Response to Public Comments on the External Review Draft Document
“Scientific and Ethical Approaches for Observational Exposure
Studies” Posted on Docket Number EPA-HQ-ORD-2007-0972

Prepared by the National Exposure Research Laboratory, Office of
Research and Development, U.S. Environmental Protection Agency, Research
Triangle Park, NC.

The external review draft of the document titled “Scientific and
Ethical Approaches for Observational Exposure Studies” was made
available for public review and comment on October 4, 2007. 
Availability of the document was announced in a Federal Register notice
on that date.  A 45-day public comment period was opened and the
document was made available on Docket Number EPA-HQ-ORD-2007-0972. 
Concurrently, the document was provided to EPA’s Human Studies Review
Board (HSRB), a Federal advisory committee, for external peer review. 
The comments from the HSRB were submitted to the EPA in their final
meeting report available on the HSRB website at   HYPERLINK
"http://www.epa.gov/osa/hsrb/"  www.epa.gov/osa/hsrb.    Following
receipt of the HSRB comments and the public comments, the draft document
was revised.  A response to the HSRB comments was prepared and submitted
to the Designated Federal Officer (DFO) who posted the response on the
docket for the HSRB.

Public comments were received from the American Academy of Pediatrics;
Syngenta Crop Protection, Inc.; and Ms. Ruth Ketvirtis.  These comments
are still available on the Docket Number EPA-HQ-ORD-2007-0972.  The
comment by Ms. Ketvirtis referenced comments from the Public Employees
for Environmental Responsibility (PEER) that were posted on that
organization’s website rather than on the docket.  Nonetheless, EPA is
also responding to the comments from PEER in this document.

The authors appreciate the commenters’ interest in the document and
the input provided in the form of the public comments.  These comments
were considered in revision of the document, which has been finalized
and published as an EPA report (EPA/600/R-08/062).

The comments from the American Academy of Pediatrics were supportive of
EPA’s effort to develop this document.  We appreciate their comments
and concur with them that the document will “…serve as a valuable
resource to investigators in designing ethically and scientifically
sound observational exposure studies.”

The following discussion presents the response to comments from Syngenta
Crop Protection, Ms. Ketvirtis, and PEER.  The response is formatted
based on the relevant sections of the document. 

Section 1. Introduction, Purpose, and Scope of the Document

Comment: PEER  commented that there was a lack of “…authoritative
guidance…” and that “…it is not clear what the purpose of the
document is or how it adds in any substantive way to published training
manuals or other prescriptive advice issued by others...”  Nor was it
clear to the commenter “…why this non-guidance research document is
being circulated for public comment…”  

Response:  The revised document further clarifies the purpose and the
process for preparation of the document.  As stated in Section 1, 

The purpose of this document is to provide information that researchers
in EPA’s Office of Research and Development’s NERL can use in the
design and implementation of observational human exposure studies to
ensure the protection of the human study participants. It is intended to
be a resource tool for NERL’s exposure science researchers, but it is
not intended to serve as a “guidelines” document or a “how-to”
checklist. This document does not meet the Office of Management and
Budget (OMB) definition for an official Agency ‘guidance document”
(“Guidance document - an agency statement of general applicability and
future effect, other than a regulatory action … that sets forth a
policy on a statutory, regulatory or technical issue or an
interpretation of a statutory or regulatory issue’)… 

ddressed as NERL researchers plan and implement observational human
exposure studies. The researchers will need to work with others ― the
study team, institutional review board members, EPA’s Human Subjects
Research Review Official, the participants and their community, and
other stakeholders ― to identify and address all of the relevant
issues for any particular study. The authors are confident that this
document will be helpful to NERL scientists in their endeavors to assure
that all of NERL’s observational human exposure studies will respect,
safeguard, and protect the participants in that research.

 The document adds, in a substantive way, to existing EPA policies and
guidelines because it brings together, in a single document, information
on approaches and procedures that researchers will use in design and
implementation of observational human exposure studies.  The document
contains extensive lists and bibliographic citations for sources of
information on ethical principles, standards, and considerations
relevant to observational studies involving human participants.  

The external review draft of the document was circulated for public
comment as part of an open and transparent process for preparation of
the document and to ensure that the document addresses concerns of
potential users and stakeholders.  The processes for collecting input
for the document and preparation of the document are described in
Section 1 and Appendix B of the final document.

Comment:  PEER commented that the document does not discuss the issues
that led to the controversy surrounding the Children’s Environmental
Exposure Research Study that was cancelled by EPA in 2005.

Response:  When developing the plan for the “Scientific and Ethical
Approaches for Observational Exposure Studies” (SEAOES) document,
input was solicited on the scope and content of the document.  A series
of meetings with stakeholders was held prior to starting preparation of
the document to get input on the scope and content.  On November 28-29,
2006, EPA held a Workshop to discuss the proposed document.  As
described in Section 1 and Appendix B of the final SEAOES document,
eleven nationally-recognized experts convened as an independent panel to
provide input on development and content of the proposed
state-of-the-science document.  The panel recommended that the document
include the six subject areas that are now included in the document as
Sections 2 through 7.  The panel discussed the value of using the
Children’s Environmental Exposure Research Study as a case study.  As
stated in the Workshop report, “The panel ultimately agreed that while
case studies can be useful, this document should not emphasize CHEERS as
a case study.  They noted that CHEERS was a complex political problem
that would require a great deal of careful analysis to reach
conclusions.”  Analyses of the issues and lessons to be learned from
CHEERS have been published in the open literature by outside experts in
human subjects research ethics, independent of EPA.  These analyses and
details on lessons learned were published by Resnik DB, Wing S, 2007,
“Lessons learned from the Children's Environmental Exposure Research
Study,” Am J Public Health 97(3):414-8; and Menikoff J, 2005, “Of
babies, bugs, and bombast: A look behind the crash-and-burn of the
CHEERS pesticide study,” Medical Research & Law Policy Report
4(14):586-512.  Theses analyses are recognized and cited in the SEAOES
document.  The issues identified in these analyses are addressed in the
SEAOES document and recommendations from these sources have been
incorporated in the document, especially in the sections on community
involvement, informed consent, the relationship between researchers and
participants, and data and safety monitoring and oversight throughout
the study.  The document appropriately addresses issues that were of
concern in CHEERS.  Additional analysis of CHEERS, as a case study, was
not necessary to meet the objectives and goals of the document.  Rather,
such an analysis would have made the document longer, more complex, and
of less value for the researchers who will use the SEAOES document in
the future.

Comment:  There were several comments from PEER and one from Ms.
Ketvirtis that pertained to research involving intentional exposure of
human subjects.

Response:  The document does not address research or studies involving
intentional exposure of human subjects.  It specifically, and only,
addresses observational human exposure studies, as is made very clear
throughout the document.  The Introduction, Purpose, and Scope (Section
1) provides a clear description of the purpose of the document and the
definitions of the terminology.  The text in the document is
supplemented in Appendix A by additional discussion of terminology and
the distinction between intentional exposure research and observational
exposure studies. 

Section 2. Elements to be Considered in Study Conceptualization and
Planning

Comment: PEER commented that “…the draft ignores situations where
the scientist knows the true dangers to the “daily life” activities
especially when those activities involve exposure to potentially harmful
chemicals, like pesticides.”

Response:  The issue is addressed in Section 2 in the subsection on
“Assessing Benefits and Risks of Study Participation” and in the
Section 5 discussion of information that should be included in the
informed consent.  Rather than ignoring the situations cited by the
commenter, the document directly addresses the issue in Section 5.1.1,
where the document states that “In observational human exposure
studies, information about the risks of the hazards being studied needs
to be conveyed to the participants during the consent process.
Information should be provided to the study participant on what hazards
pertinent to the topic of the study may be present in the
participant’s environment, particularly those microenvironments being
studied, what hazards will continue to exist in those microenvironments
after the research is completed, and how those hazards may adversely
affect the participant’s health.”  

	This recommendation is consistent with the recommendations of the NRC &
IOM committee in regard to the issue of the researcher’s ethical
responsibilities regarding the social circumstances that they study. As
described in Section 2 of the SEAOES document, the joint NRC & IOM
committee on research on housing-related health hazards involving
children discussed the ethical arguments that arise when scientists
conduct research that observes children in poor-quality housing. They
concluded that, properly applied, the ethical principle of beneficence
does indeed direct researchers who observe serious harms to child
subjects to take steps to try to prevent the harms. However, they also
argue that the researcher’s duty does not extend to “personally and
directly prevent harm by removing the child from the harmful
environment” (p. 60, NRC & IOM, 2005). They concluded instead that
“it is unrealistic and unfair to hold individual research
investigators responsible for ameliorating the social circumstances that
they study” and that “a nuanced balancing of the benefits and risks
of research” is an ethically sound approach that is firmly established
in Federal regulations (p. 60, NRC & IOM, 2005). 

Comment: Under its comment that “Minimal risk” May Include Dangerous
Behaviors in Observational Studies,” PEER raises a concern that
“When presented with the opportunity to participate in a study for
payment, people may continue behavior or exposure which they have been
informed is potentially harmful…The burden should therefore be on the
Agency to make sure that its research does not allow for these unethical
scenarios.” 

Response:  Section 2 of the SEAOES document discuses the issue in
sections on “Assessing Benefits and Risks of Study Participation”
and “Ensuring that Participant Behaviors are not Adversely Changed
Because of Being in the Study” and in two sub-sections of Section 5
(“Payments to Research Participants” and “Ensuring Recruitment or
Retention Methods Will Not Lead to Unacceptable Risk”).  The
sub-section on payments provides information on developing payment plans
to avoid undue economic inducement for participation in a research
study.  The information presented in the document clearly stresses that
identifying potential for changes in behavior as a result of being in a
research study is an important issue to be addressed by researchers as
they design observational exposure studies.  Information is presented to
help researchers address the issue, but there are no clearly defined
approaches applicable in all situations.  The approaches used will be
study-specific.  The document strongly recommends that researchers work
with community representatives and IRBs to identify potential issues and
to develop approaches that will minimize this potential problem.  

Comment:  “The draft implies that conflicts of interest (no matter how
large) will be permitted so long as they are disclosed…”

Response:  Actual conflicts of interest are never permitted.  We have
revised the relevant section of the document to make that clear.  No
human subjects research may be conducted or funded by EPA without both
IRB and the EPA HSRRO approval, and that approval will only be granted
if the IRB finds that all conflicts of interest have been resolved. 

Section 3. Ensuring Protection of Vulnerable Groups

Comment:  A concern was expressed in a public comment from Syngenta Crop
Protection, Inc.  that the definition of “potentially” vulnerable
groups was so broad that scientists may not be able to study a
representative population of people for exposure to environmental
chemicals and that it may be difficult to find human volunteers who do
not belong to these groups.

Response:  The comment seems to presume that the definition of
vulnerable populations leads to a prohibition of the inclusion of
vulnerable populations in observational research.  That is not the case,
either in the regulations governing EPA’s human subjects research (40
CFR 26) or in the text of the SEAOES document.  Neither the regulations
nor the SEAOES document prohibits the inclusion of vulnerable
populations in observational studies.  Both sources do, however, set
expectations for justifying the inclusion of the vulnerable population
and for assuring that that they are afforded additional protections. 
The information presented and discussed in the SEAOES document (Section
3.2, “Justification for Involving Vulnerable Persons in Observational
Studies”) and in the subsequent subsections is consistent with the
commenter’s recommendation that vulnerable populations should be
considered for inclusion in observational research when their
participation is “critical to the science” and only when “their
rights as human subjects under the ‘common rule’ are highly
protected.”  The document identifies concerns that exclusion of
vulnerable groups from research studies is not ethical and that failure
to conduct research with vulnerable groups may deprive them of the
benefits of research.  Revisions were made in the document in an attempt
to further clarify the issue of including vulnerable populations in
observational studies.

Comment:  PEER commented that there was “only Passing Reference to
Need for Protecting Prisoners and Other Captive Populations” and
“Subjects of Special Vulnerability Given Short Shrift.”

Response:  Section 3, titled “Ensuring Protection of Vulnerable
Groups,” is devoted to this topic.  Furthermore, one of the seven
sections of the document is included specifically to ensure that
researchers understand and address the special requirements for
including vulnerable groups in observational exposure studies. 
Prisoners are included in the discussion of vulnerable groups.  A large
number of references are provided to further assist the researchers on
this topic.

Sections 4 and 5. Relationships Between Researchers and Participants in
Observational Studies 

Comment:  Syngenta Crop Protection, Inc. commented that “The policy or
procedure of observing and reporting collateral observations is
inconsistent with one of the basic principles of the Belmont Report
(1979), the purpose of which is to promote respect for persons.  The
ethical elements of privacy and confidentiality cannot be maintained in
a research study that requires that an investigator report collateral
observations…The long-term effect of the scientific community
attempting to recruit potential study participants into observational
exposure studies where the investigator will report ‘collateral
observations’ would likely be a substantial reduction in the pool of
study participants for such important research projects…Collateral
observations by an investigator are also quite subjective and could
depend on the cultural background of the individual investigator…”

Response:  Collateral observations are discussed in Section 4, which
addresses “Potential Non-Study Hazards in the Residence” and
“Collateral Observations with Mandated Reporting Requirements.” 
Ethicists recognize that there may be justified infringements of rules
of confidentiality.  As stated by Beauchamp and Childress, Principles of
Biomedical Ethics, 2001, p. 308), if circumstances warrant that “a
person is not entitled to confidentiality, disclosure is sometimes
permissible and at other times even obligatory. Obligations to divulge
confidential information most commonly emerge when third parties face
serious dangers.”  The SEAOES document recommends that researchers
carefully plan for possible collateral observations, including their
identification, staff training, and hazard communication and reporting. 
Some collateral observations, such as child or elder abuse or evidence
of abuse or neglect, have statutory requirements for reporting to
designated authorities.  Other types of collateral observations may
include hazards with the potential for physical injury to study
participants or third parties.  The authors of the document recognize
that there may be situations in which confidentiality may be breached
and state in the introductory paragraph of Section 4.3 that
“…Potential participants should be informed of situations in which
confidentiality may be breached, such as statutory requirements of
reporting abuse or imminent harm to self or others.”  The document
also states that “Researchers should include the reporting
requirements in the informed consent form (discussed in Section 5) and
should ensure that the study participant fully comprehends this
information and the impact on their privacy and confidentiality.”  The
recommendations in the SEAOES document are consistent with the
recommendations in the NRC & IOM, 2005 report that researchers should
consider the foreseeable observations and potential hazards in advance,
develop responses to the hazardous conditions, and submit the proposed
plans to the IRB for review to ensure that they are appropriate “in
the context of the research and the affected community.” (See
discussion in SEAOES Section 4.3.1.) The authors of the SEAOES document
consider this approach, together with disclosure in the informed consent
process, to be ethically sound and consistent with the Belmont Report
and with the Code of Federal Regulations.  The document stresses that
staff be well-trained on the issue of collateral observations and that
researchers work with community representatives to identify potential
hazards that may be observed that are relevant to the study population
and community in which the research is being performed.  Although, as
the commenter states correctly, there may be a substantial reduction in
the pool of study participants willing to participate if they know
collateral observations will be made, this approach is ethically sound
and a justifiably high standard for researchers to meet.

Comment:  A comment from PEER stated that “…this draft provides no
coherent advice about payment to participants…At the very least, the
Agency should adopt the NAS recommendation by setting requirements that
payments to participants be duly considered by all reviewing officials
and people involved with the study.”

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0the commenter’s recommendation regarding review of payment programs,
which are part of required research protocols that are reviewed by
internal NERL review panels, the Institutional Review Board, and EPA’s
Human Subjects Research Review Official. 

Notice:  The final document, Scientific and Ethical Approaches for
Observational Exposure Studies, is available at the website,   HYPERLINK
"http://www.epa.gov/nerl/sots"  www.epa.gov/nerl/sots . 

For additional information, contact:

Roy Fortmann, Ph.D.

Human Exposure and Atmospheric Sciences Division

National Exposure Research Laboratory

Office of Research and Development

Research Triangle Park, NC 27711

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