• Completion of the online CITI Refresher Course
modules. As with the CITI Basic Course, refresher
modules are grouped by categories of research activity.
• Attendance at one lecture or seminar with a primary
focus on human research issues. The Agency HSRRO
and the HRPO offer courses periodically that will satisfy
this requirement.
4.1.6 IRB Research Protocol
The research protocol is prepared according to the
instructions of the IRB that will review the protocol. For most
first-party research and for some second-party research in
which EPA is involved as a Co-1, this will be the UNC IRB.
Instructions and IRB application forms can be found at
www.ohre.unc.edu/index.php.
All individuals listed on the protocol application must meet
the training requirements specified by either the UNC IRB or
the IRB responsible for the protocol review.
Organization affiliation should be listed for all investigators
and study staff. Questions regarding completion of the IRB
application should be directed to the IRB or the Agency
HRPO.
For second-party research led by an entity outside the
Agency, the organization's IRB will specify the instructions
and application forms.
4.1.7 IRB Approval Letters
The final package submitted to the HRPO for review and
approval by the Agency HSRRO will include all IRB
approval letters.
4.1.8 External Scientific Reviews
(Peer Review)
Prior to submission of a research protocol for IRB review, the
PI is responsible for obtaining external scientific peer review
of the study design document. The primary objective of the
external peer review is evaluation of the following topics:
• scientific merit.
• justification for conducting research involving human
subjects, and
• concerns regarding issues of the ethical and safe
treatment of study subjects.
All human subjects research in NERL will require an external
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peer review regardless of the scope of the study or number of
human subjects involved. The Pi's division will establish the
policy for extramural peer review requirements in the division
(e.g., number of reviews, format of the review, etc). The plan
for the extramural peer review will be developed by the PI
and approved by the Branch Chief and Division Director.
External reviews must be formal, written comments by
experts in the field. The PI should provide a written response
to each comment in the review, indicating whether the
changes suggested by the reviewer have been made. and. if
not. why not. Under certain circumstances, reviews conducted
by or required by outside collaborators, funding agencies, or
regulatory bodies, such as the Food and Drug Administration
(FDA) and NIH may serve this purpose if they address the
required elements of the review. As described below, the
response to the comments will be reviewed by the Branch
Chief and the Division Director during the NERL final review
of the research protocol.
The extramural review comments and written responses to
comments will be included in the final research protocol
package to be submitted to the Agency HSRRO for review
and approval.
4.1.9 Fact Sheet
A fact sheet provides a brief summary of any high-visibility
project or activity to the EPA Assistant Administrator for
ORD and. if warranted, to the Administrator. All NERL
projects involving human subjects research will require a fact
sheet.
Fact sheets, although for internal EPA use. are written in a
nontechnical, jargon-free style because information from
the fact sheets also may be used by the EPA Office of Public
Affairs and by Regional and Program Offices to disseminate
information about the research project to interested parties,
including the general public.
Fact sheets are required at the beginning of a research project
and may be required at other stages of the project. The Branch
Chief. Division Director, and the NERL Communications
Office should be consulted regarding these requirements. The
fact sheet should be no more than two pages in length, written
in the format specified by the NERL Communications Office,
and include the information listed below. The draft fact sheet
will be written following the guidance provided by the NERL
Communications Office. It will be approved by the Branch
Chief and Division Director prior to being included in the
package. The HRPO maintains complete files of fact sheets
for reference and review. In parallel, the draft fact sheet will
be submitted to the NERL Communications Office, which
will send a final copy of it to ORD Senior management and
will maintain a file that includes the fact sheet.
The fact sheet must include the follow ing five categories
of information.
(1) Impact Statement: Explain why this research is
important to the Agency, emphasizing the benefits to
be gained.
(2) Background: Explain why this research is being
conducted.
(3) Study Description: Provide a brief, nontechnical
description.
(4) Timeline: Include projected starting and closing
dates and the current status of IRB and EPA review.
(5) Contact: Provide name. NERL division, e-mail
address, and telephone number of the contact person.
4.1.10 NERL Sign-Off Sheet
The required sign-off sheet can be found in Appendix D.
The names of all reviewers should be typed or printed and
approving officials should sign the sheet.
4.1.11 Cover Memorandum
The PI should prepare a memorandum to the EPA HRPO
requesting review of the protocol by the HSRRO. The request
should be routed through the Pi's Branch Chief and Division
Director. It should briefly describe the study and the role of
NERL in the study and should list the complete contents of
the accompanying protocol package.
4.2 Process for Review and Approval
of a Typical NERL Study Design and
Human Subjects Research
Protocol Package
For studies in NERL involving human subjects, an integrated
approach will be follow ed for preparation of the study design
and human subjects research protocol package, as described
in the SEAOES document. Section 4.1.1 "NERL Study
Design" and section 2 of SEAOES describe "Elements To Be
Considered in Study Conceptualization and Planning" and
provide the recommended approach for developing the study
documents and for independent scientific and ethical review.
The document stresses tliat the consideration of scientific and
ethical issues be addressed concurrently. The entire package of
documentation for a human subjects research study in NERL
is prepared and reviewed in stages by the NERL division,
the IRB. and EPA. All required reviews and responses are
obtained in writing, and approvals are recorded on the NERL
sign-off sheet or other supporting documentation. Appendix B
contains a flow diagram of the process.
• Step 1: Study Design and Human Subjects
Research Protocol Preparation
To facilitate scientific and ethical review, the PI and
research team members should develop a comprehensive
and detailed study design that describes the technical
approach for the study. Elements that may be included
in the study design document are described in section
4.1.1 "NERL Study Design" and section 2 of SE AOES.
Concurrently, and follow ing the instructions of the IRB
of record, the PI and Co-Is will prepare drafts of
the human subjects research protocol and the informed
consent form. The PI and research team will develop the
proposed study design and address ethical considerations
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in collaboration with other technical stall, stakeholders,
community representatives (as appropriate), statisticians,
the branch and division QA stall, and the branch
and division management. As part of the study design
document, the PI and research team will include
a section or appendix on "Considerations for Protection
of Human Subjects in the Study" that includes elements
described in SE AOES and summarized in Appendix C
of this guidance document.
• Step 2: Initial Reviews
After completion of the draft study design, the PI
must obtain at least two internal technical reviews
prior to submission of the study design document to the
Branch Chief. The PI must then provide written
responses to the reviewers' comments and revise the
study design, if necessary. The Branch Chief will review
the study design and determine if it is acceptable for
external peer review.
• Step 3: External Peer Reviews
For all NERL human subjects research, an external
peer review of the study design must be completed. The
Pi's division will establish the policies and procedures
for conducting the external peer review. The PI. in
consultation with the Branch Chief, will prepare a plan
for external peer review. The plan will be submitted to
the Division Director for approval. Following approval,
the PI will proceed with the external peer review. As
described above, external reviews must be formal,
written comments by experts in the field. The PI should
provide a written response to each comment in the
review, indicating whether the changes suggested by the
reviewer have been made and. if not. why not. Following
the external peer review, the PI will revise the study
design as required and prepare the human subjects
research protocol that will be submitted to the IRB.
The entire package, to include the study design, human
studies research protocol, informed consent form,
brochures, advertising, and other materials to be used
in the study will be assembled into the research
protocol package.
• Step 4: NERL Human Subjects Advisory
Panel Review
The complete study design and human subjects research
protocol package will be reviewed by a NERL
Human Subjects Advisory Panel prior to submitting
the package to the IRB. The panel will consist of the
NERL Associate Director for Health, the Pi's Division
Director, the Pi's Branch Chief, and at least one
additional NERL staff member designated by the NERL
Associate Director for Health. The panel will serve
primarily in an advisory role, reviewing the research
protocol, meeting with the PI to discuss the study,
and providing verbal and written comments to the PI.
Recommendations from this panel should be considered
by the PI. and changes made to the research protocol
package, as appropriate, prior to submitting the package
to the IRB. The PI also should obtain concurrence from
the Branch Chief and Division Director prior to
submitting the package to the IRB.
• Step 5: IRB Approval
Follow ing concurrence by the Branch Chief and
Division Director, the package will be submitted to the
IRB for review.
• Step 6: Branch Chief and Division Review
Follow ing receipt of IRB approval, the PI should submit
the complete protocol package, including all components
described above at the beginning of this section, to the
Branch Chief for approval. The Branch Chief will
transmit the package with approval to the Division
Director for final NERL approval. The PI then will
incorporate any necessary changes into the protocol
prior to resubmission of the package to the IRB
(if required) and to the HRPO for consideration.
• Step 7: Administrative Approval
The package next will be reviewed and approved by
the Director of the HRPO. If any changes in the protocol
or consent form are required during this portion of
the EPA review process, the amended protocol must be
resubmitted to the UNC IRB or to the IRB of record
for the study for approval. After final HRPO review, the
completed package is to be copied to the PI and Division
Director. The Director of the HRPO then will forward
the complete protocol package to the EPA HSRRO for
final Agency review and approval.
The HRPO requires one copy of the complete protocol
and completed sign-off slieet for record keeping
and tracking.
• Step 8: Study Commencement
Recruitment of human subjects can begin only after the
Agency HSRRO sends a memorandum of approval to
the HRPO Director and the PI. Copies of this
memorandum must be distributed to the Branch Chief.
Division Director, and the Associate Director for Health.
• Step 9: Record Management
The HRPO maintains the official file for approvals and
ethics oversight of all human subjects research projects
Follow ing initial approval, the PI must ensure that
the HRPO is provided copies of all documents needed
to maintain a complete and current file, including but
not limited to copies of all protocol amendments and
renewals, current stamped consent forms, questionnaires,
advertising materials. IRB approval letters, and reports
of adverse events.
In short. If sent to the IRB, send a complete copy to
the HRPO. If sent by the IRB, send a complete copy
to the HRPO.
4.3 Protocol Review Procedures for
Special Cases
The procedure for preparation, review, and approval of human
subjects research may differ from that specified above in the
following special cases.
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4.3.1 Studies Not Meeting the Definition
of Human Subjects Research
Before beginning an investigation using either data or tissue
involving human subjects, the investigator should consult the
HRPO Director to determine whether the proposed research
is subject to EPA Regulation 40 CFR 26. The rules governing
that decision are complex. Some studies will be considered
human subjects research and. therefore, are subject to 40 CFR
26 and require a complete protocol package. Other similar
studies may not be human subjects research, are not subject to
40 CFR 26, and do not require a typical protocol package.
No protocol package is required for human research
activities that do not meet the regulatory definition of human
subjects research. Instead, the PI must write a memo, routed
through the Pi's Branch Chief and Division Director, to the
HRPO Director describing the study and the reasons why
the proposed research is not human subjects research (see
Appendix A). The HRPO must concur in writing before such
research can proceed. In the event of uncertainty as to whether
a study is human subjects research, further consultation
with the IRB of record and/or the Agency HSRRO will be
conducted by the Director of the HRPO.
4.3.2 Exempt Human Subject Research
Some protocols may be determined to be human subjects
research but are still exempt from 40 CFR 26. 40 CFR 26,
section 26.101, lists the exemption categories and the criteria
that apply to them, for example:
40 CFR 26.101(b)(4): Research, involving the collection
or study of existing data, documents, records,
pathological specimens, or diagnostic specimens, if these
sources are publicly available or if the information is
recorded by the investigator in such a manner that
subjects cannot be identified, directly or through
identifiers linked to the subjects.
Pis should consult their Branch Chief first for guidance
regarding classification of human subjects research as exempt.
Exempt human subjects research will not require IRB review
or assembly of a protocol package but still will require a
formal exemption determination by the Agency HSRRO
before the study can proceed. The Director of the HRPO will
help facilitate review by the Agency HSRRO. The PI must
write a memo, routed through the Pi's Branch Chief. Division
Director, and HRPO Director, to the EPA HSRRO describing
the study and requesting approval as exempt human subjects
research (see Appendix A).
4.3.3 Waiver of Informed Consent
Occasionally, human subjects research may qualify for a
waiver of informed consent. This is granted by the IRB. For
NERL research protocols, this is usually because the study
presents no more than minimal risk to the study subjects
and also meets the other criteria for waiver found at 40
CFR 26.116(c) or (d). In these cases, the PI should request a
waiver of informed consent from the IRB during the initial
application process. If the IRB grants the request, the PI. in
the cover memorandum to the Director of the HRPO. routed
through the Division Director, should include the reason for
requesting the waiver from the IRB.
As with all human subjects research studies, final approval
by the Agency HSRRO is still required before the study
can proceed.
4.4 Collaboration and Consultation on
Research Primarily Conducted Outside NERL
NERL investigators frequently collaborate or consult on
studies primarily conducted at other institutions, such
as other EPA laboratories, extramural contractors,
co-operators, government agencies, and universities. Note that
collaboration, as defined below, implies that EPA is engaged
in the research under the regulations, whereas consultation
does not.
Collaboration means involvement as a Co-PI or Co-I. the
possession of or access to identifiable private information, or
interaction or intervention with subjects. Collaboration by a
NERL investigator means that EPA is engaged in the human
subjects research under the regulations and requires NERL
approval. Decisions of whether an individual is a consultant
or collaborator will be made by the HRPO Director in
consultation with the PI. Branch Chief, and Division Director.
The HRPO director may consult the Agency HSRRO for
guidance in complex situations.
Consultation, on the other hand, implies less direct
involvement with a study, no interaction or intervention
with subjects, and no possession of identifiable private
information. Consultants may, on occasion, be co-authors
on publications, but their involvement is typically not at the
same level as tliat of collaborators. Consultation by a NERL
investigator does not mean that EPA is engaged in research
under the regulations and. thus, does not cause the same
regulatory requirements to kick in.
Further guidance on engagement can be found at the DHHS
Office of Human Research Protections Web site. htto://www.
hhs.gov/ohrp/humansubiects/assurance/engage.htm.
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5.0
OBSERVATIONAL HUMAN EXPOSURE STUDIES
Observational human exposure studies are conducted by
researchers in NERL to improve our understanding of when,
why, and how people come into contact with chemicals and
other stressors in their everyday environments. These studies
ty pically involve measurements of chemicals in the food
people eat. the water they drink, the air they breathe, and dust
on the surfaces they touch. In addition, information about the
study participants and their homes, work environments, and
activities are collected, as well as biomonitoring samples.
Results of these studies are used by the Agency to develop
exposure and risk assessments and. as necessary, risk
mitigation strategies. Although observational studies do not
involve intentional exposures, there are many scientific and
ethical issues that need to be considered in designing and
conducting these complex studies. Because they involve both
adults and children who volunteer to participate in the studies,
protections must be appropriate for both types of participants.
NERL has prepared the SEAOES document as a
resource of information for researchers planning and
implementing observational exposure studies. Researchers
planning observational exposure studies are to use the
recommendations in SE AOES as they develop their study
design and human subjects research protocol. These same
recommendations also are to be used by second-party
researchers funded by NERL.
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6.0
INTENTIONAL EXPOSURE STUDIES
40 CFR 26, Subpart B defines research involving intentional
exposure of a human subject as the "study of a substance
in which the exposure to the substance experienced by a
human subject participating in the study would not have
occurred but for the human subject's participation in the
study". One consequence of this definition is that "scripted"
studies generally will fall within the category of research
involving the intentional exposure of human subjects. Scripted
studies are those studies during which measurements are
performed while a participant is asked to perform specified
activities. An example would be a study in which participants
consume a diet containing food items that arc determined
and specified by the research because they may. or may not.
contain chemicals of interest to the researchers. Another
example would be a script for daily activities, including
cooking, cleaning, and other routine activities, during which
measurements of pollutants are made. Although these may be
routine activities that would probably be performed by a study
participant anyway, the scripting of such activities, instead of
allowing them to occur naturally, causes the research to fall
within the category of "intentional exposure," as defined in
40 CFR 26. Many "intervention" studies also will meet the
regulatory definition of "intentional exposure."
Researchers considering studies involving intentional
exposure of human subjects should consult with the HRPO
to discuss the potential study and study design prior to
developing the study design. The HRPO. in consultation with
the EPA HSRRO. will make a determination as to whether a
proposed study is an intentional exposure study. If the study
is determined to be an intentional exposure study, the HRPO
will advise the PI of special requirements for the human
subjects research protocol.
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7.0
STUDY OF HUMAN DATA, HUMAN TISSUES,
AND ENVIRONMENTAL SAMPLES COLLECTED
IN HUMAN SUBJECTS RESEARCH
7.1 Purpose
Before beginning an investigation using human data, human
tissues or samples, or environmental samples from another
study involving human subjects, the researcher must consult
the HRPO Director to determine whether the proposed
research is human subjects research, non-human subjects
research, or exempt human subjects research. The rules
governing the decision arc complex. Some studies will be
considered human subjects research and. therefore, are subject
to 40 CFR 26 and require a complete NERL protocol package.
Other studies may be similar, except for a slight nuance, and
considered non-human subjects research or exempt human
subjects research and. therefore, not subject to 40 CFR 26 and
not requiring a standard NERL protocol package.
Even if an IRES has decided that a particular study is exempt
from further review, only the Agency HSRRO has final
authority over whether or not a study is exempt and whether
or not it will be subject to 40 CFR 26.
7.2 Definitions
Human tissue is defined as any cells, cell lines, fluids, or other
biological tissues originally collected from a living person.
Environmental samples may include samples such as indoor
or outdoor soil, water, dust, surface wipe samples, diet
samples (solid food and/or beverages), and air
monitoring samples.
7.3 Genetic Studies
As with many types of biological research, the possibility
of identifying individuals with disease susceptibility may
occur, especially in studies that correlate genetic changes or
biomarkers with susceptibility to specific disease states. Such
studies must have stringent safeguards for subject privacy
and confidentiality. Most IRBs have specific requirements for
the use of human material in genetic studies, especially with
respect to informed consent.
7.4 Stored Specimens
There are several categories of stored specimens collected in
human subjects research, including specimens to be stored
for previously stipulated tests; for as-yet-undesignated tests,
but excluding genetic studies; for as-yet-undesignated tests
that may include genetic studies, with personal identifiers
accompanying the specimen; and for as-yet-undesignated
tests that may include genetic studies, but with no associated
personal identifiers. Each category has specific requirements
for protection of the research subject.
7.5 Specimens Obtained from Other
Researchers or Commercial Tissue Banks
Many opportunities exist for researchers to obtain specimens
of human origin from other colleagues or from commercial
tissue banks. A guiding principle is that the PI should only use
specimens that were obtained in an ethical manner.
In some circumstances, the HRPO Director may require proof
of IRES approval of the protocol being used to procure, store,
and distribute the specimens or contracts/bills of sale for the
specimens. The PI must notify the HRPO Director before any
research is initiated involving any human specimens.
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8.0
ADVERSE EVENTS AND UNEXPECTED EVENTS
Even the most careful researcher using a well-thought-out
protocol may have a research subject who has an adverse or
unexpected event during participation in a research study.
Below is the text from the UNC IRB Standard Operating
Procedures Manual on the definitions and reporting
requirements associated with an adverse or
unexpected event.
8.1 Definitions
"Adverse event" or "adverse experience" is an undesirable
and unintended, though not necessarily unanticipated, injury
or physical or emotional consequence to a human subject.
"Serious Adverse Events" (SAEs) are those that are fatal or
life threatening; result in significant or persistent disability;
require or prolong hospitalization; result in a congenital
anomaly/birth defect; or. in the opinion of the investigators,
represent other significant hazards or potentially serious harm
to research subjects or others.
"Unexpected" or "unanticipated" refers to adverse events
or other problems in the research where the nature and/
or severity are not consistent with the information already
provided to the IRB. including the investigator's brochure,
research protocol, or consent form.
"Unanticipated Problems" (UPs) may or may not include
specific events experienced by individual subjects, but are
developments within the research activity that suggest a
potential for increased risks to subjects or others.
8.2 Serious Adverse Events and
Unanticipated Problems Occurring at Sites
for Which a UNC-Chapel Hill IRB Has
Direct Oversight Responsibility
In case of an SAE or an UP, the PI is required to submit a
written report to the IRB. with the time frame for the report
depending on the type of event being reported. The Pi's report
should contain enough information for the IRB to judge
whether or not the event raises new questions about risks to
participants or the research design. This report is reviewed by
one or more experienced IRB members (typically including
the chair), and a decision is made as to whether or not
the report should be presented and discussed at a
convened meeting.
In case of an adverse event tliat is both serious and
unanticipated that occurs at a site for which a UNC IRB has
direct oversight responsibility, the PI must notify the IRB
within 24 h (or by the next working day).
In case of an adverse event tliat is serious but not
unanticipated, the PI must notify the IRB within 5 working
days.
In case of an adverse event tliat is not serious, but is
unanticipated, the PI must notify the IRB within 10 working
days.
In case of an UP involving risks to subjects or others but not
meeting the definition of an adverse event, the PI must notify
the IRB within 10 working days.
In multicenter studies, at sites outside the jurisdiction of
the UNC IRB. investigators are required to report adverse
experiences that occur in subjects enrolled elsewhere (i.e., by
non-University investigators) only when the adverse event
is both serious and unexpected. However, sponsors often
require tliat adverse events that do not meet these criteria
be reported to the IRB. and the investigator should do so.
Documentation of such reports will be filed in the IRB file
after review by a chair or a designated individual. The chair,
at his/her discretion, may add review of these reports as an
agenda item at a convened meeting. For multisite studies
in which a Data and Safety Monitoring Board (DSMB) is
performing aggregate analysis of adverse events, the IRB
should receive a copy of the DSMB report. The following
table summarizes IRB reporting timelines for SAEs and UPs.
8.3 Adverse Event Written Report
The adverse event written report submitted to the IRB must
contain the following information.
• IRB study number
• Title of protocol
• Name of PI and relevant department, division or center
• Subject identifier (study number/reference of subject)
• Date and site of event
• Description of event (nature of injury or other adverse
occurrence, assessment of severity, and assessment of
relationship to study)
• Handling/response to the event
Event type
Adverse
Adverse
Adverse
Non adverse
Serious
Unanticipated
Report within
24 hrs or next working day
5 working days
10 working days
10 working days
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• Any proposed changes in protocol or consent form due
to event
• To whom else the event has been reported
• Signature of PI
8.4 IRB Responsibilities Following Receipt
of Serious Adverse Event/Unanticipated
Problem Report
The chair or a designated subcommittee of the IRB will
review the SAE/UP and will decide whether the report should
be presented and discussed at a convened meeting. If an
adverse event occurring at the University is related to the
study intervention and is both serious and unanticipated, the
IRB will notify the Institutional Official and the event will be
reviewed by the IRB at a convened meeting.
If an SAE or UP poses serious risk to subject safety, the chair
or designated subcommittee may immediately suspend the
study before presenting the report to the convened meeting.
If the IRB suspends or terminates a study due to an SAE or
UP, it must notify the Institutional Official, who, in turn, is
responsible for making any required reports to the appropriate
Federal regulatory agencies.
If this unanticipated SAE is a death or serious injury, the IRB
must notify the University's General Counsel immediately
after it receives notification.
It is the investigator's responsibility to make all required
reports of adverse events to the FDA and/or sponsor.
Investigators may have additional reporting responsibilities
outlined in individual contracts that are not covered by
this procedure.
References:
45 CFR 46.103(b)(5)(i)
45 CFR 46.111(a)(6)
45 CFR 46.113
21 CFR 56.108(b)(1)
21 CFR 312.32
21 CFR 312.64 (b)
21 CFR 314.80
21 CFR 812.150 (a)(1)
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9.0
NERL EMPLOYEES AS RESEARCH SUBJECTS
Because the protection of human research subjects is a
high priority throughout EPA, protections extend to NERL
employees who choose to experiment on themselves,
participate in NERL human studies, or request co-workers to
take part in these studies.
9.1 Purpose
This chapter describes additional requirements governing
the participation of ERA employees as subjects in human
research activities.
9.2 Requirements for Participation of an EPA
Employee as a Research Subject
For any research activity meeting the definition of human
subjects research in 40 CFR 26 or EPA Order 1000.17A,
Change A1, EPA employees participating as subjects
are subject to the following additional guidelines and
requirements.
• Employees are very strongly discouraged from
conducting research on themselves. Alternatives to using
employees include identifying subjects through an
approved recruitment mechanism or procuring
anonymous specimens from internal or external
specimen banks. The HRPO can assist investigators in
identifying resources for suitable subjects or specimens.
• There cannot be direct or indirect coercion of employees
to participate as research subjects in NERL
investigations. Supervisors cannot ask employees they
supervise to participate as subjects in EPA research
studies.
• No employee may participate as a subject in human
subjects research that circumvents oversight by an IRES
or by Agency review and approval procedures.
• All employees must go through the same screening
process required for nonemployee subjects, including
identical inclusion and exclusion criteria for participation
and signing informed consent.
• The study protocol must contain a statement of the
expected number and duration of time periods that the
employee will be expected to spend in the study. A copy
of this statement must be provided to the employee. The
consent form must appropriately cover additional
liability issues, if any, that are generated by employee
participation either on his/her own time or on
government time.
• An employee who feels that his or her rights have been
breached or to whom an injury has occurred should
contact the HRPO Director, and/or the Chairman of the
IRES at the telephone numbers listed in the consent form.
9.3 EPA Employees in Non-Human Subjects
Research Activities
Some activities involving human subjects are not human
subjects research because they do not meet the definition of
research. Such studies are not subject to 40 CFR 26 and do
not require approval by the Agency HSRRO. The decision as
to whether a human research activity meets the definition of
human subjects research is made by the HRPO Director, with
input, if necessary, from the appropriate IRES or the
Agency HSRRO.
For some procedures that involve very low risk of personal
injury and low risk of ethical mistreatment, an EPA PI may
be granted permission to participate as a subject or to include
other EPA employees as subjects. To obtain this permission,
the PI must write a memorandum describing the non-human
subjects research activity, including risks, and the reasons
the activity does not meet the definition of human subjects
research. The memorandum must be sent through the Branch
Chief to the HRPO Director and must be approved by both
before the study can begin.
The following collections and procedures may fall into
this category.
• Human exposure air monitoring samples and data from
active or passive monitors
• Indoor or outdoor air monitoring data or samples from
active or passive monitors
• Indoor or outdoor soil, water, dust, or other
environmental media samples
• Breast milk samples
• Breath collection
• Buccal specimens
• Dermal wipes
• Fecal specimens
• Hair specimens
• Nail specimens
• Nasal lavage
• Spontaneously generated sputum
• Saliva collection
• Urine specimens
• Routine pulmonary function (spirometry and body
plethysmography)
• Blood pressure
• Pulse oximetry
• Heart rate variability
The Director of the HRPO may make additions or deletions
as needed.
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Note that several common types of samples, including venous
blood samples, are not included. Venipuncture is more
invasive and can have more significant consequences than
the other listed procedures. Semen samples are not included
because of issues concerning privacy and embarrassment
surrounding the collection process. Neither genetic analyses
nor other analyses that may yield sensitive or potentially
unfavorable information may be performed on any samples
collected under this category unless the samples are pooled
or are otherwise completely anonymous, with no means of
determining the identity of the donors.
9.4 Survey Questionnaires
For questionnaire completion by employees to be allowed
without OMB review, the following conditions must be met.
• When employees are administered questionnaires to
evaluate questions and/or the time needed for
completion, individual answers to questions cannot
be entered and stored in a database. Only evaluative
information, such as suggested changes in wording,
format, or time to completion can be collected.
• Answers to individual questions from employee
questionnaires may be entered and stored in a
database if. and only if. the questionnaires are
completely anonymous, and the identity of the
employees cannot be determined by other means.
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LIST OF ACRONYMS AND ABBREVIATIONS
BC
Branch Chief
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CITI
Collaborative Institutional Training
Initiative
Co-I
Co-investigator
CRADA
Cooperative Research and Development
Agreement
DD
Division Director
DHHS
Department of Health and Human
Services
DSMB
Data and Safety Monitoring Board
EPA
U.S. Environmental Protection Agency
FDA
Food and Drug Administration
FIFRA
Federal Insecticide, Fungicide, and
Rodenticide Act
FWA
Federal Wide Assurance
HIPAA
Health Insurance Portability and
Accountability Act
HRPO
Human Research Protocol Office
HSRB
Human Studies Review Board
HSRRO
Human Subjects Research Review Official
ICR
Information Collection Request
IRB
Institutional Review Board
NERL
National Exposure Research Laboratory
NIH
National Institutes of Health
OMB
Office of Management and Budget
ORD
Office of Research and Development
PHI
Private health information
PI
Principal investigator
PO
Project Officer
QA
Quality assurance
SAE
Serious adverse event
SEAOES
Scientific and Ethical Approaches for
Observational Exposure Studies
UNC
University of North Carolina
UP
Unanticipated problem
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APPENDIX A
TEMPLATES FOR MEMORANDUMS
FOR HUMAN SUBJECTS RESEARCH REQUESTS
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, NC 27711
OFFICE OF
RESEARCH AND DEVELOPMENT
MEMORANDUM
Date:
Subject: Request for Study Approval as Non-Human Subjects Research
From:
Through:To: XXXXXXXXXXXXXXXXXXXXX
Director, Human Research Protocol Office
CC:
This section should contain the following information.
• Description of the study—Two to three paragraphs
describing the reason for the study and a description of
the methods and samples required for the study. List
who is involved in the research, what roles they will
fulfill in the study, and what access to samples or data
they will require.
• What identifiers will be collected with the data (or
provided with the samples if purchased from a
commercial vendor or from another outside source), and
what identifiers the research team will have access to.
- Does the contract or bill of sale from the samples
include language that specifically states that no
personal identifying data will ever be shared with
users of the samples?
- Will the samples be provided with a code? Often
this code can be traced back to the sample donors,
so researchers obtaining these samples must de-link
the provided code with the samples by randomizing
the samples to make them anonymous.
• A request that the research be classified as non-human
subjects research.
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, NC 27711
OFFICE OF
RESEARCH AND DEVELOPMENT
MEMORANDUM
Date:
Subject: Request for Study Approval as Exempt Human Subjects Research
From:
Through:
Through: XXXXXXXXXXXXXXXXXXXXXX
Director, Human Research Protocol Office
To: XXXXXXXXXXXXX
EPA Human Subjects Research Review Official
CC:
This section should contain the following information.
• Description of the study—Two to three paragraphs
describing the reason for the study and a description of
the methods and samples required for the study. List
who is involved in the research, what roles they will
fulfill in the study, and what access to samples or data
they will require.
• What identifiers will be collected with the data (or
provided with the samples if purchased from a
commercial vendor or from another outside source), and
what identifiers the research team will have access to.
• Under what section of 26.101 (b) the exemption will
be classified?
• A request that the research be classified as exempt
human subjects research.
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APPENDIX B
FLOW DIAGRAM FOR THE NERL REVIEW PROCESS
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APPENDIX C
GUIDANCE FOR PREPARATION OF THE SECTION OR APPENDIX
ON "CONSIDERATIONS FOR PROTECTION OF HUMAN SUBJECTS
IN THE STUDY"
To facilitate the NERL internal scientific and ethical review
of a study design for an observational exposure study, the
study design document must include a section or appendix
entitled "Considerations for Protection of Human Subjects
in the Study." The section should discuss the approaches
that the researchers intend to follow to address potential
ethical issues in the design and implementation of the study.
This section or appendix may reference specific sections
of the study design document or briefly describe how the
researchers have addressed the scientific and ethical issues
identified in the SEAOES document. If an element identified
in SEAOES is not relevant to the study being proposed, the
researchers should describe why the element does not need
to be addressed. The recommended outline for this section
or appendix of the study design is presented below with
reference to the relevant sections of the document.
Study Element
SEAOES
Section
1.0 Elements To Be Considered in Study Conceptualization and Planning
2
1.1 Justification for the Proposed Study—Define the study problem, science questions to be
addressed, study objectives, and/or hypotheses to be tested. Describe the scientific justification for
the study, including relevance, need for the data, etc.
2.1
1.2 Justification for Including Human Subjects in the Research
2.1.2
1.3 Ensuring Scientific Validity of the Research Study—Include a brief overview of the study
design and detailed discussions of the approaches for determining feasibility, sample size, and
representativeness of the sample.
2.2
1.4 Ethical Issues in Ensuring Fair Subject Selection
2.3
1.5 Ensuring a Favorable Risk-Benefit Ratio—Discuss benefits and risks to participants and
approach for maximizing benefits to the participants.
2.4
1.6 Scientific and Ethical Reviews—Discuss plan for internal and external reviews.
2.5
1.7 Conflicts of 1 nterest
2.5.2
1.8 Considerations for Ensuring That Participant Behaviors Are Not Changed Adversely Because of
Being in the Study
2.7
1.9 Proposed Approaches for Monitoring Scientific and Ethical Issues During the Study
2.8
2.0 Ensuring Protection of Vulnerable Groups
3
2.1 Identification of Vulnerable Groups in the Study
3.1
2.2 Justification for Involving Vulnerable Persons in the Study
3.2
2.3 Consideration of Special Requirements for Vulnerable Groups (Children, Women, Other)
3.4-3.6
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Study Element
SEAOES
Section
3.0 Privacy, Confidentiality, and Other Concerns Related to Observational Human Exposure Studies
4
3.1 Privacy Issues
4.1
3.2 Confidentiality of Information and Participation
4.2
3.3 Non-Study Hazards with Mandated Reporting Requirements—Describe plans for identifying,
addressing, and reporting (including hazard communication and staff training).
4.3
3.4 Other Non-Study Hazards—Describe plans for identifying, addressing, and reporting.
4.3
3.5 Third Party Issues—Describe plans for identifying third parties and issues, addressing issues,
and reporting/communications.
4.4
3.6 Plans for Data and Safety Monitoring and Oversight (See also section 1.9 above)
4.5
4.0 Creating an Appropriate Relationship Between the Participant and Researcher
5
4.1 Informed Consent Process—Describe approaches for information, comprehension, and voluntary
participation.
5.1
4.2 Payments to Research Participants—Describe type, amount, justification, basis for payment
type and amounts, and comparison to similar studies; describe how payments will not serve as
inducements or change behavior in the study; describe special considerations for studies with
children and other vulnerable groups.
5.2
4.3 Research Rights and Grievance Procedures
5.3
4.4 Recruitment Strategies—Ethical Considerations
5.5 and 5.7
4.5 Retention Strategies—Ethical Considerations
5.6 and 5.7
5.0 Building and Maintaining Appropriate Community and Stakeholder Relationships
6
5.1 Proposed Approach(es) to Community Involvement
6.1
5.2 Issues in Community Involvement—Describe considerations and issues as identified in SEAOES.
6.2
5.3 Other Stakeholders—Describe approach for identifying, interacting with, and communicating
with stakeholders other than the community.
6.4
6.0 Designing and Implementing Strategies for Effective Communication
7
6.1 Communication Strategy and Implementation Plan—Describe the general approach and
communication strategy, individuals and groups involved, and timeline for completing the
communication plan.
7.1-7.5
6.2 Communications with Study Participants—Describe approaches and plans for communications
and reporting during all phases of the study.
7.6
6.3 Communications with the Community—Describe approaches and plans for communications and
reporting during all phases of the study.
7.6
6.4 Communications with Other Stakeholders, the Public, and the Media—Describe approaches and
plans for communications and reporting during all phases of the study.
7.6-7.10
6.5 Reporting Unanticipated Results or Observations—Describe special considerations and the
approach for determining "reporting levels."
7.8
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APPENDIX D
NERL HUMAN RESEARCH SIGN-OFF SHEET
PI (Name/Division):
PROTOCOL TITLE:
NAME OF APPROVING IRB:
IRB-ASSIGNED PROTOCOL NUMBER:
REVIEWS (Attach to EPA Protocol Package)
Reviewer
Signature
Date
Peer Reviewer 1 (printed or typed)
Peer Reviewer 1 (printed or typed)
Other
APPROVALS
Official
Signature
Date
NERL Advisory Panel (AD for Health)
IRB
(Attach signed approval letter)
Branch Chief
Division Quality Assurance Officer
Division Director
HRPO Director
(Indicated by approval letter)
Agency Human Subjects Research
Review Official
(Indicated by approval letter)
Revised June 2009
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&EPA
United States
Environmental Protection
Agency
Office of Research arid Development (8101R)
Washington, DC 20460
Official Business
Penalty for Private Use
$300
Recycled/Recyclable Printed on paper that contains a minimum of
50% posteonsumer fiber content processed chlorine free
PRESORTED STANDARD
POSTAGE & FEES PAID
EPA
PERMIT NO.G-35
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