Protection of Human
              Subjects in EPA's
                 Research and
         Non-Research Studies
           September 26 - 29, 2005
     REGION
DEVELOPMENT

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          Protection of Human Subjects in EPA's Research
                      and Non-Research Studies

                         Silver Cloud Hotel - Broadway
                               1100 Broadway
                             Seattle, WA 98122

                           September 26 - 29, 2005

                                Agenda
MONDAY, SEPTEMBER 26,2005 (DAY ONE) t

PM Moderators: Roseanne Lorenzana and Barbara Lither

1:00 - 2:00 p.m.           Sign-In at Workshop Registration Desk and Pick Up
                        Meeting Materials - (Broadway Room)

2:00 - 2:15 p.m.           Opening Remarks - Welcome and Introduction

2:15 - 2:30 p.m.           Objectives of the Workshop
                        Speaker: Roseanne Lorenzana, EPA Region 10

2:30 - 3:30 p.m.           Human Subjects Research (Common Rule, EPA Order
                        1000.17, Change 1A, Current Agency Practices,
                        Clarification of Definitions, EPA Use of Data From Third
                        Parties, Genetic Information and Selecting an IRB)
                        Speakers: Peter Preuss, ORD-NCEA, and Richard Hermann,
                        ORD-NHEERL

3:30 - 4:30 p.m.           The Role of the Institutional Review Board (IRB)
                        Speaker: Helen McGough, University of Washington IRB

4:30 - 6:30 p.m.           Meet & Greet Mixer (light refreshments provided)

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Tuesday, September 27, 2005 (Day Two)
AM Moderators: Patti Tyler and Joel Hansel
7:45- 8:15 a.m.
Continental Breakfast
8:15-8:30 a.m.

8:30-9:30 a.m.
9:30-10:45 a.m.
10:45-11:00 a.m.
Highlights From Yesterday, Review of Tuesday Agenda

Federalwide Assurance and Selecting an Institutional
Review Board
Speaker: Rebecca Calderon, Director Human Studies
Division, ORD-NHEERL

NHEERL Policy and Guidance
Speaker: Richard Hermann, Director, Human Research
Protocol Office, ORD-NHEERL

Break
11:00 a.m.-12:00 noon
Panel Discussion:  NHEERL and NERL investigators
involved in human research studies
Speakers: Rebecca Calderon, Bob Devlin, Dandle Lobdell,
Don Graff, ORD-NHEERL, and Kent Thomas, ORD-NERL
12:00 noon-1:00 p.m.      Lunch
PM Moderators: Amanda Hasty and Gilberto Alvarez
1:00-1:30 p.m.
1:30-2:00 p.m.
Managing Grants and Contracts Under the Interagency
Grants Management System (IGMS)
Speaker: Armina Nolan, Region 10, Grants Office

Determination of Human Subjects Research vs. Public
Health Practice
Speaker: Roger Cortesi, ORD-NCEA

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2:00-2:30 p.m.           Information/Responsibility Flow
                         Speaker:  Peter Preuss, EPA HSRRO and Director, ORD-
                         NCEA

2:30 - 2:45 p.m.           Break (light refreshments provided)

2:45 - 3:30 p.m.           Interactions Between EPA and ATSDR
                         Speaker:  Dr. Anne Sowell, CDC/ATSDR, National Center for
                         Environmental Health

3:30 - 5:00 p.m.           Open Forum/Panel Discussion With Q&A With
                         Speakers/Experts From Previous Sessions

Wednesday, September 28, 2005 (Day Three)

AM Moderators: Jean Zodrow and Maryann Suero

7:30 - 8:00 a.m.           Continental Breakfast

8:00 - 8:15 a.m.           Highlights From Yesterday, Review Wednesday Agenda

8:15-9:15 a.m.           Presentation and Discussion on Human Subjects Studies
                         Conducted by Regions:

                         •   Libby, MT (Aubrey Miller, Region 8)
                         •   Pacific Islander Seafood Consumption (Ruth Sechena,
                             University of Washington)
                         •   Human Mercury Biomonitoring in Alaska (Pat Cirone,
                             Region 10)
                         •   Children's Asthma Study in Idaho (Don Cole as presented
                             by
                             Roseanne Lorenzana, Region 10)

9:15 - 9:45 a.m.           Regional Case Studies - Q&A

9:45 - 10:00 a.m.          Break
                                                                              in

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10:00 a.m. - 12:00 noon     Breakout Groups- see "Breakout Session Agenda" page in
                         notebook
                         Participants in pre-assigned groups (Locations: Group 1 -
                         Broadway; Group 2 - Madison/East; Group 3 -Boardroom;
                         Group 4 - Madison/West)

12:00 noon-1:00 p.m.      Lunch

PM Moderators: Margaret Jones and Bruce Macler

1:00 - 2:00 p.m.            Breakout Groups - continue morning session

2:00 - 3:00 p.m.            Group 1 (Madison Room) - Being a Child in an
                         Epidemiologic Study (concurrent sessions)
                         Speakers: Rebecca Calderon andDanelle Lobdell, ORD-
                         NHEERL

                         Group 2 (Broadway Room) - Ozone Study - Being in a
                         Clinical  Study
                         Speakers: Bob Devlin and Don Graff, ORD-NHEERL

3:00 - 3:15 p.m.            Break (light refreshments provided)

3:15-4:15 p.m.            The Power of Perception: A Broader Perspective on Risk
                         Communication
                         Speaker: Alvin Chun, ORD, Office of the Administrator

4:15-5:00 p.m.            Open Forum - Additional Q&A Session for Regional Case-
                         Studies or Breakout Groups

Thursday, September 29, 2005 (Day Four)

AM Moderators: Alicia Alto and Suzanne Wuerthele

7:30 - 8:00 a.m.            Continental Breakfast
                                                                            iv

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8:00-8:15 a.m.

8:15-9:30a.m.
9:30-10:30 a.m.
10:30-10:45 a.m.
Highlights From Yesterday, Review of Thursday Agenda

Special Protections for Children, Fetus, Elderly, Lower
Socioeconomic Groups, English as a Second Language
Groups
Speaker: David G. Forster, Western IRB and University of
Washington

Overview of the Proposed Third Party Rule
Speaker: Ann'e Lindsay, Deputy Director for Programs,
Office of Pesticide Programs

Break
10:45-11:15 a.m.
Where To Go for Help - Overview
Speaker: Jean Zodrow, Region 10
11:15 a.m. - 12:00 noon    Draft Recommendations and Proposed Next Steps
12:00 noon
Adjourn

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                              List of Acronyms

AAHRPP     Association for the Accreditation of Human Research Protection Programs
ATSDR      Agency for Toxic Substances and Disease Registry
CDC         Centers for Disease Control and Prevention
FERPA      Federal Educational Rights and Privacy Act
FIFRA       Federal Insecticide, Fungicide, and Rodenticide Act
FOIA        Freedom of Information Act
FWA        Federal Wide Assurance
GAO        General Accounting Office
HIPAA      Health Insurance Portability and Accountability Act
HRPO       Human Research Protocol Office
HSR         human subjects research
HSRB       Human Studies Review Board
HSRRO      Human Subjects Research Review Official
IGMS        Interagency Grants Management System
IRB          Institutional Review Board
NAS         National Academy of Sciences
NCEA       National Center for Environmental Assessment
NCER       National Center for Environmental Research
NGOs       nongovernmental organizations
NHEERL     National Health and Environmental Effects Research Laboratory
NIH         National Institutes of Health
NIOSH      National Institute for Occupational Safety and Health
OHRP       Office of Human Research Protections
OPP         Office of Pesticide Programs
ORD         Office of Research and Development
PHS         Public Health Service
QAPP       Quality Assurance Project Plan
SAB         Science Advisory Board
WIRB       Western Institutional Review Board
                                                                              vi

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                                   Table of Contents

Agenda	i

List of Acronyms	vi

Summary	1

Monday. September 26, 2005 (Day One)
PM Moderators: Roseanne Lorenzana

Opening Remarks - Welcome and Introduction	4
   Roseanne Lorenzana

Objectives of the Workshop	.,	4
   Roseanne Lorenzana

Human Subjects Research (Common Rule, EPA Order 1000.17, Change 1A, Current
Agency Practices, Clarification of Definitions, EPA Use of Data From Third Parties,
Genetic Information and Selecting an Institutional Review Board (IRB))	;	10
   Peter Preuss and Richard Hermann
Questions and Answers	17

The Role of the IRB	22
   Helen McGough
Questions and Answers	24

Tuesday. September 27, 2005 (Day Two)
AM Moderators: Patti Tyler and Joel Hansel

Federal Wide Assurance and  Selecting an IRB	28
   Rebecca Calderon
Questions and Answers	29

NHEERL Policy and Guidance	36
   Richard Hermann
Questions and Answers	37

Panel Discussion: NHEERL and NERL Investigators Involved in Human Research Studies	38
   Rebecca Calderon, Bob Devlin, Danette Lobdell, Don Graff, Kent Thomas
Questions and Answers	38

PM Moderators: Amanda Hasty and Gilberto Alvarez

Managing Grants and Contracts Under the Interagency Grants Management System (IGMS)	42
   Armina Nolan
Questions and Answers	43

Determination of Human Subjects Research vs. Public Health Practice	45
   Roger Cortesi
Questions and Answers	46
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       vii

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Information/Responsibility Flow	49
    Peter Preuss
Questions and Answers	50

Interactions Between EPA and ATSDR	57
    Anne So-well
Questions and Answers	58

Open Forum/Panel Discussion With Q&A With Speakers/Experts From Previous Sessions	58

Wednesday, September 28, 2005 (Day Three)
AM Moderators: Jean Zodrow and Maryann Suero

Human Subjects Regional Case Studies:

Libby, Montana	66
    Aubrey Miller

Asian and Pacific Island Seafood Consumption Study in King County, Washington	70
    Ruth Sechena

Human Mercury Biomonitoring in Alaska	71
    Pat drone

Children's Asthma Study in Idaho.	:... 72
    Doug Cole

Regional Case Studies—Questions and Answers	,	72

Report Outs From Breakout Groups

Group 1 Recommendations	74
Group 2 Recommendations	74
Group 3 Recommendations	,	.75
Group 4 Recommendations	75

PM Moderators: Margaret Jones and Bruce Macler

Group 1 Presentation:  Being a Child in an Epidemiological Study	83
    Rebecca Calderon and Danelle Lobdell
Questions and Answers	84

Group 2 Presentation:  Ozone Study—Being in a Clinical Study	90
    Bob Devlin and Don Graff
Questions and Answers	97

The Power of Perception: A Broader Perspective on Risk Communication	 100
    Alvin Chun
Questions and Answers	100
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       viii

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Thursday, September 29. 2005 (Day Four)
AM Moderators: Alicia Alto and Suzanne Wuerthele

Special Protections for Children, Fetus, Elderly, Lower Socioeconomic Groups, English
as a Second Language Groups	112
   David Forster
Questions and Answers	113

Overview of the Proposed Third Party Rule	115
   Anne Lindsay
Questions and Answers	116

Where To Go for Help—Overview	118
   Jean Zodrow

Draft Recommendations and Proposed Next Steps	118

Appendix A: List of Resources	121
Appendix B: Participants List	128
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       ix

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Summary

The Workshop on the Protection of Human Subjects in EPA's Research and Public Health
Studies, organized by a cross-Agency planning group within the U.S. Environmental Protection
Agency (EPA), was the first meeting to bring together Regional and Program Office staff, and
ORD scientists to discuss the Regional activities that may be subject to human subjects review
and processes described in EPA's Order 1000.17, change 1A, (40CFR Part 26) Policies and
Procedures for the Protection of Human Subjects in Research Conducted or Supported by EPA
and the Federal Common Rule (40 CFR 26).

As part of the workshop objectives, draft recommendations were developed, and following the
workshop they have been finalized through the continuing work of those participants.  The
overall goal of the following workshop recommendations is to create a culture where the
protection of human subjects is the number one priority of EPA-conducted or funded studies,
regardless of whether they are research or public health practice.

1. Increase management attention on human subject research (HSR):

•  Briefing for Deputy Regional Administrators (DRA's) from Seattle Workshop participants
•  Briefing for DRAs and Regional Administrators (RAs) on Human Subjects Research (HSR)
   requirements by the Human Subjects Research Review Officical (HSRRO)
•  Develop  a briefing strategy for senior management
•  Identify HSR activities on EPA's tracking system.

2. Establish expertise or access to  expertise in each Region:

•  Regions to develop and implement interim guidance and process
•  Each Region to evaluate the extent of their involvement in Human Subjects Research and
   their needs for establishing a regional process for assuring compliance with the Common
   Rule and other applicable requirements. During this evaluation, the Regions may consider
   the need  for identifying a process that may include a Human Subjects Coordinator to serve as
   a central  point of contact in each Region. The Coordinator's role may include directing staff
   through the agency process for HSR; coordinating with the HSRRO in HQ and keeping
   current regarding HSR activities within the Region and across Regions.

3. Request  an opinion from the Office of General Counsel on the legal questions that were
   developed by the Workshop planning group:

•  Recommend that each Office of Regional Counsel designate a point of contact on HSR.

4. Provide  additional guidance for the Integrated Grants Management System (IGMS) to
   reflect the HSR determination and approval process:

•  The 12 Regional Grants Management Officers incorporate definition of HSR, its relevance to
   EPA's Grants Program, and its requirements into Project Officer training
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop

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•  Insert language into grant solicitations to define HSR and public health practice; to inform
   potential grantees of the necessity of Institutional Review Board (IRB) review prior to
   funding approval of HSR
•  Reconcile grant funding timelines with the HSR approval process; including consideration of
   provisional grant awards prior to HSR approval
•  Create a tracking system for HSR and public health practice grants
•  Modify Question 14 in IGMS, asking whether human subjects are involved, to include a
   following  question as to whether the study is HSR. If the answer is "yes," require approval
   by the Agency's HSRRO; if "no," require attachment of the Regional decision memo.

5.  Create a Council composed  of Human Subjects points of contact from each Region and
   National Program Office, and chaired by the Agency HSRRO to:

•  Develop consistent, written, Agency-wide guidance and policy for HSR and public health
   practice
•  Develop an Agency-wide human subjects training plan and program
•  Identify how to adapt the existing HSR tracking system for additional needs (e.g., query
   capability)
•  Communicate across the Agency new developments in HSR
•  Develop a HSR Web site, including a list of references and subject experts for public input
   and comment in the Federal Register
•  Explore the Workshop suggestion that EPA create its own accredited, independent IRB
•  Explore the Workshop suggestion to accredit IRBs used by the Agency.

6.  Workshop planning group to develop a straw proposal for the new HSRRO.

7.  Review and provide comments on the Proposed Rule for Protections for Subjects in
   Human Research.

8.  Ensure regional participation in determining specifics involved with implementing the
   Human Subjects Review Board required by EPA's 2006 Appropriations Act.

Meeting participants have continued to work on addressing the workshop recommendations.
There is much progress being made with the first recommendation with respect to increasing the
regional awareness of human subjects research. For the second recommendation, Appendix A
identifies contacts  for assistance with human subjects research issues. Specific regional contacts
for human subjects research issues also are provided.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop

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Day One

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                         U.S. Environmental Protection Agency
                                Office of Science Policy
                    Protection of Human Subjects in EPA's Research
                         and Non-Research Studies Workshop
                                 September 26-29, 2005
                                   Silver Cloud Hotel
                                     1100 Broadway
                                      Seattle, WA

                                  Meeting Summary

Monday, September 26, 2005 (Day One)

PM Moderators: Roseanne Lorenzana and Barbara Lither

Opening Remarks - Welcome and Introduction
Roseanne Lorenzana, EPA Region 10

Ann Williamson, Associate Director of Region 10's Office of Environmental Assessment,
welcomed everyone to the workshop and commended Roseanne Lorenzana, Patti Tyler, and Jean
Zodrow for their efforts in organizing the workshop. She pointed out that it took a team of about
20 individuals to coordinate this workshop, which answers a need to discuss the important issue
of human subject research (HSR) studies. She introduced Dr. Lorenzana, who gave an overview
of the logistics for this meeting, and thanked Ms. Tyler for all of her work in organizing the
workshop as well as the contractors from The Scientific Consulting Group, Inc.

Objectives of the Workshop
Roseanne Lorenzana, EPA Region 10

Dr. Lorenzana pointed out that the purpose of the Office of Research and Development (ORD)
regional workshops was to create connections between the Regions and ORD. She thanked
ORD staff for their efforts in planning the regional OSP science topic workshops. For more
information, she referred participants to EPA's intranet under "Region Workshop." The desired
workshop outcomes include an understanding of EPA Regions' activities that qualify as "human
subjects research"; the roles and responsibilities of EPA Regions and headquarters in the "HSR
approval process; the processes that HSR must undergo to obtain approval; processes, contacts,
and timeframes, as well as coordination and consistency approaches appropriate for EPA
Regions; the vulnerabilities and liabilities of EPA Regions' staff; how the EPA Regions can
provide better human subject study information; and EPA Regions' activities needed to protect
human subjects involved in Regions'non-research activities." She then presented peer awards to
the following individuals for their hard work in the planning efforts and also for advancing the
team's efforts: Alicia Aalto, Region 8; Gilberto Alvarez, Region 5; Barbara Barron, Region 8 (in
absentia); Rebecca Calderon, National Health and Environmental Effects Research Laboratory
(NHEERL); Alvin Chun, Region 9; Brenda Groskinsky, Region 7; Joel Hansel, Region 4;
Amanda Hasty, Region 8; Rich Hermann, NHEERL; Ariel Iglesias, Region 2; Margaret Jones,
Region 5; Barbara Lither, Region 10; Bruce Macler, Region 9; Wendy O'Brien, Region 8;
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop

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Maryanne Suero, Region 5; Patti Tyler, Region 8; Lee Tyner, Region 3 (in absentia); Winona
Victery, Region 9 (in absentia); Suzanne Wuerthele, Region 8; and Jean Zodrow, Region 10.

Dr. Lorenzana pointed out that the Regions did not have a shared knowledge of what defined a
human subjects study, or what is research, or what EPA does to protect human subjects. Many
of the participants had questions that were of a legal and/or policy nature. Participants were
encouraged to write down their questions, which the group could then request advice from the
Office of the General Counsel and for which responses could be provided at a future date.

Dr. Lorenzana explained that she saw Peter Preuss, Director of EPA's National Center for
Environmental Assessment (NCEA) in ORD, at a March 2005 Society of Toxicology Workshop
in New Orleans and asked him to hold a workshop on the issue of HSR studies. She introduced
him as an expert on risk assessment, priority, and law as well as being EPA's Human Subjects
Research Review Official (HSRRO). She pointed out that his presentation would attempt to
clarify the Common Rule as it pertains to HSR, Richard  Hermann also would speak on this topic
following Dr. Preuss' presentation.

Dr. Lorenzana informed the participants that Dr.  Hermann is board certified in clinical oncology,
has several years of experience in ethics, has worked at ORD's NHEERL, and now is the
Director of Human Research Protocol at NHEERL.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop

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                                                        What is Human Subjects Research?


                                                            Many different types of studies fall under
                                                            this heading:
                                                             -  Epidemiological studies
                                                             -  Surveys
                                                             -  Studies involving intentional exposures,
                                                               such as:
                                                               > Exposure and biomonitonng studies
                                                               > Metabolism
                                                               > Clinical trials
                                                               > Repellent efficacy tests

                                                            > -s.

  Value of Human Research
Human subjects research has been central to
many medical and public health advances
Human subjects research has been central at
the EPA for a number of key standards and
regulations, for example:
  - Ozone
  - Particulate matter



    Background and History
 I hue have hern othir^l ti insqras ions in the past such as,
Mudies cainrri out by the NVR during \A orlrl "Var II  ind the
 lus^get syphilis study
 Ihoso twnujiejsioiis. drnung olhor lliinqb led lo incrca^d
othi< al oversight or human oub|i ott. rcs,cdn h
Nuremberg Code (1917)
  Follow d N u\ iol rtoris
   > T/JG txp^///? ol i °hrulahu ^uf? as to iJdfiui1 ul icsulsiortl o
    looclafso aw i to tmblob) other n tndform€0nsQt$t(*a/
    nut n )t i n lorn 01 linn ) OS9 j/j in n ituro
Declaration of Helsinki (1964)
  Voild Mt ditil A sornlion l)e>
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  EPA Human Subjects Research:
            The
EPA follows the Common Rule (40 CFR 28),
EPA promulgated the ryle along with 17 other
Agencies and Departments in June 1991.
The internal Administration  of ihe Common Rule is
given by EPA Order 1000,17 (July 1999):
 - Poiic/os and Procedures for the Protection of Human
   Subjects in Research Conducted or Supported by 17PA.
 - This Order establishes a Human Subjects Research
   Review Official (HSRRO) to assure that all  EPA
   conducted or supported research using human subjects
   comports wilh the Common Rule
            The Common Rule (2)
                                                                   The Common Rule spcudf t, if quiit merits for approval by dti
                                                                   Institution il Rtvitv Bcwid (IRB) and infoimed content
   Die of the Common RU!P is. mandatory for reseaK h conduotf d 01
   sponsored by 18 signatories
   Use of the Common Rule by parties outside of the USC is not
   requned but rrw have some voluntary compliance
   Many private U fe institutions adopt C ommon Kulp standards for
   human subjocls rosodtUi
   fhe Common Ruk dulyof EPA is log<»t certification thai the
   re March has racoivod dppropnak. othic al review
   LPA goes furthei  LPA requires the I ISRRO to review jnd approve
   i>uch research before human i>ub|ectb can tx  involved This !•>
   done in addition to other institutional reviews

       EPA  Reviews under the



   On occasion, EPA has'decided that the IRB has
   overlooked possible risks to subjects. When this has
   happened, discussions have resolved the issue,
   On occasion, we have requested changes in the
   consent document.
   Over the past six years, EPA has averaged about fifty
   projects per year requiring decisions from the
   HSRRO.
   Of these a -.mail number have exposed people
   deliberately to environmental pollut ints
^ja^m^'mimamasammmimii&mamsmaiasitiamsumtsias.'mM,
      Examples of EPA Intentional Dosing
             Human Subject Research
    Piysiok'Cfjt ilrli nqo n hcnlthv vo In9 ^ iult  

cci to onc-optr Uud i n •. m partlclo COOl) i^eii'-sk HIIS ^pd jiiilj In (V jrif in 'umi b( in hid! aiiw ^ nif dnin-jioiy lespotl f in liumdi {''OQ \ I hy lolotjicdl v,h oonocf trtH cl d ribient dir o rtit i^ ind nurocsan ox de& (20f ^ A&be rn nt ot i rvvdy ph -i joc^ t Tunction in IH ^ t ty Indiv dUdU expo t d to coar mod air pollution pin clos (-001 ; Effete rolut-nc oxi osuic on nunnn igm! d ta tion (y'OOl ) Ph^ i logical cni!uhr indbioci mical ofioct o Die c1! Exn j t n hoilthy /OUIKJ /;lnn KHMS f ^001) Inff^f v / md vimlfrlt e )t Ci /plosporldiurn C f-rK)l>pw H oo > Is it hi illiiy PhdrrndcoKinetiMb of 13C Brotr odi hlofcricth ne ir nuiridn F hvsio!^ j\< -il t n iae In mild to mjd&rd'e ilhmiit1 ^xto fodto onoer altd inibtfa H d rpdrticle H-!9^) Cidiopulmonar rosoon Q ot p \tiuiiH with chron c oustructl /3 Itrq d 01 Q following expo u 0 to concentrated -sli p-litirh (t^9 ) What Is Human Subjects Research? What Are HSR Exemptions? sss*s s -WS n* Certain HSR activities may bo exempt from IRB review ! hose a« identified in 40CrR26 eg existing specimens or dald si ii vey procedures Many IRBs choose to review exempt HSR activities on an expedited bdsis> For EPA the HSRRO decicios whelhei a human subjects study is exempt not the puncipdl mve&ligdtoi or j pi oject officoi


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   Process for Conducting HSR at EPA
•Requirements apply to all situations where EPA
 staff or funding are used to conduct HSR.

•Applies equally to Headquarters and Regions
• HSR must follow the Common Rule and EPA
 Order1000.17

•HSR must have IRB approval

•HSR must have additional EPA approval from
 HSRRO
•Annual follow-up requirements on investigators
 through IRB
Process for Conducting HSR at EPA (2)
 Project officers provide the following paperwork,
 via the designated HSR coordinator in their
 laboratory, program or region, to Roger
 Cortesi/Peter Preuss (HSRRO):

   1 .  Federal Wide Assurance (FWA) number (institution and its
     associated IRB; http://wvifw.hhs.gov/ohrp/as3urances/)
   2.  Copy of IRB approval for research
   3.  Copy of consent forni(s)
   4.  Copy of research proposal and documentation provided to
     IRB
 Start early - return time ~2 weeks+
     Proposed Changes to HSR at EPA


   Some proposed HSR rule changes applicable to
   EPA conducted or sponsored research:
  •  Proposed categorical ban on all EPA intentional
     dosing studies of any environmental substance to
     children (<18) and pregnant women.
  •  Proposal that al! EPA intentional dosing studies of
     pesticides (banned in children and pregnant women)
     will need to be reviewed by the (to be constituted)
     Human Studies Review Board (HSRB)
  •  Proposed formal adoption of DHHS additional
     protections for Children (Subpart D), Pregnant
     Women and Fetuses (Subpart B) - already instituted
     informally at EPA,
     Third Party Human Studies


 "Third party" studies are those not
 conducted or sponsored by a U.S. federal
 agency. Third parties include:

  - State Agencies (California Air Resources Board)
  - Other national government1! (Health Canada,UK Medical
   Resodreh Council, European Commisbion)
  - International organisations (WHO  QhCD)
  - NCOs
  - Industry
  - Acailomia
  - Others

 Conditions of research (e.g., use of the
 Common Rule) may be unknown
   Third Party Human Studies (2)
    Third-party studies may be retrieved from the
    literature by EPA or submitted to EPA by others

    Third-party studies may be published or
    unpublished

    Third-party studies may, or may not, have been
    done in accord with Common Rule

    Third-party studies may, or may not, be peer
    reviewed

    Submitters of third-party studies may be regulated
    entities, public interest groups, or others

      Controversy Concerning

          PartyJHuman Research^_


  In 1998, the Environmental Working Group issued a
  report "The fnglibh Patients " that strongly cniic i/ed
  EPA's consideration of industry generated human
  studies on pesticides

  In response, EPA convened a SAB/SAP Ethics Panel
  to review OPP use of human subjects studios and
  procedures for accepting data from third parties
  (Report  September 2000)

  In fall of 2001 articles onticdl of EPA s approach to
  using human studies appeared in LA Times NV
  Times Washington Post, etc

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           Recent Controversy (2)
   Since the 1996 FQPA, Office of Pesticide Ptogiam*
   hat, received sonic 20 third paity intentional dosing
   studios of systemic toxicily in humans
    -  Funded by private industry with interest in pesticide
      legislation
    -  In geneial, intentional dosing of human subjects with
      small number of subject  limited bioacl  swontifk, int.
    -  Sludif" setup with metea-ing doae« to deiprrnint,
       f No Oh  erveJ Adverse Lifect Levels (NOAII) 01
       f I ownt OM was released February 2004

• Recommendations
   -  ( ttHtion of d boatU tu teview thy psotooolb and justification for al!
     intcmfionfsi "3o*uno studios c nnductod foi r PA rogui itoiy pui pose* *
   -  Adoption of Uomrnon Ruie Subp^rt D on rose art h involving {liildron
   -  Recommendation that there is tooiLtni benefit ftyrn  tudie^ that &e*-k
     t >impiu*'p thoacruiacy of! FAscotiSions but do not pro /idm
     pubiio health os environm *hta! benefit SL.  'rpu as they Cdn be
     reliably ^ntic spaleti to [K>S^ no idoniifwblo nsk io stuciy prirtK ipdnis
   -  At t,( ptdnc c* of s< lenlffK 3l!v v i!ici stucin^ oxiMn  o before1 new rules
     unlo* «s thorp i -. olosi  and < onvlnnng ovidonc p that the ronduc t of
     those ludies wrfb funddmontHiiy unelhiwl or thdt the conduct wab
     ci^fK tent rek-siive to then piev iHinQ othiod! stdnd srds
                                       ^^^^^?

EPA Proposed 3rd Party HSR Regulation


   •   Comprehensive rule adopting NAS recommendations for 3r" Party
      intentional dosing studies Intended tor submission under FIF-'RA.
   •   3ra Party intentional dosing studies of pesticides:
         must be conducted subject to the Common Rule;
      •   are banned^ in children and pregnant women;
         must be; reviewed by the EPA Human Studies Review Board
         (to be established)
   •   Study m roptribility rcinu"^!"f!{>n^
      •   Studii s conducted pnoi to the rult, will be evaluated against a
         sUiridaKl of not funddrnpnUslly unethic A\ 01 signifK anily l(^iK tent
         compared to the ethiral standaid« of the time
         Studies commenced attet the rule must have heen conducted
         consistent with fhc Common FSuio
      00 day publK comment process open
      http //w\v\v epa gov/oppfeadl/guidatlce/fedieg hs pdf
                                                                                                                                          4

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Human Subjects Research (Common Rule, EPA Order 1000.17, Change 1A, Current
Agency Practices, Clarification of Definitions, EPA Use of Data From Third Parties,
Genetic Information and Selecting an Institutional Review Board (IRB))
Peter Preuss, ORD-NCEA,  and Richard Hermann, ORD-NHEERL

Dr. Preuss informed attendees that he had received numerous e-mails (about 20-30 per day) from
the group organizing this workshop. He began his presentation by defining HSR and explained
that many different types of studies are included under this type of research such as
epidemiological studies, surveys, and studies involving intentional exposures (e.g., exposure and
biomonitoring studies, metabolism, clinical trials, and repellent efficacy tests). He added that
HSR has been central to many medical and public health advances as well as in establishing a
number of key standards and regulations at EPA for ozone and participate matter.  Dr. Preuss
gave some background and history on HSR, pointing out the ethical transgressions in such
studies as conducted by the Nazis during World War II and in the Tuskegee  Syphilis Study.
Such transgressions led to an increase in ethical oversight of HSR. The Nuremburg Code,
established in 1947, states that "The experiment should be such as to yield fruitful results for the
good of society, unprocurable by other methods or means of study, and not random or
unnecessary in nature." In addition, the Declaration of Helsinki, established in 1964, states "The
primary purpose of medical research involving human subjects is to improve.. .the understanding
of the etiology and pathogenesis of disease."

Dr. Preuss encouraged the workshop attendees to read The Belmont Report (1979), which
became the basis for all other U.S. human subjects ethics documents. The Belmont Report, he
added, was well thought out and based on three very important principles with regard to human
subjects studies:  (1) respect persons,  (2) conduct the studies equitably, and (3) include justice.
In addition, he provided an  overview  of the Common Rule (1991), which was developed jointly
by EPA and 17 other Agencies and describes what can and cannot be done as well as the
principles and practices that must be adhered to when the U.S. government is conducting or
supporting HSR. He then pointed out that EPA has different roles with HSR data. For example,
EPA performs or funds HSR studies in ORD laboratories, Program Offices and Regions, and
provides extramural funding through ORD  STAR grants.  All EPA HSR studies must comply
with the Common Rule. EPA also retrieves and uses data generated by third parties, but these
parties are not necessarily subject to the Common Rule. The internal administration of the
Common Rule is executed under EPA Order 1000.17 (July 1999). The Order establishes an
HSRRO to ensure that all EPA-conducted or -supported research using human subjects complies
with the Common Rule. The Common Rule gives requirements for approval by an Institutional
Review Board (IRB) and informed consent. On occasion, EPA has decided  that the IRB has
overlooked possible risks to subjects. In these cases, discussions usually resolve the issue. On
other occasions, EPA has requested changes in the consent document. In addition, EPA requires
that the HSRRO review and approve research before human subjects are involved in addition to
other institutional reviews.  It is the duty of EPA to get certification, meet the highest standards,
and ensure that the proposed research goes  through an IRB review and complies with the
Common Rule.  Over the past 6 years, EPA has averaged approximately 50 projects per year
requiring decisions from the HSRRO. Of these, only a very small number of projects have been
found to expose people deliberately to environmental pollutants.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      10

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Dr. Preuss discussed HSR exemptions and began by pointing out that certain activities may be
exempt from IRB review, which are defined in 40CFR26.101(b)(l)-(6) and include existing
specimens or data and survey procedures. Many of the IRBs choose to review exempt HSR
activities on an expedited basis.  EPA's HSRRO decides whether a human subjects study is
exempt, not the Principal Investigator (PI) or Project Officer (PO). As part of the process of
conducting HSR at EPA, he explained that the POs provide paperwork (i.e., Federal Wide
Assurance [FWA] number, copy of IRB approval for research, copy  of consent form(s), and
copy of research proposal and documentation provided to the IRB) via the designated HSR
coordinator in their laboratory, program, or Region, to Dr. Roger Cortesi and Dr. Preuss (EPA
HSRRO). Right now, Dr. Preuss is the only person in EPA who can determine if the proposed
research can be conducted; the Regions cannot make this determination.  EPA has proposed
some changes to HSR activities being conducted at EPA, including the following: (1) place a
categorical ban on all EPA intentional dosing studies of any environmental substance to children
(less than 18 years old) and pregnant women; (2) require that all EPA intentional dosing studies
of pesticides (banned in children and pregnant women) be reviewed by a new group, the Human
Studies Review Board (HSRB), which is being developed; and (3) encourage formal adoption of
DHHS additional protections for Children (Subpart D), Pregnant Women and Fetuses (Subpart
B), which is already instituted informally at EPA.

Dr. Preuss addressed concerns about third-party  human studies. Third-party studies, he clarified,
are those not conducted or sponsored by a U.S. federal agency and include state agencies, other
national governments, international organizations, nongovernmental organizations (NGOs),
industry, academia, and others.  In addition, he pointed out that the conditions of the research
might be unknown (i.e., whether the research followed the Common Rule). He referred to the
1998 Environmental Working Group report entitled "The English Patients" that strongly
criticized EPA's consideration of industry-generated human studies on pesticides. In response,
EPA convened an SAB/SAP Ethics Panel to review the Office of Pesticide Program's (OPP) use
of human subjects studies and procedures for accepting data from third parties. In fall 2001,
articles criticizing EPA's approach to using human studies appeared in the LA  Times, NY Times,
The Washington  Post, and other newspapers. OPP has received about 20 third-party intentional
dosing studies of systemic toxicity in humans, which were funded by private industry with an
interest in pesticide registration. Studies were set up with increasing doses to determine either
"no observed adverse effect levels" or "lowest observable effect levels." In February 2004, the
National Academy of Sciences (NAS) issued a report on "Intentional Human Dosing Studies for
EPA Regulatory Purposes." NAS recommended creation of a board to review the protocols and
justification for all intentional dosing studies conducted for EPA regulatory purposes; adoption
of Common Rule Subpart D on research involving children; acceptance of the societal benefit
from studies that seek to improve the accuracy of EPA's decisions but that do not provide a
public  health or environmental benefit as long as they can be presumed to pose no identifiable
risk to  study participants; and acceptance of scientifically valid studies existing before new rules
were established, unless  clear and convincing evidence exists that the conduct of those studies
was fundamentally unethical or that the conduct was deficient relative to then-prevailing ethical
standards. EPA proposed a comprehensive rule  adopting NAS recommendations regarding
third-party intentional dosing studies intended for submission under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA). Study acceptability requirements include that studies
conducted before the existence of the Common Rule be evaluated against a standard of not


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      H

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fundamentally unethical or significantly deficient as compared to the ethical standards of the
time, and studies begun after the Rule must have been conducted in compliance with the
Common Rule.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      12

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                                                                         Why are we here?

                                                              To protect the safety, confidentiality, privacy,
                                                              and respect of our research volunteers
                                                              Our system for protecting human subjects has
                                                              come under intense scrutiny
                                                              Several reports suggest lack of knowledge or
                                                              understanding on part of investigators, IRBs,
                                                              Institutional officials
                                                              Increased penalties for non-compliance
                                                              Erosion of public trust
                                                              New mandates for ethics training
Department of Health and Human Services
  Office of Human Research Protections
          ' Determination Letters
 May 2, 2005
 May 19, 2005
 May 23, 2005

 June 29, 2005

 July 19, 2005
 July 28, 2005
August 5, 2005  Unjve
August 18, 2005 y3m8te.ol.l
August 18, 2005 UQtt
August 25, 2005 NM!SC§ilflaB»teLOf.H«a|tt).
          Does 45 CFR 46 Apply?
                                                            Human Subject Research?
45 CFR 46 Does
Not Apply
Exempt?]'

 HSRRO
45 CFR 48
Does Not Apply


45 CFR 46
Applies HI!
 What is Human Subjects Research?

 Research
  - means a systematic investigation, including research
   development, testing, and evaluation, designed to
   develop or contribute to aeneralizable knowledge.

 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.
           Identifiable information
 The identity of the subject is or may readily be
   ascertained by the investigator or associated
   with the information.


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             Private Information

Information about behavior that occurs in a context
  in which an individual can reasonably expect
  that no observation or recording is taking place,
  and information which has been provided for
  specific purposes by an individual and which the
  individual can reasonably expect will not be
  made public( for example, a medical record)
               Subject Identifiers
Health Insurance Portability and Accountability Act of 1996
                     (HIPAA)

    Names
    Telephone numbers
    Any elements of dates (other than year if less than 89)
    for dates directly related to an individual, including birth
    date, admission date, discharge date, date of death.
    Any geographic subdivisions smaller than a State,
    including street address, city, county, precinct, zip
    code and their equivalent geocodes, except for the
    initial three digits of a zip code
•    Fax numbers

         Subject Identifiers (cont'd)
                      HiPAA

    Electronic mail addresses
    Social security numbers
    Medical record numbers
    Health plan beneficiary numbers
    Account numbers
    Certificate/license numbers
    Vehicle identifiers and serial numbers (VIN), including
    license plate numbers
    Device identifiers and serial numbers (e.g., implanted
    medical device)
         Subject Identifiers (cont'd)
                      HIPAA

  Web universal resource locators (URLs)
  Internet protocol (IP) address numbers
  Biometric identifiers, including finger and voice prints
  Full face photographic images and any comparable
  images
  Any other unique identifying number, characteristic or
  code, other than dummy identifiers that are not derived
  from actual identifiers and for which the re-identification
  key is maintained by the health care provider and not
  disclosed to the researcher
             "De-identified" Data


  Data contains none of the 18 identifiers listed in
  HIPAA about the individual, employers, or
  household members	OR	
  Expert opinion that the risk of individual
  identification is very small
  Examples:
   - Data about how many times a procedure is performed
     on patients by age range
   - Patient health outcomes, age and sex with no
     individual identifiers
             "Exempt" Research

                 45CFR46,101(b)

  Common Rule lists 6 major categories:


   1)  Educational practices, curricula
   2)  Educational tests, surveys, interviews, observation
      of public behavior
      • unless identifiers are present
      • unless risk of criminal or civil liability
      • unless risk of damage to finances, employment, or reputation
   3)  #2 if performed on elected officials or candidates

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             "Exempt" Research
                45CFR46.101(b)

4) Existing data, documents or specimens if publicly
   available or if investigator records in such a manner
   that subjects cannot be identified
5) Public benefit or service programs
6) Taste and food quality evaluation, consumer
   acceptance studies (provided approved by FDA,
   EPA, USDA)
  *** 'No exemptions If study Involves prisoners, fetuses, pregnant
  women, human in vitro fertilization, or some types of children's
  research

    Examples of Expedited Review

 Blood samples (routine methods, small
 amounts)
 Noninvasive collection of biological samples or
 clinical data (exm., hair, toenails, dietary history)
 Voice, video, digital recordings
 Individual or group behavior, surveys,
 interviews, oral histories
 Select types of continuing review
   Level of Risk Determines Level
             of iRB Review
More than Minimal Risk
Minimal Risk
                            Full Committee
                            Expedited
                    RISK

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Dr. Hermann listed several reasons behind organizing such a workshop, one of which is to
protect the safety, confidentiality, privacy, and respect of research volunteers.  Other reasons
include the fact that the system for protecting human subjects has come under intense scrutiny;
several reports suggest a lack of knowledge or understanding on the part of investigators, IRBs,
and institutional officials; there have been increased penalties for noncompliance with the
Common Rule; there is an erosion of public trust; and there are new mandates for ethics training.
Dr. Hermann pointed out that EPA took Subpart A of the Common Rule and made it formally
40CFR26. He added that the determination of what constitutes HSR and what is exempt are
decisions made by Dr. Preuss. He then defined the terms "research" and "human subject."
"Research" is a systematic investigation, including development, testing, and evaluation,
designed to develop or contribute to generalizable knowledge.  A "human subject" is a living
individual about whom an investigator (whether professional or student) conducting research
obtains data through intervention or interaction with the individual, or identifiable private
information.  He added that identifiable infoAnation allows for the identity of the subject to be
readily ascertained by the investigator or be associated with the information. Private information
about behavior is such that occurs in a context in which an individual can reasonably expect that
no observation or recording is taking place, information has been provided for specific purposes
by an individual, and that the individual can reasonably expect the information will not be made
public such as a medical record.

Dr. Hermann explained that there are several  subject identifiers, such as the following listed by
the Health Insurance Portability and Accountability .Act of 1996 (HIPAA): names; telephone
numbers; any elements of dates (other than year) directly related to an individual, including birth
date, admission date, discharge date, and date of death; any geographic subdivisions smaller than
a state, including street address, city, county,  precinct, zip code and their equivalent geocodes,
except for the initial three digits of a zip code; fax numbers; electronic mail addresses; social
security numbers; medical record numbers; health plan beneficiary numbers; account numbers;
certificate/license numbers; vehicle identifiers and serial numbers (VIN), including license plate
numbers; device identifiers and serial numbers (e.g.,  implanted medical device); Web universal
resource locators (URLs); Internet protocol (IP) address numbers; biometric identifiers,
including finger and voice prints; full face photographic images and any comparable images; and
any other unique identifying number, characteristic, or code,  other than dummy identifiers that
are not derived from actual identifiers and for which  the re-identification key is maintained by
the health care provider and not disclosed to the researcher. Dr. Hermann added that the
Common Rule lists  six major categories of "exempt" research: (1) educational practices and
curricula;  (2) educational tests, surveys, interviews, and observations of public behavior; unless
identifiers are present, there is risk of criminal or civil liability, or there is risk of damage to
finances, employment, or reputation; (3) #2 if performed on elected officials or candidates; (4)
existing data, documents, or specimens, if publicly available  or if the investigator records in such
a manner that subjects cannot be identified; (5)  public benefit or service programs; and (6) taste
and food quality evaluation,  and consumer acceptance studies (provided or approved by FDA,
EPA, USDA).  Dr. Cortesi commented that Office of Human Research Protections (OHRP) has
developed a list of what can be exempted. Dr. Hermann pointed out that the level of risk
determines the level of IRB review of an HSR study. He concluded his presentation by
providing examples of expedited reviews, including: blood samples (routine methods, small
amounts); noninvasive collection of biological samples or clinical data (hair, toenails,  dietary


         Protection of Human Subjects in EPA's  Research and Non-Research Studies Workshop        16

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history); voice, video, and digital recordings; individual or group behavior, surveys, interviews,
and oral histories; and select types of continuing review.

Questions and Answers

One question raised by an attendee asked who has the ultimate responsibility on making a
decision on whether a study is an HSR study. Dr. Preuss responded that either he or Dr. Cortesi
should be consulted about such matters, as well as on matters that may be exempt. He added that
he is the HSRRO for EPA and not just ORD. He has been advocating for the past 5 years that
the HSRRO task be rotated/assigned to another staff person. He noted that the Administrator
agreed to move the HSRRO out of ORD and into the Office of the Science Advisor. Another
question raised was about whether there would be something in writing that a study is exempt
from the Common Rule.  Dr. Preuss responded that written information would be provided, and
he pointed out that he is the only person who could make a decision whether a study is exempt.
He also added that later in the workshop Dr. Hermann will discuss what is exempt and what is
considered HSR.

An attendee asked if any other process was available other than going through an IRB and then
Dr. Preuss for approval.  Dr. Preuss clarified that the Common Rule does not call for an Agency
IRB. When a local institution sets up an IRB, it needs to be approved by DHHS, and it must
meet all of the requirements laid out in the Common Rule such as having at least five members
who would represent a broad spectrum of people.  He added that it appears that EPA is moving
in the direction of having an Agency IRB. Dr. Hermann pointed out that IHS has its own IRB
process. Dr. Cortesi commented that the Common Rule requires the Administrator to ensure that
research has been approved by the appropriate IRB. In addition, he  stated that many institutions
have given authority to their IRBs to decide what should be exempted.  Dr. Preuss added that the
Common Rule does not state that each Agency must have its own IRB;  most agencies do not
have their  own IRB. If he or Dr. Cortesi are consulted and the study is considered to be HSR,
then that researcher needs to go  through the process required at the institution where the research
will be conducted, such as preparing materials for the IRB (i.e., consent forms, protocols, etc.) to
get approval from that IRB. Most larger universities have multiple  IRBs so that cases can be
approved quickly.  Once  IRB approval is received, a copy of that letter should be submitted to
him and Dr. Cortesi, for review  and approval for, the work to begin.  If no difficult issues are
involved, the process should be  complete within 2 weeks. A comment was made that, at the
Centers for Disease Control and Prevention (CDC), grantees are not required to make the
exemption determination. If a project is proposed and it is determined that it is an exempt study,
it does not have to be submitted through the system for exemption determinations. Another
question arose regarding  whether genetic information from a small group such as a tribe would
be considered identifiable information, even if the tribe's name was  not attached to it.  Dr.
Hermann responded that  it could be considered identifiable information. He added that if the
right endpoints are available, then information might be identifiable. It is something to consider
when looking at any sort of outcome that could be easily linked to a smaller group of individuals.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       17

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                                                  Protecting Human Subjects is
                                                     a collective responsibility
                                                  • Researchers and research staff
                                                  • Institution's Human Subjects Protection
                                                   Program
                                                  • Sponsor
                                                  • Research subjects
                           1"'1''
        ,^B:  What is it?

 A group of people who meet face-to-face
 to evaluate research involving humans
 Membership:
 - At least 5 people
 - Not all one gender
 - At least one non-scientist
 - At least one scientist
 - At least one person unaffiliated with the
   institution hosting the 1KB
 institutional Responsibilities
• Institution supporting or conducting
  research must have an Assurance with US
  federal Office for Human Research
  Protections (CHRP)
  -Assurance may name its own IRB
   plus others                     ^am
  - Assurance may name only others
• Institutions bear full respon-
  sibility for all research involving   • ^ 5
  human subjects covered under
  their Assurance.              H I Si   '
 Institutional Responsibilities

• All requirements of 45 CFR 46 must be
 met for all EPA and other federally-
 sponsored research
• OHRP strongly encourages institutions to
 apply the HHS regulations regardless of
 sponsorship, and to commit to this
 standard in their Assurance.

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Institutional Responsibilities
Institutional Responsibilities
 Designate one or more Institutional Review
 Boards (IRBs) to review and approve all
 nonexempt research covered by an the
 Assurance
 Provide sufficient space and start to K.v pg
 support the IRB's review and record- K?£
 keeping duties                   "^r;M/s
 Ensure that appropriate Assurances and
 certificates of IRB review are submitted for
 all their federally sponsored research for
 their own site and for cooperating
 performance sites.
      Institutional Official

     • Authorized to act for the institution
       and assumes on behalf of the
       institution the obligations in the
     , Assurance
     • Sets the "tone" for an institutional
       culture of respect for human
       subjects
     • Knowledgeable point of     ,
       contact for OHRP          \ ";
      Institutional Official
 Appoints IRB members and Chair
 Provides IRB with necessary resources and
 staff                         I
 Supports IRB decisions         j
 Ensures effective institution-wide   ^
 communication and access to human'0"
 subject information
 Encourages participation in human subject
 educational activities
            IRB Chair

 Ensures IRB Carries Out its Responsibility
 — each approved protocol meets all
   requirements of 45CFR46
 Conducts or delegates expedited review of
 amendments or minimal risk, projects
 Keeps Institutional Official informed
 Educates IRB Members and       '
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Has the authority to suspend or terminate
previously approved research that is not
being conducted in accordance with the
IRB's requirements or that has been
associated with unexpected serious harm
to subjects.
 Must be familiar with:
 -the ethical principles of human subject
   research,
 -the requirements of the Federal regulations,
 - applicable state law,            .5?
 -the Institution's Assurance,:.-  •£•{
    md institutional policies     •<£
   and procedures for the     -M,
   protection of human      ^MP1^     ^_
   subjects.               .  '^l$y      7:

  Must have effective knowledge of
  - subject populations,
  - institutional constraints,
  -differing legal requirements, and
  - other factors which can       ^^
    foreseeably contribute to a   <
    determination of risks and
    benefits to subjects and
    subjects' informed consent.
Researcher/Research Staff

Has primary responsibility for protecting the
rights and welfare of human research
subjects and for complying with all
applicable provisions of their institution's
Assurance.
           Researcher

Must be familiar with:
- the ethical principles of human subject
  research,
— the requirements of the Federal regulations,
- applicable state law,
-the Institution's Assurance, and
- institutional policies and procedures for the
  protection of human subjects.      r
           Researcher

Conducts all research according to the
IRB approved protocol and complies with
all IRB determinations.
Ensures that each potential subject
understands the nature of the research
and of the subject's
             1                 maau
participation and takes
whatever steps are          g
necessary to gain that
comprehension.

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          Researcher

Provides a copy of the IRB-approved
informed consent document to each
subject at the time of consent, unless the
IRB has specifically waived this
requirement.
Retains all signed consent
documents according to    /
institutional policies, but at .>.'/  \'....*i&h;
least three years beyond   ifi. /. fa'jjr'1
the completion of the      (   •"
research.                   • _,-•
          Researcher
 Promptly reports proposed changes in
 previously approved human subject
 research activities to the IRB.
 Does not initiate changes without IRB
 review and approval, except where
 necessary to eliminate apparent immediate
 hazards to the subjects.
          Researcher
 Reports progress of approved research to
 the IRB, when and how the IRB requires,
 but not less than once per year.
 Promptly reports to the IRB any
 unanticipated problems involving  risks to
 subjects or others.
       Choosing an IRB

Must have an Assurance with OHRP if \
research is funded by EPA
If award is made to an institution, that
institution is responsible to provide IRB
review
If research involves more than one site:
- One IRB can conduct review if other sites
  enter into an agreement
- Each site may insist on site-level IRB review

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The Role of the IRB
Helen McGough, University of Washington IRB

Ms. Barbara Lither, Region 8, ORC, introduced Ms. Helen McGough, Director of the Human
Subjects Division at the University of Washington. Ms. McGough began her presentation by
stating that protecting human subjects is a collective responsibility of the researchers and
research staff, the institution's human subjects protection program, the sponsor, and the research
subjects. She stated that her staff review approximately 65 protocols every year, and that she has
been doing such reviews for 21 years. Ms. McGough pointed out that even she did not know
what an IRB was early in her career when she was an anthropologist.  She defined an IRB as a
group of people who meet face-to-face to evaluate the ethics and safety of research involving
humans. Membership of an IRB requires at least five people, not all of one gender, at least one
non-scientist, at least one scientist, and at least one person unaffiliated with the institution
hosting the IRB. The institutional responsibilities involve supporting or conducting research
with an assurance from OHRP. Furthermore, institutions have full responsibility for all research
involving human subjects covered under OHRP's assurance. All requirements of 45CFR46 must
be met for all EPA and other federally sponsored research. OHRP strongly encourages
institutions to apply the DHHS regulations, regardless of sponsorship, and to commit to this
standard in their assurance.  She added that it is not known how many commit to this standard.

Ms. McGough suggested that institutions designate one or more IRBs to review and approve all
nonexempt research covered by the OHRP assurance. In addition, sufficient space and staff
should support the  IRB's review and record-keeping duties. She mentioned that currently she is
struggling to pay IRB reviewers who are performing their IRB duties but who spend many hours
conducting reviews. Institutions should ensure that appropriate assurances and certificates of
IRB review are submitted for all of their federally sponsored research for their own site and for
cooperating performance sites. An institutional official should be designated to act on behalf of
the institution and to assume the obligations in the assurance. That individual should set the
"tone" for an institutional culture of respect for human subjects and should be a knowledgeable
point of contact for OHRP.  The institutional official's responsibilities also include appointing
IRB members and the Chair, providing IRB with necessary resources and staff, supporting IRB
decisions, ensuring effective institution-wide communication and access to human subject
information, and encouraging participation in human subject educational activities. There is a
steep learning curve for the institutional official because this job usually falls on whoever is
around (e.g., Dr. Peter Preuss for EPA).  The IRB Chair ensures that the IRB carries out its
responsibilities and that each approved protocol meets the requirements of 45CFR46, conducts
or delegates expedited review  of amendments or minimal risk projects, keeps the institutional
official informed, and educates IRB members and researchers.

Ms. McGough described the responsibilities of the IRB: reviews and approves, requires
modification  in, or disapproves all research activities, including proposed changes in previously
approved HSR; conducts continuing review of approved research at intervals appropriate to the
degree of risk, but not less than once a year; and suspends or terminates previously approved
research that is not conducted  in accordance with the IRB's requirements or that has been
associated with unexpected serious harm to subjects.  The researcher or research staff has
primary responsibility for protecting the rights and welfare of HSR and for complying with all


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       22

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applicable provisions of their institution's assurance. In addition, the researcher must conduct all
research according to the IRB approved protocol and must comply with all IRB determinations.
The researcher must ensure that each potential subject understands the nature of the research and
of the subject's participation and take whatever steps are necessary to gain that comprehension.
A copy of the IRB-approved informed consent document must be available to each subject at the
time of consent, unless the IRB has waived this requirement.  All signed consent documents are
retained according to institutional policies at least 3 years beyond the completion of the research.
The researcher should report proposed changes in previously approved HSR activities to the
IRB.  Changes to previously approved HSR activities cannot be initiated without IRB review and
approval, except as necessary to eliminate apparent immediate hazards to the subjects. Progress
of approved research should be reported to the IRB, when and how the IRB requires, but not less
than once a year.  Also, the researcher must report to the IRB any unanticipated problems
involving risks to  subjects or others.

Ms. McGough concluded her presentation with tips on how to choose an IRB. She stated that
the Cherokee and  Navajo Nations, for example, have their own IRBs.  Currently, there are
approximately 20  Indian Tribal IRBs. First, there must be an assurance with OHRP if the
research is to be funded by EPA.  Second, if an award is made to an institution, it is that
institution's responsibility to provide IRB review.  Third, if the research involves more than one
site, one IRB can conduct the review if other sites enter into an agreement, and each site may
insist on site-level IRB review.  The University of Washington outsources its IRB reviews.
Ms. McGough referred to a handout that she and Dr. Zane Brown, Chair, Human Subjects
Review Committee A, compiled that lists the top 10 problems researchers face in getting their
applications approved for HSR: consistency among documents (e.g., application, grant proposal,
consent forms, etc.); shared responsibility; use of lay language; too much information; poorly
written consent forms; poor assessment of risks and benefits; conflict of interests; not working
out compensation for treatment of adverse events before submitting the application; not
consulting with staff regarding problems before submitting the application; and not tracking
numbers correctly (i.e.,  submitting the same information as  the previous year) or checking
funding sources. In addition, she  added that researchers should consult with the IRB before
submitting an application because they might receive good advice on what will or will not be
acceptable in the application.

Ms. McGough referred to the genetic research'performed on a small northern Arizona tribe  in
which the researcher kept blood samples frozen and then gave them to other researchers.  This  is
a good example of a researcher not considering the  potential harm this could bring towards  the
tribe. Another example of group harm can be found in the Tuskegee Syphilis  Study conducted in
Alabama in which adequate treatment was withheld from a  group of poor black men with the
disease.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       23

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Questions and Answers

One attendee asked Ms. McGough if she thought that the IRBs were going to make the decisions
on HSR applications. She replied that it seems to be the direction in which EPA is headed.
Another question arose regarding how researchers will know which IRBs are good and which
ones are not. She advised visiting OHRP's Web Site to find reliable IRBs. Ms. McGough added
that some of the questions researchers should ask are: How many meetings does the IRB hold
for reviews? How many protocols does the IRB follow?  Does the IRB invite the investigator to
its meetings? What are the standards for the  IRBs processes? What are the standards for consent
forms? Finally, she suggested that researchers check the IRB's Web Site to see if the site is a
good one and noted that word-of-mouth recommendations are usually a good way to select an
IRB. Another question was asked regarding  oversight of IRBs. Ms. McGough responded that
there is no real oversight of IRBs; however, she belongs to the Association for the Accreditation
of Human Research Protection Programs (AAHRPP), which is the only accredited organization
that evaluates IRBs.  If there is a problem with an IRB, it can be reported to CHRP, EPA, FDA,
and so on. If the research involved is non-federal, non-regulated research, the only recourse
would be to take the IRB to court.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       24

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Day Two

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                                                                                 The Federal Wide Assurance (FWA) Is the only type of new assurance of
                                                                                 compliance accepted and approved by OHRP for institutions gjj
                                                                                 non-exempt human subjects research conducted or supported"
                                                                                 Under an FWA, an institution commits to HHS that it will comply with the
                                                                                 requirements set forth in ^.I^Rj&U'klU. as well as the Xgrr.tii^i

                                                                                 FWAs also are approved by OHRP for federal wide use, which means that
                                                                                 other federal departments and agencies that have  adopted the Federal
                                                                                 Policy for the Protection of Human Subjects (also known as the Common
                                                                                 Rule) may rely on the FWA for the research that they conduct or support,
                                                                                 Institutions engaging In research conducted or supported by non-HHS
                                                                                 federal departments or agencies should consult with the sponsoring
                                                                                 department or agency for guidance regarding whether the FWA is
                                                                                 appropriate for the research In question There are two versions of the
                                                                                 FWA and the Terms of Assurance, one of each for^'xi* «•   j,U
                                                                                 tfiirtjUJljon/j and for international (non i*   ) ii.  w i nn<

Human Subjects Research must be guided by Ethical Principles
 All of the Institution's HSR regardless of funding is subject to ethical principles
Applicability - all HSR conducted or supported by any federal department or
Agency that has adopted the Common Rule
Compliance with Federal Policy for the Protection of Human Subjects and Other
Applicable Federal State, Local or Institutional Laws, Regulations and policies
EPA 40 CFR part 26
Written Procedures -
Scope of IRBs Responsibilities
Informed Consent Requirements
Requirements for assurances for collaborating Institutions
Written Agreements with Independent Investigators Who are not Otherwise
Affiliated with the Institution
Institutions Support for the IRB
Educational training
Renewal of Assurance (every 3 years)
                                                                                                                    •i?
  The Association for the Accreditation of Human
  Research Protection Programs, Inc. (AAHRPP), is a
  nonprofit organization that works with organizations that
  conduct human research to raise the level of protection
  for research participants.  AAHRPP accredits
  organizations that can demonstrate they provide
  participant safeguards that surpass the threshold of
  state and federal requirements. The accreditation
  program utilizes a voluntary, peer-driven, educational
  model. For organizations interested in learning more
  about AAHRPP accreditation, visit www.aahrBE.w3..
1  Specified service - contractual service
1  Western Institutional Review Board
  (WIRE)
•  Schulman Associates Institutional
  Review,  Inc
1  Sterling  Institutional Review Board
1  Independent Review Consulting, Inc

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•  FWA- IRB listed (HSD - UNC)
•  Collaborators
•  State/local requirements
•  Special populations (Indian Health
  Service)
•  International Studies
•  Multiple IRB - Primary then concurring
•  Fed » State » Local
  Messing up?
     • Administrative
     • Adverse Events
     • IRB but no EPA approval
     • No approval at all (surveys)

     Reporting requirements IRB and/or HSSRO

Recommendation to HSD to establish
IRB - HSPPO
ORD moving to harmonize
ORD IRB?
EPAIRB?
Uniform and flexible
HSSRO
the protection of participants in research
EPA employee on IPA
Paper Reduction Act
Communication
 - Individual Consent Form
 - Community (Report or Presentation)
 - Officials
Ownership of data
Protection of confidentiality

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Tuesday, September 27, 2005 (Day Two)

AM Moderators:  Patti Tyler and Joel Hansel

Federal Wide Assurance and Selecting an IRB
Rebecca  Calderon, ORD-NHEERL Human Studies Division

Dr. Calderon explained that a Federal Wide Assurance (FWA) is the only type of new assurance
of compliance that is accepted and approved by OHRP for institutions engaged in nonexempt
HSR activities conducted or supported by DHHS. Under an FWA, an institution commits to
DHHS that it will comply with the requirements in 45CFR46 as well as the Terms of Assurance.
FWAs are approved by OHRP for federal wide use, which indicates that other federal
departments and agencies that have adopted the Federal Policy for the Protection of Human
Subjects  (also known as the Common Rule) may rely on the FWA for the research that they
conduct or support.  Institutions that engage in research conducted or supported by non-DHHS
federal departments or agencies should consult with the sponsoring department or agency for
guidance regarding whether the FWA is  appropriate for the research in question.  In addition, she
stated that there are two versions of the FWA and the Terms of Assurance (one of each for
domestic [U.S.] institutions and for international [non-U.S.] institutions). The Terms of an FWA
provide information on the following areas: ethical principles for HSR; adoption of the Common
Rule for all HSR activities  conducted or supported by any federal department or Agency;
compliance with the Federal Policy for the Protection of Human Subjects and Other Applicable
Federal, State, Local, or Institutional Laws, Regulations, and Policies (EPA 40CFRpart 26);
written procedures; scope of IRB responsibilities; informed consent requirements; requirements
for assurances for collaborating institutions; written agreements with independent investigators
who are not otherwise affiliated with the institution; institutions' support of the IRB; educational
training;  and renewal of assurance (every 3 years). More specific information on each of these
areas can be found at
Dr. Calderon pointed out that the AAHRPP is a nonprofit organization that works with
organizations conducting HSR to raise the level of protection for research participants.
AAHRPP accredits organizations that can demonstrate they provide participant safeguards that
surpass the threshold of state and federal requirements. The accreditation program uses a
voluntary, peer-driven, educational model. Additional information on AAHRPP accreditation
can be found at http://www.aahrgp.org. Some commercial IRBs include the Western
Institutional Review Board (WIRE); Schulman Associates Institutional Review, Inc.; Sterling
Institutional Review Board; and Independent Review Consulting, Inc.

Dr. Calderon mentioned the future job announcement for the HSRRO.  However, Dr. Preuss
would like to remain current on the HSR studies that are being conducted. She also stated that
the approval for an HSR application takes approximately 8 months. Some people, she added, do
not think that conducting a survey is HSR, but in fact it is. Also, she pointed out that all studies
related to a specific community should be reported back to the local folks; however, there is
much discussion ensuing about how much information should be reported back.  Every grant
contains boiler plate language that states all data collected may have to be provided to the
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       28

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Agency.  She also cautioned that researchers who are trying to obtain confidential information on
individuals should be extra careful in how they obtain it.

Questions and Answers

An attendee presented a scenario in which funds are being allocated for a grant but the regional
office has concerns that the IRB was not performing well. What should be the next step?
Dr. Calderon responded that Dr. Cortesi or Dr. Preuss should be contacted. Another question
was raised whether there was an exemption in the Freedom of Information Act (FOIA) for data
confidentiality.  Dr. Calderon responded that she did not think an exemption existed in FOIA.  A
comment was made that the IRBs in the state were not performing, and it seems that scientists
could collaborate on studies. Is there any ban on international studies data collection? Dr.
Calderon replied that some researchers have to certify the ethical use of the data. Researchers
should always check if the country in which the data are being collected follows the Helsinki
Accord. All federally funded research must undergo IRB review, at least during the past 4 years.
Another question concerned the hierarchy of data ownership. Dr. Calderon responded that the
data belong to the Federal Government, but ownership can be challenged legally. Another
question involved whether there is any type of audit performed  to ensure that a university
actually did what it agreed to do? Dr. Calderon commented that a review can occur to make sure
that a university conducting HSR activities is following protocol. She also suggested that
participants talk to Dr. Preuss if managers are not ensuring that a protocol is followed.
Incentives are needed for people to come forward and talk about any mistakes that might have
been made  in this regard.  The comment was made that it is important to realize that it is the
manager's responsibility to ensure that researchers report to them, the work is performed
appropriately, a QA person is present, and that a timeline exists. Another comment was made
that if there is a problem with a study following protocol, it should be reported to the IRB.
Another attendee added that if anyone is involved in individual projects, problems should be
caught early.  Additionally, DHHS' Certificate of Confidentiality protects data from FOIA but
applies only to identifiable information. With international studies, there is no guarantee that the
study population will not be adversely affected. Grants can be pulled if there are any breaches of
protocol. IRB review also is required if a survey instrument is to be tested on humans.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       29

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                                                          NHEERL Human Research Polic\
                                                         Research must be conducted in a manner
                                                         consistent with the Common Rule
                                                        (40 CFR 26), EPA and NHEERL policy
                                                         Provides guidance to NHEERL investigators and
                                                         managers on the ethical conduct,  review, and
                                                         approval of all human research activities
                                                         Ensures the safety and rights of human research
                                                         subjects
             Human Reses
 Details the responsibilities of:
 - Principal Investigator
 - Branch Chief
 - Division Human Research Officer
 - Division Director
 - Director, NHEERL Human Research Protocol Office
 - NHEERL Associate Director for Health or Ecology
 - All NHEERL employees
NHEERL Human Research Guidance
A "how to" manual for the preparation and
review of the NHEERL protocol package
First decision - does study meet the definition of
Human Subjects Research?
Human subjects?  Research?
Determination made by the NHEERL HRPO
Director
       Chapter
Purpose
Overview of Document
NHEERL Human Research Protocol Office
   Director of the Nh
  Research Protocol
Human
(HRPO)
Oversees all HSR in NHEERL
Ensures that the safety and rights of all human
subjects are protected
Advises on preparation of HSR protocols
Assists investigators and managers to
understand their responsibilities
Maintains official NHEERL records

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            2 - Historical  Overview
Nuremberg Code
Declaration of Helsinki
Belmont Report
Common Rule
EPA Order 1000.17, Change A1
Health Insurance Portability and Accountability
Act (HIPAA)
NHEERL Human Research Policy
                                                                         on
                             Rule
Definitions of Research and Human Subject
Role of IRB and need for Federal Wide
Assurance
Listing of remaining sections of the Common
Rule
               Chapter 4
  •EPA Order 1000,17, Change A1

HSR must comply with Common Rule and be
approved by Agency HSRRO
HSRRO - Final word on exempt studies
Approval process for foreign studies not covered
by Common Rule
                       /, and Approval of
            Djects Research Protocols
        Typical NHEERL HSR

           Protocol Package

Consent Form
 - A process, not just a form designed to help individually
  voluntarily decide whether or not to participate
 - Standard EPA-UNC Tort language and HRPO contact info
Initial Internal EPA Reviews
 - Scientific merit, safety
 - Statisticians, scientists, or medical personnel, etc
Extramural Scientific Reviews -
 - Scientific merit
 - Value added by conducting human research rather than animal
  or in vitro research
 - Issues of ethics, subject safety, and subject risks
        Typical NHEERL HSR
      Protocol Package  (cont'd)

Fact Sheet- non-technical, jargon-free style for
internal EPA use, including the EPA Office of
Public Affairs
 - Impact Statement - importance to Agency
 - Background of the study
 - Study Description
 - Timeline
 - Contact

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                  NHEERL
       Protocol Package (cont'd)


Study Justification Document
 - Relsvance to the Agency's mission
 - Why existing animal or tissue studies are insufficient
 - Anticipated public health benefit
 - Value added to decision-making
 - Subject safety
 - Researcher training
 - Communications strategy for communities and EPA Regions
   affected by study, if applicable
 - Reference to extramural reviews

         Typical NHEERL HSR
       Protocol Package (cont'd)

IRB Approval Documentation
   - All correspondence to and from IRB -
         START to FINISH

Ethics Training
 - All study staff involved in the design, conduct of study,
  or data analysis (if UNC affiliated - CITI web-based
  training)
 - Major contractors also need proof of training
   HSR Protocoi Package (cont'd)


   Full-scale exposure study
    - Reviews
       • Peer Reviewer 1
       • Peer Reviewer 2
       • Statistician
       • Physician
       • Other

    HSR Protocol Package (cont'd)


 Full-scale exposure study
 - Approvals
    • Division Human Research Officer
    • Branch Chief
    • IRB
    • Dosing Review Officer
    • Division Quality Assurance Officer
    • Division Director
    • Director of NHEERL Human Research Protocol Office
    • NHEERL Associate Director of Health (or Ecology)
    • EPA Human Subjects Research Review Official
   Approval Process for non-HSR
Any study involving human data or tissue which
does not meet definition of HSR
NHEERL needs a transparent, reproducible,
accountable process for review and approval.
Division Director sends memo to Director of
HRPO describing the study and the reason s/he
believes the study does not meet the definition
of HSR.
Director of HRPO concurs (or not) and study
begins. If not, then regular approval process.
    Collaboration vs. Consultation
Collaboration implies:
 - Involvement as a Co-Pi or Co-l
 - Possession of personally identifying information, interaction with
   subjects
 — Involvement in other activities such as analyzing samples or
   interpreting data and drawing conclusions
 - Expectation of co-authorship of publications.

Consultation implies:
 - Less direct involvement with a study
 - No interaction with subjects, no possession of personally
   identifying information
 - Generally does not result in recognition or co-authorship on
   publications.

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    Collaboration vs. Consultation
                (cont'd)
Collaboration, but not consultation, implies that
the NHEERL investigator is engaged in HSR,
and such participation requires NHEERL
approval as previously outlined
                                                        Chapter 8

                                          Human Controlled-Exposure Studies



Human Cor
>lled-Exposure Studies
(cont'd)
 Deliberate exposure by any modality that may
 include inhalation, ingestion, intravenous
 administration, dermal exposure, or other
 methods
 As risks increase to subjects, potential benefit to
 society must be more compelling
introlled-Exposure Studies
     (cont'd)
                                          Will not be initiated unless there are prior data:
                                           -Toxicity testing in laboratory animals
                                           - Other human exposure research, such as
                                            epidemiologic studies or controlled human
                                            exposures.
                                           - Studies of a very closely related chemical
                                            compound
Human Controlled-Exposure Studies
                (cont'd}
Pollutant Selection and Administration Criteria
 - Must be present in the environment
 - Must be under consideration for introduction into that
  environment
 - Must have review of toxicology, epidemiology,
  structure-activity relationships, and exposure
  assessment
                                          Human Controlled-Exposure Studies:
                                                           Dosing

                                          Calculations of the pollutant dose that a typical
                                          subject will receive
                                          Comparison to doses that a typical individual
                                          would be exposed to in the environment
                                          Maximal allowable doses calculated
                                          Delivered  by an on-site engineering support
                                          contractor with rigorous QA/QC procedures for
                                          accuracy and reproducibility


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Human Controlled-Exposure Studies:
            Special Review

Medical Review - controlled exposure to
pollutants, procedures involving significant
physical risk to subjects (e.g. bronchoscopy,
methacholine challenge)
 - Known risks identified
 - Measures to reduce risk are in place
 — Appropriate medical criteria in place for selection of
   the proposed study subjects
 - Team qualified to deal with any foreseeable adverse
   events
               Chapter 7

      Epiderniological Studies

        Epiderniologicai Studies

 Considerations
 - Subject burden
 - Community-based observational studies need
   communications plan for planning stages, for
   the conduct of the study, and for sharing the
   results
 - Plan shared with EPA Office of Public Affairs
   and local, state, and regional offices
  '±^SKHKKSSSttli
 Geographical Information System?
               (GIB) Data


Personal identifiers
Appropriate confidentiality safeguards
Report as aggregate data
Special precautions for sparsely populated
areas or rare outcomes
               Chapter 8

Studies of Data and Human Tissues,
      Including in~vitro Research

            Genetic Studies

 Possibility of identifying individuals with a
 disease
 Most stringent safeguards for subject privacy
 and confidentiality
 Has implications on storage of specimens
 - Future genetic studies with identifiers?
 - Future genetic studies' without identifiers?

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            Chapters

NHEERL Employees as Research
             Subjects
                                                       NHEERL Employees as Subjects
Strongly discouraged from conducting research
on themselves
No direct or indirect coercion of employees
Supervisors are not allowed to ask employees
they supervise to participate as subjects
Approval and screening processes are the same
as for other HSR protocols
                                                         Studies conducted by HSD


                                                       Total Open HSR Protocols - 58

                                                            Clinical studies - 26

                                                            Epidemiologic studies - 32

                                                       Non-Human Subjects Research

                                                            Data studies - 5

                                                            Tissue specimen studies - 2

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NHEERL Policy and Guidance
Richard Hermann, ORD-NHEERL Human Research Protocol Office

Dr. Hermann detailed the requirements of NHEERL's human research policy, which states that
research must be conducted in a manner consistent with the Common Rule (40CFR26).
NHEERL's human research policy provides guidance to NHEERL investigators and managers
on the ethical conduct, review, and approval of all HSR activities, and details the responsibilities
of the PI; Branch Chief; Division Human Research Officer; Division Director; Director,
NHEERL, Human Research Protocol Office (HRPO); NHEERL's Associate Director for Health
or Ecology; and all NHEERL employees. In addition, NHEERL's policy ensures the safety and
rights of human research subjects. NHEERL's Human Research Guidance is provided in a "how
to" manual for the preparation and review of the NHEERL protocol package.  The first decision
needed is determining whether the study meets the definition of HSR. This determination is
made by the NHEERL's HRPO Director, whotoversees all HSR in NHEERL; ensures that the
safety and rights of all human subjects are protected; advises on the preparation of HSR
protocols; assists investigators and managers to understand their responsibilities; and maintains
official NHEERL records.

Dr. Hermann outlined NHEERL's Human Research Guidance document. The Nuremberg Code
and the Declaration of Helsinki both have good principles and led to the development of The
Belmont Report.  The Common Rule was established next, which defines "research" and "human
subject" as well as the role of the IRB and need for an FWA. The Common Rule was followed
by EPA Order 1000.17, Change Al, which  ensures that HSR complies with the Common Rule
and is approved by the Agency HSRRO.  Dr. Hermann pointed out that the approval process for
foreign studies is not covered by the Common Rule. HIPAA was developed next.  All of these
regulations and policies led to the development of NHEERL's Human Research Policy.  He
explained that a typical NHEERL HSR protocol package includes consent forms; initial internal
EPA reviews; extramural scientific reviews; a nontechnical, jargon-free fact sheet; a study
justification document; IRB approval documentation; ethical training; and a full-scale exposure
study. He added that in the approval process for non-HSR studies (studies involving human data
or tissue that do not meet the definition of HSR), NHEERL needs a transparent, reproducible,
accountable process for review and approval.  The Division Director sends a memo to the
Director of HRPO describing the study and the reason the study does not meet the  definition of
HSR, and the Director of HRPO concurs (or not) and the study begins. Otherwise, the study
must undergo the regular approval process.

Dr. Hermann explained the difference between collaboration and consultation. Collaboration
implies a researcher's involvement as a Co-Pi or Co-I; possession of personally identifying
information and interaction with subjects; involvement in other activities such as analyzing
samples or interpreting data and drawing conclusions; and expectation of co-authorship of
publications.  Consultation implies less direct involvement with a study; no  interaction with
subjects and no possession of personally identifying information; and generally does not result in
recognition or co-authorship on publications.  Collaboration, but not consultation, implies that
the NHEERL investigator is engaged in HSR, which requires NHEERL approval.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       36

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Dr. Hermann defined human controlled-exposure studies as those studies in which deliberate
exposure by any modality that may include inhalation, ingestion, intravenous administration,
dermal exposure, or another method. As risks increase to subjects, potential benefit to society
must be more compelling. In addition, human controlled-exposure studies will not be initiated
unless there are prior data such as from toxicity testing in laboratory animals, other human
exposure research like epidemiologic studies or controlled human exposures, or studies of a very
closely related chemical compound. Human controlled-exposure studies also must follow
pollutant selection and administration criteria. With regard to dosing, calculations must be made
of the pollutant dose that a typical subject will receive. A comparison also must be made to
doses that an individual would be exposed to in the environment. Maximum allowable doses
should be calculated as well. Doses must be delivered by an onsite engineering support
contractor with rigorous QA/QC procedures for accuracy and reproducibility.  Finally, a medical
review must be conducted of the controlled exposure to pollutants and the procedures involving
significant physical risk to subjects (e.g., bronchoscopy, methacholine challenge).

Dr. Hermann pointed out that genetic studies have the possibility of identifying individuals
who have a disease.  The most stringent safeguards are put into place for subject privacy and
confidentiality in genetic studies. There are, however, implications on the storage of specimens.
He also stated that it is strongly discouraged that NHEERL employees conduct research on
themselves, and supervisors are not allowed to ask employees they supervise to participate as
subjects. The approval and screening processes are the same as for other HSR protocols.

Dr. Hermann concluded his presentation by listing the number of HSR studies conducted by
NHEERL's Human Subjects Division. There were a total of 58 open HSR protocols, of which
26 were clinical studies and 32 were epidemiologic studies.  For non-human subjects research,
there were 5 data studies and 2 tissue specimen studies.

Questions and Answers

An attendee inquired that if a Region wanted to set up its own guidance, where would it be able
to get training? Could Dr. Hermann's office provide guidance? Dr.  Hermann affirmed that his
office could provide guidance. He added that if anyone has a grasp of HSR, then they will have
approximately a 90 percent chance of doing the right thing. Another question was asked
regarding whether someone in a Regional office could be sent to Dr. Hermann for about 3
months  of training. He replied that he could spend some time with them.  In addition, he referred
attendees to OHRP's online training manual and mentioned that CITI also provided online
training. Dr. Hermann reiterated that a name could not be on the protocol. Groundwater data,
soil data, etc. that are connected to places on the map where the data originates does not fall
under data confidentiality rules.  Dr. Hermann was asked if he was establishing Agency-wide
guidance. Also, it would be useful to have some consistency in the guidance.  He agreed and
stated that the goal is to have consistency, which is critical to basic human subjects
confidentiality protection. A comment was made that there are gaps in the system, such as the
type of training that is needed. ORD would be willing to work with  everyone to develop  a better
system.  Another attendee asked where the details of the Guidance and Policy documents could
be found.  Dr. Hermann replied that they are available on the Web at the Human Subjects
Division's QuickPlace and on EPA's Intranet workshop site. A comment was made that Dr.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        37

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Hermann was the person to contact at NHEERL, much like Dr. Preuss is the HSRRO for all of
EPA. A question was asked whether anyone looked at sample protocols from one organization
to another, especially with regard to ethical considerations. Dr. Hermann stated that EPA does
not share protocols, but that a good point was being made regarding ethical considerations; the
world of ethics is vast and it is important to stay abreast of changes. Another attendee wondered
whether EPA's employee ethics training could be used for "ethics" training. Dr. Hermann
agreed that it could be used.

Panel Discussion: NHEERL and NERL Investigators Involved in Human Research Studies
Rebecca Calderon, Bob Devlin, Danelle Lobdell, Don Graff, ORD-NHEERL;  and Kent Thomas,
ORD-NERL

Dr. Calderon asked the panel discussants to introduce themselves, address questions from the
attendees, and discuss their experiences and background.

Dr. Devlin, Chief of the Clinical Research Branch (CRB), Human Studies Division, has been
involved in more than 100 human studies involving elderly, children, and those in between with
regard to exposure to sulfides, organic vapors, toluene, chlorine, and particulate matter (PM).
Dr. Lobdell,  an epidemiologist trained at a university medical school, not a school of public
health, has been involved in studies with pregnant women. She conducted a pilot study for the
National Children's Study. Dr. Graff,  also at the CRB, does most of his work studying PM,  He
has experience outside EPA, as does Dr. Thomas, with a pharmacy background. Dr. Calderon is
an epidemiologist with a background in studying microbes in drinking water.

Questions and Answers

One  attendee commented that she was glad to hear that there was an attempt to have consistency
across the Agency and asked how to better connect with the community.  Dr. Lobdell responded
that a pilot study was conducted that focused on the recruitment and retention  issues regarding
the National  Children's Study. Some public support is needed, however,  to accomplish this
effectively. Two sets of focus groups were conducted, the first of which did not have a diverse
ethnic representation (mainly Caucasians and African Americans), and thus a second set that
targeted specific ethnic racial groups was conducted.  In doing so, some different themes were
heard that were not captured in the first set of focus groups (e.g., not providing hair samples
because of Voodoo beliefs, etc.). Dr. Thomas  added that one of five theme areas  is community-
based research.  Another comment was made regarding how to talk to people in the community
about protecting their children from pesticide exposure. To what extent are the researchers going
to learn about these issues? Is it included in the protocol package? Dr. Calderon  replied that it
was being included in the protocol package, but not all types of studies allow for its inclusion.
With regard to the National Children's Study, it will be included where possible (e.g., Arabic
community needs information available in a different language). Dr. Calderon emphasized the
importance of translating information accurately.  Dr. Thomas pointed out that with regard to
NHEERL's Research Program, more discussion is needed with the Regions to discover what
types of studies are being conducted. With the release of the NAS report, it is important to be
aware of the hazards.
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Another attendee pointed out that in the Lead Research Program, she had a research study in
which 90 percent was public health and that the 10 percent HSR element was eliminated to allow
for the award of the grant.  Dr. Calderon replied that black-and-white guidance could not be
provided on this scenario.  In discussions with those in the community, investigators sometimes
become "twisted" in their study; in such cases, the study probably should not have been done.
Community organizations should be contacted and then it should be determined whether the
study should be continued or not.  The greatest fear is about what unintended consequences
might result.  A comment was made regarding intentional exposures in that there is no benefit.
What is the benefit to the Agency or to the community?  Dr. Graff responded that it is a good
point, but also it is a quagmire. The question arose regarding payment to human subjects. In
conducting the study, there needs to be a beneficial outcome in the end, and it needs to be clear
that there is a public health benefit.

Dr. Graff added, as an example, that some subjects receive a placebo in testing the flu vaccine
but there is a beneficial outcome in the long run. Another example is the ozone study in North
Carolina in which the ozone standard  is lower now than in 1986, and the folks living there know
it. It is important to speak in terms with which people are familiar. One attendee commented
that this is a major cultural/ethical issue.  EPA has a "bipolar" nature with regard to pesticides in
that it regulates pesticides but also exposes people to pesticides.  Dr. Devlin expressed that
NHEERL's studies do not expose people to toxic levels of pesticides. Another question was
raised regarding the use of children as research subjects. Will they be exposed to pollutants? Dr.
Devlin replied that two studies have been done with children:  the first was conducted in the
1980s in homes where parents smoke; the second  study similarly involved children but in
vulnerable populations. He was not aware of any  other studies that exposed children directly to
toxins. Dr. Graff added that it was recently decided that studies be conducted on children
because their physiology is different than that of adults.  He pointed out that intentional dosing
studies could be done as a more ethical way of reporting effects. These studies are more
observational. Dr. Calderon emphasized that children should never be coerced in any way to
participate in a study. Studies should  be considered in light of their recruitment techniques to
ensure that children are not being coerced. Investigators also should take care not to allow
parents to coerce their children into participating in a study. Dr. Thomas added that there are no
known cases of the IRB looking into minimal risk effects of something on a child. A question
was raised on how to balance the issues that arise  in observational studies and those involving
second-hand smoke.  Dr. Devlin responded that a  line has to be drawn somewhere. If the effects
of diesel exhaust on people leads to cancer and there is any doubt that there might be irreversible
damage, then the study should not be  conducted. Another question involved the legal consent of
a child participating in a study and the use of funds to educate the public about the study.  Dr.
Calderon replied that there is definitely a need for more communication to address these issues
and to share information on how they  have been handled thus far.
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PM Moderators: Amanda Hasty and Gilberto Alvarez

Managing Grants and Contracts Under the Interagency Grants Management System
(IGMS)
Armina Nolan, EPA Region 10, Grants Office

Ms. Amanda Hasty, EPA Region 8, introduced Ms. Nolan, who has worked for EPA for 15 years
and for local government for 9 years. Ms. Nolan began her presentation by pointing out the
vulnerability of grants in that they are subject to external investigations by the Inspector General
(IG) and the General Accounting Office (GAO). In addition, there are often Congressional
concerns related to some grants and contracts. As  a result, there have been some internal
improvements regarding policies and procedures.  Some of the major areas of concern deal with
grantee accountability, specifically with regard to environmental outcomes and the performance
of grantees and sub-recipients.  Program management and accountability is another area of
concern, especially with regard to workloads and new training requirements.  The Grants Office
is motivated by fear about many things, including how GAO is evaluating the work  done by the
Grants Office. There are approximately 150 grant specialists at EPA, mostly business majors
and accountants. There have been IG audits conducted on the Grants Office. About 15 IG audits
have been done in Region 10 in the past 2 weeks alone. Ms. Nolan emphasized that EPA's goals
are to enhance the skills of EPA personnel, promote competition in grants, leverage  .technology
to improve performance, strengthen EPA oversight of grants, and support identifying and
achieving  environmental outcomes. IGMS' funding recommendations are that for each grant,
there is a project description, the project links to the goals, and there is statutory authority.  The
Administrator's Office wants to know what proposals are in-house before they are even
reviewed.  This high level of scrutiny is a new development. She occasionally receives inquiries
from the press.  For example, she received two different telephone calls last week: one regarding
a study in  Oregon on the Columbia River and another regarding lead testing.  The press is always
seeking a story. She pointed out that the grant specialist for the Oregon study is at Headquarters
and that there seems to be a policy not to answer any questions from the press, which does not
help the Grants Office. Because everything is posted on the Web site regarding the grant, there
is no need to avoid answering questions.  It just makes everyone nervous, which impacts the
service received from the Grants Office. Perhaps,  there is some way to consolidate some of the
research grants so that POs can deal with the same group of grant specialists and not have to re-
educate them every time a research grant is requested.

EPA has a major plan  for internal controls.  One of the questions faced by IGMS is determining
if something is a research grant. For research grants, two extramural reviews and one intramural
review are required. The PO must provide an electronic summary, enter the electronic copy of
response to contrary reviews, and indicate if the proposal is unsolicited. Another question  IGMS
has to address is whether the project involves human subjects or animal subjects.  The PO must
provide the name and title of the ORD approver and the date of approval. Some of the
challenges to grants management are that Regions  issue very few research grants, EPA Orders
are confusing, and some projects are controversial. In the  case of the transfer of human brains to
a university for study,  the media interpreted this as a case of brains being stolen. This is one of
several examples that has caused EPA Headquarters to write a policy to protect human subjects.
As  a result, grants specialists are facing many new and exciting policies. The major areas of


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concern are: Did the grantee do what they were supposed to? Did the work ever manifest itself
.in improving the environment or public health? There is trouble monitoring the grantee's work,
which is part of the audits being conducted.  It is being found that either the Grants Office or the
POs are not doing a very good job in monitoring the research. Project descriptions are very
interesting and are posted on the Web site, along with the link to the goal of the project.  The
other  important thing that is posted on the Web is the statute of authority under which the grant
was issued.  The press often looks at the information posted on the Web site.

Questions and Answers

An attendee commented that the Regions identify few research grants and that it seems there are
research studies being conducted that POs are not aware about because they are not trained
properly. Ms. Nolan agreed and stated that there is the problem of research being conducted that
the grant specialist was not informed about.  She also added that more training would be given to
POs.  The job of the grant specialist is to award grants quickly and legally. She cautioned
everyone to be aware that there are all sorts of political caveats.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       43

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 CDC - OCSO - Human Research Protection Office - Guidelines for Defining Public Health Research and Public Health Non-Research
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                   Human Research Protection Office

 Guidelines for Defining Public Health Research and Public Health Non-
                               Research

Revised October 4, 1999

PURPOSE

The Centers for Disease Control and Prevention (CDC) is committed to
preventing disease and injury and improving health for all Americans. CDC is
also committed to protecting individuals  who participate in all public health
activities. In the conduct of public health research, CDC follows the Code of
Federal Regulations, Title 45, Part 46, The Public Health Service Act as
amended by the Health Research Extension Act of 1985, Public Law 99-158,
which sets forth regulations for the protection of human  subjects.

This document, Defining Public Health Research and Public Health Non-
Research, sets forth CDC guidelines on the definition of public health
research conducted by CDC staff irrespective of the funding source (i.e.,
provided by CDC or by another entity). Under Federal regulations (45 CFR
46), the final determination of what is research and whether the Federal
regulations are applicable lies with CDC and, ultimately, with the Office for
Protection from Research Risks (OPRR). Thus, this document is intended to
provide guidance to state and local health departments and other institutions
that conduct collaborative research with CDC staff or that are recipients of
CDC funds. The guidelines are intended  to ensure both the protection of
human subjects and the effective practice of public health.

BACKGROUND

In 1974, the Department of Health and Human Services  (formerly the
Department of Health, Education and Welfare) developed regulations to
assure the protection of human subjects from research risks. These regulations
were developed to address ethical issues  raised in connection with biomedical
or behavioral research involving human subjects. Because most biomedical
research is funded by the National Institutes of Health (NIH),  the regulations
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                         were developed to deal specifically with the types of research funded by NIH.
                         The regulations have been revised several times; currently the Department is
                         operating under Title 45 Code of Federal Regulations Part 46, 1991 revision.
                         The regulations will be referred to as 45  CFR 46.

                         The practice of public health poses several challenges in implementing 45
                         CFR 46.  Although some public health activities can unambiguously be
                         classified as either research or non-research, for other activities the
                         classification is more difficult. The difficulty in classifying some public
                         health  activities as research or non-research stems either from traditionally
                         held views about what constitutes public health practice or from the fact that
                         45 CFR 46 does not directly address many public health activities. In
                         addition, the statutory authority of state and local health departments to
                         conduct public health activities using methods similar to those used by
                         researchers is not recognized in the regulations. Human subject protections
                         applicable for activities occurring at the boundary between public health non-
                         research  and public health research are not readily interpretable from the
                         regulations.

                         The regulations state that  "research means a systematic investigation,
                         including research development, testing and evaluation, designed to develop
                         or contribute to generalizable knowledge." Obtaining and analyzing data are
                         essential to the usual practice of public health. For many public health
                         activities, data are systematically collected and analyzed, blurring the
                         distinction between research and non-research. Scientific methodology is used
                         both in non-research and research activities that comprise the practice of
                         public  health. Because scientific principles and methodology are applied to
                         both non-research and research activities, knowledge is generated in both
                         cases. Furthermore, at times the extent to which that knowledge is
                         generalizable may not differ,greatly in research and non-research. Thus, non-
                         research  and research activities cannot be easily defined by the methods they
                         employ. Three public health activities - surveillance, emergency responses,
                         and evaluation - are particularly susceptible to the quandary over whether the
                         activity is research or non-research.

;                         The key word in the regulations' definition of research for the purpose of
                         classifying public health activities as either research or non-research is
                         "designed." The major difference between research and non-research lies in
                         the primary intent of the activity. The primary intent of research is to generate
                         or contribute to generalizable knowledge. The primary intent of non-research
                         in public health is to prevent or control disease or injury and improve health,
                         or to improve a public health program or service. Knowledge may be gained
                         in any  public health endeavor designed to prevent disease or injury or

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                        improve a program or service. In some cases, that knowledge may be
                        generalizable, but the primary intention of the endeavor is to benefit clients
                        participating in a public health program or a population by controlling a
                        health problem in the population from which the information is gathered.

                        Classifying an activity as research does not  automatically lead to review by an
                        institutional review board (IRB) for the protection of human subjects. Once an
                        activity is classified as research, two additional determinations must be made:
                        (1) does the research involve human subjects  and, if so, (2) does the research
                        meet the criteria for exemption from IRB review.  This policy deals only with
                        the first determination of whether a public health activity is research or non-
                        research.

                        DEFINITIONS
                                              i

                        Research - As defined in 45 CFR 46, research means "a systematic
                        investigation, including research development, testing and evaluation,
                        designed to develop or contribute to generalizable knowledge."

                        Human Subjects - As defined in 45 CFR 46, a human subject means "a living
                        individual about whom an investigator conducting research obtains (1) data
                        through intervention or interaction with the individual or (2) identifiable
                        private information. Intervention includes both physical procedures by which
                        data are gathered and manipulations of the subject or the subject's
                        environment that are performed for research purposes. Interaction includes
                        communication or  interpersonal contact between investigator and subject.
                        Private information includes information about behavior that occurs in a
                        context in which an individual can reasonably expect that no observation or
                        recording is taking place, and information which has been provided for
                        specific purposes by an individual and which the individual can reasonably
                        expect will not be made public (for example,  a medical record). Private
                        information must be individually identifiable  (i.e., the identity of the subject is
                      :  or may readily be ascertained by the investigator or associated with the
                      '  information) in order for obtaining the information to constitute research
                        involving human subjects."

                        Surveillance - The ongoing, systematic collection, analysis, and interpretation
                        of outcome-specific data, closely integrated with the timely dissemination of
                        these data to those responsible for preventing and controlling disease or injury
                        (Thacker and Berkelman, 1988).

                        Emergency Response - A public health activity undertaken in an  urgent ons
                        emergency situation, usually because of an  identified or suspected imminent

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                        health threat to the population, but sometimes because the public and/or
                        government authorities perceive an imminent threat that demands immediate
                        action. The primary purpose of the activity is to document the existence and
                        magnitude of a public health problem in the community and to implement
                        appropriate measures to address the problem (Langmuir, 1980).

                        Program Evaluation - An essential organizational practice in public health
                        using a systematic  approach to improve and account for public health actions
                        (Centers for Disease Control and Prevention, 1999)

                        Evaluation - The systematic application of scientific and statistical procedures
                        for measuring program conceptualization, design, implementation, and utility;
                        making comparisons based on these measurements; and the use of the
                        resulting information to optimize program outcomes (Rossi and Freeman,
                        1993; Fink, 1993).

                        POLICY

                        CDC is required to and has an ethical obligation to ensure that individuals are
                        protected in all public health research activities it conducts. All CDC
                        activities must be reviewed to determine whether they are research involving
                        human subjects. When an activity is classified as research involving human
                        subjects, CDC and its, collaborators will comply with 45 CFR 46 in protecting
                        human research subjects.

                        Some surveillance  projects, emergency responses, and evaluations are
                        research involving human subjects; others are not. Each project must be
                        reviewed on a case-by-case basis. Although general guidance can be given to
                        assist in classifying these activities as either research or non-research, no one
                        criterion can be applied universally. The ultimate decision regarding
                        classification lies in the intent of the project. If the primary intent is to
                        generate generalizable knowledge, the project is research. If the primary
                        intent is to prevent or control disease or injury or to improve  a public health
                        program, and no research is intended at the present time, the project is non-
                        research. If the primary intent changes to generating generalizable knowledge,
                        then the project becomes research.

                        GUIDANCE FOR COMPLIANCE

                        I. General

                              The  Human Subjects Contact (HSC) in each Center, Institute, or
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                               Office (CIO) determines whether the project constitutes research. If
                      ;         the HSC is unclear about classifying a project, the HSC should consult
                               with the CDC's Deputy Associate Director for Science. This
                               determination is made by examining the intent of the project. What is
                               the primary purpose for which the project was designed?

                               General Attributes of Public Health Research - Intent of the project is
                               to generate generalizable knowledge to improve public health practice;
                               intended benefits of the project may or may not include study
                               participants, but always extend beyond the study participants, usually
                               to society; and data collected exceed requirements for care of the study
                               participants or extend beyond the scope of the activity. Generalizable
                               knowledge means new information that has relevance beyond the
                               population or program from which it was collected, or information that
                               is added to the scientific literature. Knowledge that can be generalized
                               is collected under systematic procedures that reduce bias, allowing the
                               knowledge to be applied to populations and settings different from the
                               ones from which it was collected. Generalizable, for purposes of
                               defining research, does not refer to the statistical concept of population
                               estimation or to the traditional public health method of collecting
                               information from a sample to understand health in the population from
                               which the sample came. Holding public health activities to a standard
                               of studying every case in order to classify an activity as non-research
                               is not practical or reasonable.

                               General Attributes of Non-Research - Intent of the project is to identify
                               and control a health problem or improve a public health program or
                               service; intended benefits of the project are primarily or exclusively
                               for the participants  (or clients) or the participants' community; data
                               collected are needed to assess and/or improve the program or service,
                               the health of the participants or the participants' community;
                               knowledge that is generated does not extend beyond the scope of the
                               activity; and project activities are not experimental.

                               Other attributes, such as publication of findings, statutory authority
                               (see discussion in next section), methodological design, selection of
                               subjects, and hypothesis testing/generating, do not necessarily
                               differentiate research from non-research because these types of
                               attributes  can be shared by both research and non-research projects.

                               A non-research project may generate generalizable knowledge after
                      ;         the project is undertaken even though generating this knowledge was
                               not part of the original, primary intent. In this case, since the primary

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                               intent was not to generate or contribute to generalizable knowledge,
                               the project is not classified as research at the outset. However, if
                               subsequent analysis of identifiable private information is undertaken to
                               generate or contribute to generalizable knowledge, the analysis
                               constitutes human subjects research that requires IRB review.

                               If a project includes multiple components and at least one of those
                               components is designed to generate generalizable knowledge, then the
                               entire project is  classified as research unless the components are
                               separable.

                        II. Specific

                           A. Surveillance - Surveillance is a term describing a method for public
                               health data collection. Surveillance systems may be either research or
                               non-research. Surveillance systems are likely to be non-research when
                               they involve the regular, ongoing collection and analysis of health-
                               related data conducted to monitor the frequency of occurrence and
                               distribution of disease or a health condition in the population. Data
                               generated by these systems are used to manage public health programs.
                               They have in place the ability to invoke public health mechanisms to
                               prevent or control disease or injury in response to an event. Thus,  the
                               primary intent of these surveillance systems is to prevent or control
                               disease or injury in a defined population by producing information
                               about the population from whom the data were collected. These
                               attributes of surveillance that is non-research are generally found in
                               state statute or regulation where the intent of the activity, its purposes,
                               and uses of the data are specified. Surveillance systems that most
                               easily fit into this category are ones in which the data are limited to
                               describing the occurrence of a health-related problem (disease
                               reporting) and systems in which no analytic (etiologic) analyses can be
                               conducted. Subjects are rarely selected according to a design; rather,
                               all cases are entered into the surveillance system because they are
                               passive reporting systems. Hypothesis testing is not part of the system.

                               Surveillance systems are likely to be research when they involve the
                               collection and analysis of health-related data conducted either to
                               generate knowledge that is applicable to other populations  and settings
                               than the ones from which the data were collected or to contribute to
                               new knowledge  about the health condition. The information gained
                               from the data collection system may or may not be used to invoke
                               public health mechanisms to prevent or control disease or injury, but
                               this is not a primary intent of the project. Thus, the primary intent of

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                               these surveillance systems is to generate generalizable knowledge.
                               Characteristics of surveillance systems that most easily fit into this
                               category are: longitudinal data collection systems (e.g., follow-up
                               surveys and registries) that allow for hypothesis testing; the scope of
                               the data is broad and includes more information than occurrence of a
                               health-related problem; analytic analyses can be conducted; and cases
                               may be identified to be included in subsequent studies.

                               In general, lawful state disease reporting, monitoring requirements and
                               other data collection activities conducted under state statute or under
                               recognized public health authority are non-research. Disease reporting
                               activities are not research. Disease reporting, for these purposes, is
                               defined narrowly to include the reporting of the  specific health
                               condition or disease, demographic information; and accepted, known
                               risk factors as specified in state statutes or regulations. When reporting
                               systems collect data beyond standard reporting information, the
                               reporting activity is not automatically considered to be non-research.
                               Collection of data that would allow etiologic analysis is likely to be
                               research.

                               If other activities are added to a surveillance project with the specific
                               intent of generating new  or generalizable knowledge, these additional
                               activities are considered  to be research. It becomes  important to
                               distinguish between disease reporting activities that are non-research
                               and uses of the reported data that may be either non-research or
                               research.

                               Sometimes, CDC funds state and local health departments to establish
                               surveillance systems with dual intentions on the part of CDC: to build
                               state capacity in disease reporting and for CDC to generate new
                               knowledge. Disease reporting activities conducted at the state level are
                               generally non-research. However, if CDC uses the data collected
                               through such reporting to generate new knowledge, CDC would be
                               engaged in research. CDC may consider state health departments to be
                               engaged in the research depending upon their role. If state health
                               departments are participating beyond merely providing the data, they
                               may be considered as engaged in the research. Institutions providing
                      1         information to state health departments would not be considered
                      ;         engaged in the research (see OPRR memorandum dated 1/26/99).

                      :         Some surveillance projects do not fit easily into  the categories
                               described above. For these projects, the primary intent and elements of
                    -  ;'         the project must be examined carefully.

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                           B.  Emergency Responses - Most emergency responses tend to be non-
                               research because these projects are undertaken to identify,
                               characterize, and solve an immediate health problem and the
                      I         knowledge gained will directly benefit those participants involved in
                               the investigation or their communities. However, an emergency
                               response may have a research component if:  1) samples are stored for
                               future use intended to generate generalizable knowledge or 2)
                               additional analyses are conducted beyond those needed to solve the
                               immediate health problem. When investigational new drugs are used
                               or drags are used off-label, the emergency response is almost always
                               research. The same applies to medical devices. For emergency
                               responses, whenever a systematic investigation of a non-standard
                               intervention or a systematic comparison of standard interventions
                               occurs, the activity is research.
                           C.  Evaluation - The terms "evaluation" and "program evaluation" are
                               used interchangeably. Yet, there are subtle differences between the two
                               terms (see definitions  and reference provided above). Evaluation is a
                               term, broad in meaning, that refers to the systematic use of scientific
                               methods to measure efficacy, implementation, utility, and so on of a
                               program in its entirety or its components. Evaluations may or may not
                               be research. Program evaluations are a subset of evaluations. As
                               defined here program  evaluations are almost never research.

                               When the purpose of an evaluation is to test a new, modified, or
                               previously untested intervention, service, or program to determine
                               whether it is effective, the evaluation is research. The systematic
                               comparison of standard or non-standard interventions in an
                               experimental-type design is research. In these cases, the knowledge
                               gained is applicable beyond the individual, specific program. Thus, the
                               primary intent is to generate new knowledge or contribute to the
                               knowledge in the scientific literature. Further, it is intended to apply
                               the knowledge to other sites or populations.

                               When the purpose is to assess the success of an established program in
                               achieving its objectives in a specific population and the information
                               gained from the evaluation will be used to provide feedback to that
                               program, the evaluation, referred to as program evaluation, is non-
                               research. In the non-research scenario, the evaluation is used as a
                               management tool to monitor and improve the program. The evaluation
                               activity is often  a component of the regular, ongoing program.
                               Information learned from the evaluation has immediate benefit for the
                               program and/or the clients receiving the services or interventions. The
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                              information is often not generalizable beyond the individual program.
                              Interventions and services that are evaluated are never experimental or
                              new; they are known (either from empirical data or through consensus)
                              to Be effective.         -

                              Sometimes, the term "formative evaluation" is used to describe data
                              collection activities that occur prior to the implementation of an
                              intervention, service, or program. Whether the "formative evaluation"
                              is research or non-research depends upon its intent. If the evaluation is
                              conducted prior to implementing a new, modified, or previously
                              untested intervention, the evaluation is part of the overall research
                              project. If the evaluation is conducted to provide information on how
                              to tailor a proven-effective intervention, service, or program in a
                              specific setting  or context, the evaluation is not research.
                                              i-

                              Evaluations of CDC's national programs, i.e., programs that CDC
                              funds to all state health departments and in which evaluation is one
                              component, are not research. These evaluation activities are on-going
                              and involve generally the collection of minimal,  standard data
                              elements across all sites. The data are generally used at the local level
                              as a management tool as well as at the national level for the same
                              purpose.  Sometimes, data from these evaluation activities will be
                              aggregated at CDC and used for other purposes. When this occurs,
                              subsequent use  of the data may be research.

                              In some cases, program activities and evaluation activities are
                              separable. For example, interventions or services are being provided;
                              they have a history of being provided and there is an intention to
                              continue to provide them. An evaluation is conducted to determine the
                              efficacy of these program activities. In another example, a public
                              health department, under its public health authority, may  provide an
                              untested intervention in an outbreak situation. An evaluation
                              component is added. In both of these examples, because the
                      ;        intervention and evaluation activities are undertaken  with different
                              intentions and are separable, the intervention activities are not research
                              but the evaluation activities are research.

                        APPENDIX
                      i
                      i1
                      ;  Examples of CDC surveillance, emergency responses, and evaluation
                        activities that are non-research and research.

                        SURVEILLANCE:

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                        Non-research -

                        National Notifiable Diseases Surveillance System (NNDSS) - States and
                        territories have asked CDC to act as a common data collection point for data
                        on nationally notifiable diseases. A notifiable disease is considered by the
                        Council of State and Territorial Epidemiologists to be a condition for which
                        regular, frequent, and timely information about individual cases is necessary
                        at the national level for the prevention and control of disease.  NNDSS data
                        are collected and published weekly in the Morbidity and Mortality Weekly
                        Report and annually in the Summary of Notifiable Diseases, United States.
                        The NNDSS is essential to the day to day practice of public health. The
                        primary intent of the surveillance system is to provide CDC and state and
                        local health officials with information to  detect and control outbreaks of
;                        disease. The NNDSS is also used to measure the impact of programs such as
                        immunization. The intended benefits resulting from the NNDSS are for the
                        residents of the states and local areas who contribute data to the system.

                        Diabetes Surveillance Report - Using public use data from several national
                        surveys, a national diabetes surveillance system is produced. Data from the
                        surveillance system are used to describe the burden of diabetes and its
                        complications on a national and state level. The primary intent of the
                        surveillance system is to provide information for the development of national
                        and state public health priorities and policies regarding the prevention and
                        control of diabetes. The intended benefits are for those who have diabetes or
                        those who are at risk of developing diabetes.
                        Research -              f

                        A Sentinel Surveillance System for Lassa Fever in the Republic of Guinea
                        - Four study sites were selected to identify and describe cases of Lassa fever.
                        Cases were identified from hospital and outpatient admissions. The purpose
                        of the project was to generate baseline information on the Lassa virus and
                        human clinical Lassa fever in the Republic of Guinea. No public health
                        interventions were planned as part of this project; there was no direct benefits
                        for study participants. Thus, the primary intent was to contribute to the
                        knowledge of Lassa fever.

                        Developmental Disabilities in Very Low Birthweight Children: Linkage
                        of the Georgia Very Low Birthweight Study and the Metropolitan
                        Atlanta Developmental Disabilities Surveillance Program - The

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                        Metropolitan Atlanta Developmental Disabilities Surveillance Program, an
                        ongoing CDC surveillance program to monitor trends in the occurrence of
                        selected developmental disabilities in children living in the metropolitan
                        Atlanta area, and the Georgia Very Low Birthweight Study, conducted in the
                        1980s to investigate the environmental and other risk factors for very low
                        birthweight were linked for specific investigations of adverse developmental
                        outcomes. Linkage of these primary files provides a unique opportunity to
                        assist efforts to assess the occurrence of selected developmental disabilities in
                        metropolitan Atlanta children and to identify causes of these conditions
                        without the additional time and resource expenditure of additional field data
                        collection. For these investigations involving secondary analyses of the linked
                        primary data sets, no individuals were contacted; only  information available
                        from the linkage were used. The purpose of the project was to estimate the
                        prevalence of cerebral palsy, mental retardation, and hearing and visual
                        impairments and to identify pre- and perinatal medical and sociodemographic
                        risk factors for these disabilities in a population-based  cohort of very low
                        birthweight children in Atlanta. The primary intent was to generate
                      .  generalizable knowledge about developmental disabilities.
                        EMERGENCY RESPONSES:

                        Non-research -

                        Outbreak of Gastroenteritis - Three days after a cruise ship left Los
                        Angeles, California for several ports in Mexico, CDC was notified that 24 of
                        1,899 passengers and 6 of 670 crew had presented to the ship=s infirmary with
                        gastrointestinal illness. The purpose of the investigation was to determine the
                        cause and extent of the outbreak and to prevent and control gastrointestinal
                        illness among the ships passengers and crew. Although this type of
                        investigation is often undertaken after the outbreak has occurred and therefore
                        information gained is likely to benefit the ship=s next set of cruise passengers
                        and crew, the primary intent of the investigation is to assist in controlling the
                     }  current disease outbreak.

                        Recall of Six Lots of Influenza Vaccine - One of the pharmaceutical
                        companies who manufactures influenza vaccine instituted a voluntary recall
                        of six lots of influenza vaccine. The lots were recalled due to decreased
                        potency of the A/Nanchang/933/95 (H3N2) component of the vaccine. CDC
                        was notified by a state health department that a nursing home had vaccinated
                     ^  its residents with the recalled vaccine. The purpose of the investigation was to
                      -  determine whether residents of this nursing home who received the vaccine

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                       had a suboptimal immune response and required revaccination. The primary
                       intent of this investigation was to prevent the occurrence of influenza among
                       the participants if they demonstrated a suboptimal immune response; there
                       was a potential for participants to receive a direct benefit in the form of
                       revaccination if they participated.

                       Research -

                       Childhood Exposure to Nicotine-Containing Products in Rhode Island -
                       Between January 1, 1995 and June 30, 1996, 90 cases of nicotine-containing
                       products were reported to the Rhode Island Poison Control Center. No known
                       population-based investigation has been conducted to determine risk factors
                       associated with nicotine-containing products poisoning. The purpose of the
                       Epi-Aid was to determine risk factors associated with childhood exposure to
                       nicotine-containing products, and to develop appropriate control measures.
                       Although there may be some benefit to the 90 children exposed in Rhode
                       Island, the benefits from this study extend beyond the study participants to the
                       population of children who are at risk of exposure to nicotine-containing
                       products. In addition, there was no immediate health problem to be controlled.
                       Thus, the primary intent of the investigation was to generate generalizable
                       knowledge about the risk factors associated with childhood exposure to
                       nicotine-containing products.
                       Azithromycin Used as Prophylaxis Against the Spread of Illness Due to
                       Mycoplasma Pneumoniae in the Setting of an Outbreak - During the first
                       week of freshman entering a post high school academic institution, a cluster
                     .  of respiratory illness was recognized by the infirmary staff. Early serologic
                       testing suggest Mycoplasma pneumoniae as the etiologic agent. About four
                       weeks later 42% of the freshman and 17% of the upperclassmen reported a
                       respiratory illness; 50% of those tested had serologic evidence of
                       Mycoplasma pneumoniae infection. The lower attack rate among
                       upperclassmen was likely a consequence of them returning to campus 15 days
                       after the freshmen arrived. A trial of chemoprophylaxis with azithromycin
                       was proposed. Highly effective control measures in the setting of an outbreak
                       have not been described. There is limited information about the role of
                       antimicrobials in controlling an epidemic of Mycoplasma pneumoniae. Thus,
                       the primary intent of the investigation was to generate generalizable
                       knowledge about the efficacy of azithromycin to prevent the spread of
     •-•;-., x           Mycoplasma pneufnoniae in an outbreak.situation.

                       PROGRAM EVALUATION:

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                        Non-research -

                        Evaluation of School-based HIV Prevention Program - As part of the
                        evaluation of the school-based HIV prevention program in Denver public
                        schools, principals, teachers, student contact staff, students, and parents were
                        interviewed. HIV program efforts in policy awareness, staff development,
                        curriculum implementation, and status of students receiving HIV prevention
                        education were assessed.

 ;                       The purpose (primary intent) of the program evaluation was to provide
                        information to Denver public schools that will be used to improve their
                        school-based HIV prevention programs. The results from the evaluation were
                        used to assess the success of the interventions in a specific population
                        (Denver public school children) and to refine the interventions in that
                        population.

                        IMPACT Progress Reports - The Office on Smoking and Health awarded
;                       32 states and the District of Columbia health departments cooperative
                        agreements to build capacity to conduct tobacco use prevention and control
                        programs. These cooperative .agreements are part of CDC=s Initiatives  to
                        Mobilize for the Prevention and Control of Tobacco Use (IMPACT), which is
                        a nationwide effort to establish comprehensive, coordinated tobacco use
                       . prevention programs. Evaluation of IMPACT is comprised of awardees
                        submitting semi-annual progress reports. Information in the evaluation
                        includes staffing, coalition composition and efforts, status of a state tobacco
                        control plan, development of a resource center, training efforts, community
                        outreach and mobilization, and participation in CDC national campaigns.

                        The primary intent of these state tobacco control program evaluations  is to
                        assess the success of the intervention activities within each state. The
;                       information gained from the evaluation is used to refine the interventions in
                        that state. In addition, the information is used nationally to evaluate the
                        success of the IMPACT program.

                        Research -

                        Evaluation of Community Based Organization Intervention to Reduce
                        Sexually Transmitted Disease (STD) Rates Among STD Patients in
                      ;  Miami - Male STD Patients were randomized to either the  standard HIV
                        prevention counseling or intensive counseling comprised of four sessions of
                        HIV counseling from a community based organization. STD clinic  records
                        were reviewed to determine whether there was a difference in return rates

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                        with new STDs between the groups. The objective of intervention and
                        evaluation is to determine whether intensive counseling reduces the
                        acquisition of new STDs among high risk people attending a STD clinic. The
                        purpose of the project was to evaluate a new intervention for reducing the
                        transmission of STDs. Knowledge gained from this evaluation would be used
                        to generalize to other sites.

                        A Comprehensive Evaluation for Project DIRECT (Diabetes
                        Intervention:  Reaching and Educating Communities Together) - Project
                        DIRECT is a community diabetes demonstration project targeting African
                        American adults residing in Raleigh, North Carolina. The project is three-
                        tiered and addresses diabetes care, community screening for persons at high
                        risk for developing diabetes, and population based approaches to increase
                        physical activity and reduce dietary fat intake (two risk factors for diabetes).
                        The goals of the community project are to reduce preventable complications
                        of diabetes via a health systems approach, increase the proportion of persons
                        at risk for diabetes who are screened, and increase the proportion who
                        participate in regular vigorous physical activity and eat a  reduced fat diet.
                        Baseline and follow-up population-based surveys are planned to evaluate the
                        community intervention. The purpose of this project is to evaluate new and
                        innovative interventions to prevent diabetes and its complications. Knowledge
                        gained from this project will be used to develop similar intervention projects
                        in other communities.
                                                       References

                        Fink, A. Evaluation fundamentals. Newberg Park: California: Sage
                        Publication, Inc., 1993    ,,

                        Centers for Disease Control and Prevention. Framework for program
                        evaluation in public health. MMWR 1999;48(No. RR-11):1-40.

                        Langmuir, AD. The Epidemic Intelligence Service of the Center for Disease
                        Control. Public Health Reports 1980;95:470-7.

                        OPRR Memorandum. Engagement of Institutions in Research, January 26,
                        1999.

                        Rossi, PH and Freeman, HE. Evaluation: A systematic approach. Newberg
                        Park, California: Sage Publications, Inc., 1993.
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                        Thacker, SB and Berkelman, RL. Public health surveillance in the United
                        States. Epidemiologic Review, 1988; 10:164-190.
                                                    I  OCSQ Home |           Us

                                                  I           I          Topics

                                       This page last reviewed  March 14, 2001
                                                         URL:
                                             (.'
                                          Office of the Chief Science Officer
                                     .Centers,for Disease  Control and Prevention
                                           1600  Clifton Road, Mailstop D-50
                                                  Atlanta, GA 30333
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Determination of Human Subjects Research vs. Public Health Practice
Roger Cortesi, ORD-NCEA

Dr. Cortesi provided copies of the HRPO Guidelines for Defining Public Health Research and
Public Health Non-Research. He pointed out that the Guidelines were developed by CDC and
follows 45CFR46, the Public Health Service Act as amended by the Health Research Extension
Act of 1985, Public Law 99-158, which sets the regulations for the protection of human subjects.
The Guidelines are intended for ensuring the protection of human subjects and the effective
practice of public health. In the practice of public health, there are challenges in implementing
45CFR46. Part of the difficulty in classifying some public health activities as research or non-
research lies in traditionally held views about what is defined as public health practice and that
45CFR46 does not address many public health activities. The key word in the definition  of
research for the purpose of classifying public health activities as either research or non-research
is "designed." The major difference between research and non-research is in the primary intent
of the activity. The primary intent of research is to generate or contribute to generalizable
knowledge, while the primary intent of non-research in public health is to prevent or control
disease or injury and improve health, or to improve a public health program or service.
Dr. Cortesi also pointed out, as stated in the Guidelines, that classifying an activity as research
does not automatically lead to an IRB review for the protection of human subjects. Once an
activity is determined to be research, there are two additional decisions that must be made:  (1)
Does the research involve human subjects? (2) Does the research meet the criteria for exemption
from IRB review?

Dr. Cortesi also provided copies of the Council of State and Territorial Epidemiologists' "Public
Health Practice vs. Research, A Report for
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Questions and Answers

An attendee referred to the manganese study in Ohio that is trying to determine its effects on the
cognitive development in children. The question arose whether this study can be applied to other
areas in the United States. Dr. Cortesi pointed out that this is a public health project.  Dr. Preuss
offered another perspective and stated that consultation with others should be made in such cases
because these studies could be either a public health project or a human subjects study.  Another
attendee commented that if something addresses a public health problem, it could be considered
public health research if only generalizable information is being tested. One attendee asked a
question regarding generalizing the decision-making process.  For example, in the case  of tribes
requesting, grants and receiving funds from EPA for doing research, what will be done with the
generalizable information that is collected? Also, what oversight will exist when humans are
being used in research?  Dr. Cortesi reiterated that one key way in making decisions is to discuss
these issues  with him and Dr. Preuss, as well as others, before making a decision.  In addition, it
would be a good idea to have the approval of a supervisor or higher level staff when making a
request to Dr. Preuss.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        46

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                                                                              What/Who is the
                                                               Human Subjects Research Review Official?
                                                                  HSRRO established under EPA Order 1000.17
                                                                  Change A1
                                                                  http://lntranet.epa.gov/rmpblicy/ad3/ord9rs/100Q. ..17a.pdf

                                                                    "Ail hus^an subject rosewrch studios supported by EPA must
                                                                    either be ^ppfovsd or be determined io be exempt research by
                                                                    the BRA Human .Subjects Research Review Official... before
                                                                    any contract, grant, cooperative agreement, cooperative
                                                                    research and devotopnifint  agreement [CRADA], intorayenoy
                                                                    agreement, or any formal agreement involving EPA support of
                                                                    such studies is awarded or  entered into. All human subjects
                                                                    studies conducted by EPA also must be approved or
                                                                    determined to be exempt by the Review Official before work
                                                                    can start. Approval: will be giver? on!y to research which
                                                                    complies with |the Common Ruiej."

                                                                  I am the current HSRRO
   Current Functions of the HSRRO

  Additional EPA oversight to assure compliance
  with the Common Rule (i.e., IRB approval,
  informed consent, etc.) and ethics standards
  Approval/disapproval of aJi EPA HSR, whether
  in house or extramural
  Authority to suspend ot terminate HSR btudics
  if non compliance
  issue smgie/multi-project assurances for
  institutions conducting teseatch (hPA now
  lehos on DHHS CHRP FWA<)
  Consultative  role in [ PA HSR ethics
  considerations
     Increased Role of the HSRRO


  The HSRRO is to be moved to the Office of the
  Science Advisor in the Administrator's Office, in
  response to the HAS recommendation
  The HSRRO position competitively advertised
  Support staff anticipated
  Tho HSRRO role under the diaft HSR iuk> is to
   1 Continue existing HSRRO responsibilities
   • Oversee tho review of intentional dosing human study
     pioposal^ by f PA and covered 3rd Parties (pertades)
   • Conduct ethics screening of completed studies
   • I wise wilh lht  Human Studies Review Board
   • Deve'op additional policies training, and guldanre

Regional Relationship to the HSRRO
 Regional responsibilities (iGOO 17 AI 6 b )
  « The n A program or u  fi m >ibl
    fo' i >mpli tncc with it In the fust instance tho office will
    decide whether Ihe piojed involve«. human subject1
    and i^ rose arch ds  per [this ordcil and home is a
    covered project
  » flieiegion is resporioibte for inlrt/inible
    for cnssunng that the  wnit^n approval or  xf mpii )ii
    del irniiti'ition fi<)in the  i l3Kf (i  is submitted as part of
    the funding package
    Do facto The Region is responsible for obtaining
 Human Subjects Approval Process
\ Laboi atoi y/Pi ogi am/Region j_jliSR?
i      Pi o/ecl Of/icei
       Gi an,
       A\vai
out: act
'focess
      GAD/Conli acts
   Awai d/Con/i act Official
                   Lab/Region/Pi'ogram
                  Human Subjects Officer
Senior Science Advisor
  Dr. Roger Cortesi


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          Human Subjects Officers

   ORD laboratories, programs and regions may
   nominate "human subjects officers" to assist in the
   implementation of HSR policies and procedures to:
    •  Work with project officers to make determinations on what is HSR
    •  Assist project officers in preparing adequate HSR documentation for
      submission to the) HSRRO
    •  Coordinate with the HSRRO and Senior Science Advisor on
      questions and process for HSR approval

   Human subjects officers should be senior staff
   experienced with decision-making on HSR

   Not a substitute HSRRO.  There is only one
   HSRRO to maintain consisiency across the Agency

   This process may be modified by the new HSRRO
Additional Responses to HSR Questions

   - •  is an iPA employee to a state covered?
       • See Rule on "any formal agreement involving EPA support for
         such studies."
       • Most institutions are. covered by the Common Rule, so the
         impact is generally limited to obtaining HSRRO approval

    r Do we have a fist of human subjects officers?
       • Yes, Dr. Gortesi maintains list of ORD and Program officers
       * No, it is not maintained on a web sits

    •  Ultimate responsibility?
       • Spellod out in Rule 1000,17 (Change i)
       • Reyion/pioqiart's supporting HSR is re'sponwbks for compliance
         with the Rufn and io notify Grants/Contracts of HSR
       * Grants/Contracts Is respon&ibie to not award without HSRRO
         approval
       • HSRRO is responsible Io ascertain Common Rule compliance
       * The institution conducting the research is responsible for the
         conduct of the research.
        Human SubjectsTraining
All EPA project officers undergo training on the EPA
human subjects approval process
EPA staff conducting human subjects research are
required to annually complete CITI ethics training
https://www.cltiprogram.org/default.asp
General  HSR information is available at OHRP
http://www.hhs.gov/ohrp/
Additional training for EPA  human subjects officers
can be arranged regionally or at a central location

Recognize that human subjects training, needs can
vary depending on the activity being considered, i.e:
    •  Approval process for EPA supported HSR
    *  Protection of subjects during the conduct of HSR
    *  Ethics reviews of existing literature

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Information/Responsibility Flow
Peter Preuss, ORD-NCEA

Dr. Preuss began his presentation by asking the question of "What/Who is the Human Subjects
Research Review Official (HSRRO)? He pointed out that the position was established under
EPA Order 1000.17, Change 1A, which states that "All human subject research studies supported
by EPA must either be approved or be determined to be exempt research by the EPA Human
Subjects Research Review Official...before any contract, grant, cooperative agreement,
cooperative research and development agreement (CRADA), interagency agreement, or any
formal agreement involving EPA support of such studies is awarded or entered into. All human
subjects studies conducted by EPA also must be approved or determined to be exempt by the
Review Official before work can start. Approval will be given only to research that complies
with [the Common Rule]." More information can be found at
http://intranet.epa.goy/rmpolicy/adj/prfo                Dr. Preuss is the current HSRRO, and
his duties include providing additional EPA oversight to ensure compliance with the Common
Rule (i.e., IRB approval, informed consent, etc.)  and ethics standards; providing
approval/disapproval of all EPA HSR, whether in-house or extramural; suspending or
terminating HSR studies if they are noncompliant; issuing single/multi-project assurances for
institutions conducting research; and consulting in EPA HSR ethics considerations.  He pointed
out that he has suspended entire laboratories from continuing HSR research if they were
noncompliant.

Dr. Preuss discussed the increased role of the HSRRO.  He pointed out that the HSRRO would
be moved to the Office of the Science Advisor in the Administrator's Office,  in response to
NAS' recommendation.  In addition, he stated that the HSRRO position would be competitively
advertised and that support staff are anticipated to provide assistance to the HSRRO. The
HSRRO role under the draft HSR rule is to continue existing responsibilities, oversee the review
of intentional dosing human study proposals by EPA and covered third parties (pesticides),
conduct ethics screening of completed studies, liaise with the HSRB, and develop additional
policies, training, and guidance. Dr. Preuss also  discussed the regional relationship to the
HSRRO. He also indicated that the EPA program or regional office that conducts or supports
research covered by the Common Rule is responsible  for compliance with it.  The office will
decide whether the project involves "human subjects" and constitutes "research." The Region is
responsible for notifying the EPA Award Official/Contracting Officer that human subjects are
involved. The Award Official/Contracting Officer, however, is responsible for ensuring that the
written approval or exemption determination from the HSRRO is submitted as part of the
funding package. In addition, the Region is responsible for obtaining HSRRO approval.
Dr. Preuss informed the participants that ORD laboratories, programs, and Regions may
nominate "human subjects officers" to assist in the implementation of HSR policies and
procedures.
Also, human subjects officers should be senior staff experienced with decisionmaking on HSR.
Human subjects officers, he added, are not a substitute for the HSRRO; there is only one
HSRRO to maintain consistency across the Agency.

Regarding human subjects training, Dr. Preuss stated that all EPA POs undergo training on the
EPA human subjects approval process. EPA staff who are conducting HSR are required to


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       49

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complete an annual CITI ethics training (for additional-information, see
http://wwwx^                        General HSR information is available at OHRP
(http://ww\v..hhs.gQy/Qhyrp/). Dr. Preuss added that additional training for EPA human subjects
officers could be arranged regionally or at a central location.  He also stated that Dr. Cortesi at
the National Center for Environmental Research (NCER) maintains a list of ORD and Program
Officers.

Questions and Answers

A question was raised whether it would be illegal to put a condition on a grant request before it is
approved. Dr. Preuss responded that sometimes conditions are added to a grant. Another
attendee asked how many Regions have human subjects officers. Dr. Preuss replied that there
were none in the Agency. In response to  a question on recordkeeping, Dr. Preuss noted that his
signature on documentation is adequate. Anqther attendee commented that the process currently
in place does not provide any incentive to conduct HSR. Dr. Preuss advised that it is not a good
idea to conduct HSR without approval. It is very important to ensure that human subjects are
well protected. Also, if something is determined to be a public health project, it is important to
attach any files or documentation on how that decision was reached.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       50

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Interactions Between EPA and
             ATSDR

          Anne:Sowell, PhD
        Human Subjects Contact
    >        NCEH/ATSDR
           Definitions

 Human Subjects - living individuals
 about whom an investigator obtains
 (1) data through intervention or
 interaction With the individual, or (2)
 identifiable private information (40
 CFR part 26.102 (f))
           Definitions

Identifiable information -
information that would allow the
person it describes to be identified:
information may be identifiable even if
it does not include name, address,
social security number, or other
common identifiers
           Definitions

 Private information - information
 about behaviors occurring in a context
 which an individual would expect not to
 be observed or recorded, or information
 provided for a specific purpose which an
 individual would reasonably expect to
 not be made public (40 CFR part
 26.102(f))
^             ATSDR            IBfl
           Definitions

Research - a systematic
investigation, including research
development, testing and evaluation,
designed to develop or contribute to
generalizable knowledge (40 CFR
part 26.102(d))

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            Definitions

  Generalizable Knowledge-
  knowledge that can be applied in
  another context
           Definitions

Exempt Research - certain types of
human subjects research projects
specified in the Common Rule (40
CFR part 26.101 (b)) to which the
remainder of the Rule does not apply
            Definitions

• OHRP-approved Assurance - An
 agreement between an institution and the
 HHS Office for Human Research
 Protection (OHRP) that the institution will
 comply with the Federal regulations for
 protecting human research participants
 (45 CFR part 46) when engaged in non-
 exempt research involving human
 mrticipants      47,np    ;        .
Interactions Between EPA and
            ATSDR
  Most ATSDR projects do not include
 :human subjects research.
  They are not designed to generate
  generalizable knowledge.
  ATSDR requires that participants in
  non-research studies receive a level
  of protection similar to that offered
  participants in research projects.
 ^              ATSDR             i
    Interactions Between EPA
           and ATSDR
Generally ATSDR and EPA work in
parallel rather than in partnership because
of differing skill sets and mandates.
The ATSDR regional staff is an exception.
ATSDR human research studies do not
include EPA partners engaged in
research.

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    Interactions Between EPA
           and ATSDR
 EPA may sponsor human subjects
 research projects, but not be engaged in
 research. In this situation there is no
 requirement for IRB oversight of the EPA
 activities.
 ATSDR grantees may also be EPA
 grantees. If they are receiving any HHS
 funds for human subjects research, they
 are obligated to follow the HHS rules.
  *              ATSDR             T
        ATSDR Activities

 Health Studies
 Registries
 Grants to state, tribal, or local partners
 Exposure Investigations
 Public Health Assessments
 Health Outcome Data Review
 Exposure Dose Reconstructions
         "Health Studies"

 Investigation into the health effects of
 individuals exposed to an environmental
 contaminant
 Involves human subjects
 Is research, not exempt
 ATSDR is engaged or sponsoring
 IRB oversight needed
            Registries

 Collection of names and contact
 information from individuals exposed to an
 environmental contaminant, possibly
 additional information
 Involves human subjects
 Often involves research intent
 ATSDR is engaged
 May or may not need IRB approval
IT    -:       ATSDR     :  ...  .  P
    "Exposure Investigation"

 Investigation to determine if environmental
 exposures high enough to cause health
 concerns are occurring
 Involve human subjects
 Not normally generalizable therefore not
 research
 ATSDR engaged in the project or
 sponsoring the project                __
O              ATSDR
              Grants

 Advertised as research or non-research
 IRB approval required for award recipient
 and any sub-contractors engaged in non-
 exempt human subjects research
 Determination of exemption made by
 either grantee's institution or by ATSDR

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     Grants Including Human
        Subjects Research

 Award recipient must hold OHRP
 approved assurance
 Project must receive IRB approval
 Grant applications reviewed for human
 subjects research activities
 Funds are withheld until IRB approval
 obtained
       Non-Research Grants

  Application considered non-responsive if human
  subjects research is included
  Grant funds may not be use for human subjects
  research
  Awardees may use other funds for related
  research activities
  If they have an OHRP-approved assurance, they
  must comply with HHS human subjects
  protection regulations regardless of funding
  source
                                                    Does the project involve human
                                                                subjects?
     The Human Subjects
  Research Decision Process
  Will investigators be using identifiable
  private data about living individuals?
          ;        OR
  Will the investigators be interacting with
  people to obtain data or specimens?
    Is the project research?

Is the project a systematic investigation
designed to develop or add to a
knowledge base?
            AND
Will the data be generalizable?
 Is the project exempt research?

1.: Is the research conducted in educational
f-;.  setting on educational techniques or
 •  materials?
2.  Does the research involve only
   educational tests, survey or interview
   procedures, or observations of public
   behavior, and will the data be
   unidentifiable or if disclosed not able to
   put the individuals at risk of harm?

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 Is the project exempt research?
  Is ATSDR engaged in research?
3. Does the research involve only educational
  tests, survey or interview procedures, or
  observations of public behavior, and are the
  participants elected or appointed public officials
  or candidates for public office or protected by a
  federal statute that prohibits release of
  identifiable information during and after the
  research?
4. Does the research involve the use of existing
  purposes which are either publicly available or
  not identifiable?        :
  ^              ATSDR            H"
 Will ATSDR staff be interacting with
 participants?
 Will ATSDR staff have access to
 identifiable data or specimens?
 Is ATSDR responsible for the study
 design?
 Is ATSDR conducting the study?
    Is ATSDR sponsoring the
             research?
  Is ATSDR funding the project?
                 OR
  Is ATSDR supplying the identifiable data?
 What about ATSDR's partners
      in research projects?
                                                                 ATSDR
  ATSDR may conduct human subjects
  research with or sponsor human
  subjects research at another
  institution only if that institution holds
  an OHRP-approved assurance of
  compliance and certifies IRB approval
  to conduct that research.
For ATSDR funded or collaborative
 human subjects research projects

•  Partner must have CHRP approved
  assurance.
•  Partner may use own IRB or rely on a
  CDC IRB.

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 Research conducted by ATSDR on
   behalf of another organization

» ATSDR may conduct human subjects
  research for another organization which
  does not hold an OHRP-approved
  assurance.
• Any employee of that organization
  engaged in the research must be covered
  by GDC's assurance through an
  unaffillated investigator agreement
  No HHS policy requiring research ethics or
  human subjects protection training.
  NIH requires grantees conducting human
  subjects research to obtain such training.
  CDC/ATSDR does not have a similar
  requirement
  NIH and CDC/ATSDRfequire
  investigators to take research ethics
  training                   v       ^__^
 *"&  '•:';-           AjSDR     V": —
Trammel is available through several
vendors.
There are a number of online courses,
some of which are free.
                                                                                               6

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Interactions Between EPA and ATSDR
Anne Sowell, CDC/Agency for Toxic Substances and Disease Registry (ATSDR), National Center
for Environmental Health

Dr. Sowell began her presentation by defining several terms, as follows:

Human subjects are "living individuals about whom an investigator obtains (1) data through
intervention or interaction with the individual, or (2) identifiable private information"(40CFR
part 26.102 (f)).
Identifiable information is "information that would allow the person it describes to be
identified; information may be indentifiable even if it does not include name, address, social
security number, or other common identifiers."
Private information is defined as "information about behaviors occurring in a context which an
individual would expect not to be observed or recorded, or information provided for a specific
purpose which an individual would reasonably expect to not be made public."
Research is "a systematic investigation, including research development, testing and evaluation,
designed to develop or contribute to generablizable knowledge (40CFR part 26.102(d)).
Generalizable knowledge is "knowledge that can be applied in another context.
Exempt Research refers to "certain types of HSR projects specified in the Common Rule (40CFR
part 26.101 (b)) to which the remainder of the Rule does not apply."
OHRP-approved Assurance is  "an agreement between an institution and the DHHS OHRP that
the institution  will comply with the Federal regulations for protecting human research
participants (45CFR part 46) when engaged in nonexempt research involving human
participants."

Dr. Sowell discussed the interactions between EPA and ATSDR. She stated that most ATSDR
projects do not include HSR activities, and they are not designed to generate generalizable
knowledge. ATSDR requires that participants in non-research studies receive a level of
protection similar to that offered to participants in research projects. In addition, ATSDR and
EPA generally work in parallel rather than in partnership because of different skill sets and
mandates.  ATSDR HSR activities do not include EPA partners engaged in research. Dr. Sowell
observed that EPA can sponsor HSR projects but not be engaged in research. ATSDR grantees
also may be EPA grantees; if they receive any DHHS funds for HSR, they are obligated to
follow DHHS  rules.  She added that ATSDR activities focus on health studies; registries; grants
to state, tribal, or local partners; exposure investigations; public health assessments; health
outcome data review; and exposure dose reconstructions.

Dr. Sowell described the HSR decision process at ATSDR. Some of the questions typically
asked about an HSR study include: Does the project involve human subjects?  Is the project
"research"? Is the project "exempt research"?  Is ATSDR engaged in the research?  Is ATSDR
sponsoring the research? In addition, ATSDR can conduct or sponsor HSR activities at another
institution if that institution holds an OHRP-approved assurance of compliance and certifies IRB
approval to conduct that research.  For ATSDR funded or collaborative HSR projects, partners in
the projects must have an OHRP-approved assurance and may use their own IRB or rely on a
CDC IRB.  ATSDR may conduct HSR on behalf of another organization that does not hold an
OHRP-approved assurance. Also, any employee of that organization involved in the research


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       57

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must be covered by CDG's assurance through an unaffiliated investigator agreement. Dr. Sowell
ended her presentation on the topic of training and stated that DHHS policy does not require
research ethics or human subjects protection training.  The National Institutes of Health (NIH)
require grantees conducting HSR to obtain such training. CDC/ATSDR does not have a similar
requirement.

Questions and Answers

One attendee commented that exposure studies were generalizable. Dr. Sowell commented that
exposure investigations provide few solid results; however, ATSDR must conduct them because
of being responsive to the community.  She said that it is rare to collect blood samples from
humans; usually only environmental samples are taken.  In addition, cancer cluster studies are
not usually conducted by ATSDR; these studies are often conducted by CDC as case-controlled
studies.  Another question arose about how the determination is made of biological samples with
exposure to a toxin or pollutant.  Dr. Sowell noted that two divisions at ATSDR deal with this
type of issue. If the exposure investigation is conducted in a Superfund site, peer review is
required, which can be time consuming. She added that there is an OMB exemption to respond
to a community emergency; there is no  way to circumspect OMB's involvement, but the case can
undergo IRB review quickly.

Open Forum/Panel Discussion  With Q&A With Speakers/Experts From Previous Sessions

With regard to research vs. non-research studies, one attendee asked how to protect human
subjects in these varied situations. In the case of exposure studies, for example, ATSDR tells
homeowners if something is going to affect their property's resale value.  EPA does not seem to
do this.  This type of situation is  a big gap in EPA's practice right now, and something needs to
be put into place to protect human subjects. An attendee asked if the Regions should adopt
standards in this regard. The response was that although it is a good idea, it would be better if
practices were consistent across the Agency. Moreover, when deciding to conduct a research
study, oversight is needed to ensure  that the project is conducted appropriately, ethical principles
are being followed, good processes are  in place, and identifiers are removed.  A comment was
made in regard to the lack of a real system for research involving human subjects;  it is something
that the  Regions could develop themselves. With regard to the public health part of a study,
consolidation of a system might not work.  Another comment was made regarding the limited
number of people in the Regions to handle grants properly. A suggestion was made for Regions
to meet more often each year, which could help to reduce some of the burden. With regard to
HSR, there is no intermediary position,  so perhaps the processes at NCER could be transferred to
the Regions.

Another attendee added that if a study addresses the needs of the community, then it  is not
research. A comment was made regarding the fact that EPA was criticized years ago for
producing questionable data, which has lead to an increase in the quality assurance and quality
control on research projects. The response was given that the focus on public health is a very
sensitive issue right now and that more  resources  are needed to address the situation.  ORD will
continue to conduct research and approve research grants.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       58

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A question was asked if the process would change with a new HSRRO.  The response given was
that it is recommended at this time that only one official at EPA respond to questions. Regarding
HSR activities, is there some way in ORD to obtain funding and get the project completed if the
project cannot be conducted through a cooperative agreement? The suggestion was made for
people from NCER to sit down with attendees of this workshop and review how they do things;
it could be a helpful learning experience. Another suggestion was made to conduct the study as a
RARE project and ORD will approve it. With regard to Dr. Preuss' tremendous responsibility as
the HSRRO for the entire Agency, the suggestion was made to have a broader group of scientists
to openly discuss these issues, even to bounce case studies off each other, perhaps in once-a-
month type meetings. The comment was made that it is a good idea to not have just one person
taking responsibility for the entire Agency.  The HSRRO should be viewed as a consultant to the
Regions. Another suggestion was made to have some type of group put together that could
determine where things were going on the topic of HSR. A comment was made that when
submitting a research application for approval, it has to pass peer review and it has to pass every
requirement after peer review.  Regarding the National Children's Health Study, who is the
HSRRO? The response was that the NICHD at NIH is the HSRRO in this study. NIH meets all
of EPA's requirements. Another question raised was who is responsible for a multi-site research
study? The response was that the Science Advisory Council is responsible for it.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       59

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Day Three

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     Superfund Human Testing
    VBI-70/CO               Urinary Arsenic
    Leadville, CO             Blood Lead ,
    Eureka, UT               Blood Lead
    East Helena, MT           Blood Lead
    Minot, ND derailment (NH4) Lung Testing
    Libby, MT                Asbestos
            Libby, Montana
Located northwest Montana
Population: 2600 city; 5000 city + surrounding area
About 1100 hornes; city       : ,  / '{^^"^^i^
               Zonolite Mine
Vermiculite mine started 1920's
Produced up to 80% of worlds vermiculite
WR Grace bpught 1?63 & closed in 199Q (» 5 million tons)

Typically 150-200 working at mine & facilities (> 1800 workers
employed in total)
                                                         EXPOSURES
                                                         Earlier up to 130 r/CG

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own                   id frprn mine.
     Libby Non-occupational Exposures
             Historical & Present
Family Contact with workers
Other
 » Playing in vermiculite piles
 • School Areas
 « Garden use
                                                                Asbestos: Non-Cancer Diseases

                                                         Asbestosis: Fibrosis of lung parenchyma (air sacs)

                                                         Pleural Fibrosis: Scarring / thickening lining around lung


                                                          • All types of asbestos

                                                            • Under-reported
                                                           Severity
                                                            « Dose, Duration, Personal Factors
                                                           Usually 10+ yrs to develop (Latency Period)
                                                           Clinical: No impairment to severe disease & death

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       Asbestos: Carcinogenic Disease
            Cancer reported 1935:
    Lung Cancer
    Mesottielioma         —

    GI Cancer

    Other Cancers
      Laryngeal, Kidney, Ovaries
.Clearly associated
Most studies
Some studies
                          Libby  Health Data Since 1999
                        Mortality Studies
                        Medical Testing ;v, '  \|
                        Case-Series
         Libby Medical Testing
            Groups Involved
                EPA Region 8
                  ATSDR
      US Public Health Service Region 8
               Montana DHHS ;
 Libby local government & medical community
                          Major Roles & Responsibilities

                       • Protocol development was collaborative

                       • EPA: provided $11M & physical infrastructure

                       • ATSDR: actual testing & HSRB

                       • PHS Region 8: health care delivery efforts
                            • HRSA, SAMHSA, CMS, MT Primaiy Care Assoc.
         HSRB Requirements

  Full testing protocols
a Health pros & cons of all tests
  Info regarding any benefits of participation
  Draft letters to convey participant results
 i All consent forms (easily understandable)
a Consent to send results to designated MDs
m Record keeping plans

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     Crude Pleural Abnormality Rates (%)
         All CXR Views, 2/3 B-readers *
                                          HSR Medical Testing Issues
                                        Health Study vs Exposure Investigation
Ever WRG employed       S1
Secondary Contractor      35
Lived with WRG worker    20

Verm. Insul. In Home      21
Vermiciilite Gardening     20

Handled Vm-m. Insulation
  Sometimes           2
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      Health Care Issues
Evaluation of those with abnormalities
Needs Assessments
Federal  Programs / Financial Aid
  Increase coverage medicare & medicaid
  Eligibility designations (MUP, HPSA)
  Community Health Center (opened Dec 01)
             Health Care Results
Development effective community coalitions
Center for Asbestos-related Disease
  p • Support for specially care for those affected

Community Health Clinic
   • Primary care for Libby & surrounding communities
   * Application submitted 5/01, started 12/01
Mental health services
                                                         More information is widely available
                                                         on Libby & Asbestos Issues
                                                         EPA « ATSOR websites, books,
                                                         scientific literature, news &
                                                         magazine articles.'  ;
                           TH IT  If II  I C
                           HAS
                           How the Asbestos Poisoning
                              of Libby, Montana
                           Uncovered a National Scandal
                                                                                    AntJtew Schneider AND David McCumtier

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Wednesday, September 28, 2005 (Day Three)

AM Moderators:  Jean Zodrow and Maryann Suero

Human Subjects Regional Case Studies:

Libby, Montana
Aubrey Miller, EPA Region 8

Dr. Miller presented HSR information from the Libby, Montana, site.  The site has a population
of 2,600, with 5,000 in the city plus surrounding areas and approximately 1,100 homes in the
city. The city was involved in vermiculite (zonolite) mining, which began in the 1920s and
produced up to 80 percent of the world's vermiculite. The W.R. Grace Co. bought the mine in
1963 and closed it in 1990, at a time that it w^s producing more than 5 million tons of
vermiculite. There were 150-200 employees who worked at the mine and facilities and more
than 1,800 employees in total. Raw ore surface mining resulted in 100 percent asbestos
exposure. The raw ore was sent to a dry mill (later wet mill) at the site for beneficiation.  The
beneficiated ore was transported across the United States for heat exfoliation to more than 300
processing plants. Asbestos exposures in the earlier days at the mine were up to 130 f/cc (vs.
OSHA PEL 0.1 f/cc) but were reduced later depending on the job type. The town of Libby was 6
miles downwind from the mine. Approximately 5,000 Ibs/day of asbestos went into Libby's
airshed.  Non-occupational exposures to asbestos resulted from family contact with the workers,
children playing in vermiculite piles, school areas, garden use, and attic insulation made from
Libby ore.  EPA has no information prior to the time that the W.R. Grace Co. bought the mine.
Estimates range between 10-35 million affected homes.

EPA, ATSDR, and NIOSH issued national warnings against asbestos exposure in 2003. There
has been evidence of non-cancer diseases such as asbestosis and pleural fibrosis as well as
carcinogenic diseases such as lung cancer, mesothelioma, GI cancer, and laryngeal, kidney, and
ovarian cancers.  EPA Region 8, ATSDR, U.S. Public Health Service (PHS) in Region 8,
Montana DHHS, and Libby local government and the medical community became involved in
Libby's medical testing. Protocol development was collaborative.  EPA provided $11 million
and the physical infrastructure; ATSDR performed the actual testing; and PHS Region 8 became
involved in health care delivery efforts.  The HSRB requirements included full testing protocols,
health pros and cons of all tests, information regarding any benefits of participation, draft letters
to convey participant results, easily understandable consent forms that had to be evaluated, setup
of a system involving consent to submit results to designated physicians, and record keeping
plans. In 2000 and 2001, 7,307 people were tested. ATSDR developed a community advertising
campaign to encourage residents of Libby to come for free  asbestos testing. Assessment
interviews, chest x-rays, and pulmonary function tests were conducted on study participants.
HSR medical testing issues included whether the study was a health study or an exposure
investigation; generalizable knowledge and its intended use; cost/benefit of medical testing (i.e.,
risks of procedures, especially radiation to kids; lack of effective treatments for asbestos; risk of
losing/not getting insurance coverage); and confidential record keeping.  Health care issues
included evaluation of those with abnormalities, needs assessments, and federal
programs/financial aid. Health care results included setup of a community health center, which


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        66

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opened in December 2001; setup of the Center for Asbestos-related Disease; development of
effective community coalitions; and provision of mental health services. Dr, Miller
recommended that workshop attendees visit EPA and ATSDR Web Sites for more information
on Libby and asbestos issues, as well as checking the scientific literature, news and magazine
articles, and books such as An Air That Kills: How the Asbestos Poisoning of Libby, Montana
Uncovered a National Scandal by Andrew Schneider and David McCumber.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       67

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IRB  Case  Study:
   Asian and Pacific Islander Seafood
   Consumption Study In King County,
   .Washington
                                                            Grant Award Details
                                                            • Environmental Justice
                                                              Community/University Partnership Grant
                                                              EQ925003-01
                                                               a Application Date: Feb 1996
                                                               <•• Study period: Aug 1996 to July 1998
                                                               * Funding:  $205,316
Background
    API Immigrants were
    hypothesized to
    consume greater
    quantities of SF,
    different species and
    different tissue parts
    when compared to the
    general US population.
                          Concerns:
                            •Self-harvesting In urban
                            waters
                            •Increased risk of toxic
                            chemical exposure
Methodology—Overview
• 10 API ethnic groups surveyed: (Cambodian,
  Chinese, Filipino, Hmong, Japanese, Korean, Laotian, Mien, Samoan
  and Vietnamese)
• Respondents were also:
   * 1"or 2nd generation;
   ' i18 years old;
   < SF consumers; and
   • residents of King County, WA

* SF consumption survey administered by
  trained bilingual Interviewers.
                                                             The SF consumption survey
                                                             solicited Information about:
                                                               types/sources of SF;
                                                               preparation methods;
                                                               frequency of consumption and
                                                               portion size consumed;
                                                               demographic Information.
                                                              •Seafood models were used to elicit more accurate serving size
                                                              estimations from respondents,

                                                              •Random sampling strategies: community group rosters volunteers)

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Study Oversight
  • Multiple sources
    •a Community Advisory Committee
    - Scientific Advisory Committee
    * UW-IRB
Community Advisory Committee
UW—IRB Review
  • Once grant was funded and final work
   plan finalized, UW researchers applied
   for UW—IRB approval
  * If risks to human subjects is low, e.g. a
   survey, approval usually given within 2
   weeks.
  • A mid-study methods change required
   2nd UW—IRB approval
                                  J
Please adjust your glasses

EPA IRB Approval
Study Outcomes
                                                 • EPA Report 910/R-99-003, May 99
                                                 ' Original SF consumption data posted to
                                                  EPA Website
                                                 • Journal Publication in: J Exp Anal &
                                                  EnvirEpid. (2003) 13, 256-266.

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Asian and Pacific Islander Seafood Consumption Study in King County, Washington
Ruth Sechena, University of Washington

Dr. Sechena pointed out in her presentation that the study period covered August 1996 to July
1998, with grant funding of $205, 316. It was hypothesized that Asian and Pacific Islander
immigrants consumed larger quantities of seafood, including different species and tissue parts,
than the general U.S. population.  Concerns about this special population involved self-
harvesting in urban waters and the increased risk of toxic chemical exposure. Because of
cultural and language barriers, studies within this population required specialized survey tools
and methods. Some of the strategies employed to reach this population included University
researchers partnered with the Refugee Federation Services Centers; cultural guidance was given
by the Asian and Pacific Islander Community Advisory Committee; and culturally appropriate
survey tools and methods were developed and tested on a focus group.  In this study, 10 Asian
and Pacific Islander ethnic groups were surveyed (e.g., Cambodian, Chinese, Filipino, Hmong,
Japanese, Korean, Laotian, Mien, Samoan, and Vietnamese).  The seafood consumption survey
solicited information about the types/sources of seafood, preparation methods, frequency of
consumption and portion size, and demographic information.  Seafood models were used to elicit
more accurate serving size estimations from respondents.  The strategy behind random sampling
was to use community group rosters of volunteers. The rosters, however, were difficult to
obtain.  The Community Advisory Committee kept the study design culturally appropriate by
rejecting a creel design, telephone survey, or mail survey that would have been considered
offensive or threatening and instead supported a one-on-one interview approach that used
appropriate cultural protocols. In addition, the Community Advisory Committee rejected a
statistical sampling method based on U.S. Census data because it appeared that certain groups
were favored and that groups they considered most at risk, such as those entering the United
States recently, were not adequately included. Dr. Sechena stated that once  the grant was funded
and a final work plan was finalized, University of Washington researchers applied for University
of Washington-IRB approval.  She further noted that if the risks to human subjects were low, as
in the case of conducting a survey, approval would be given within 2 weeks but the survey had to
be voluntary. A mid-study methods change, however, required that a second University of
Washington-IRB approval be completed. The study outcomes resulted in publication of a
Technical Report (Asian and Pacific Islander Seafood Consumption Study in King County,
Washington, EPA Report 910/R-99-003, May 1999); publication of an article (Ruth Sechena,
Shiquan Liao, Roseanne Lorenzana, Connie Nakano, Nayak Polissar, and Richard Fenske.
Asian American and Pacific Islander seafood consumption—a community-based study in King
County, Washington. Journal of Exposure Analysis and Environmental Epidemiology
2003;13:256-266); and posting of the original seafood consumption data on EPA's Web Site.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       70

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Human Mercury Biomonitoring in Alaska
Pat drone, EPA Region 10

Dr. Cirone pointed out that this study began with a fish tissue monitoring grant given by EPA to
the State of Alaska to obtain data on levels of mercury found in humans. There were two
components to this study:  one was to measure tissue contaminants and the other involved
mercury biomonitoring. She added that the Human Biomonitoring Program resulting from this
study was considered routine public health practice and did not have to comply with the
Common Rule or go through IRB review. The involvement of human subjects was to obtain hair
samples from the community to determine the contaminant levels.  The State of Alaska is still
collecting fish tissue, but the results are not yet available. A document prepared in 2005 focused
on the state's whole biomonitoring program rather than this particular study.  Dr. Preuss added
that this grant should have gone to him for approval.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        71

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Children's Asthma Study in Idaho                ;.
Doug Cole, EPA Region 5 (presented by Roseanne Lorenzana, EPA Region 10)

Dr. Lorenzana informed workshop participants that this study was conducted during the field-
burning season in Idaho. The Idaho Department of Health and Welfare grant application for
state-level collaboration to address childhood asthma was submitted in August 2003, and was for
approximately $50,000 to investigate health risks associated with field burning in Northern
Idaho. The study involved collecting and correlating existing health data with  air quality/
meteorological data, and information on field burning activities in the Rathdrum Prairie of
Northern Idaho during a 3-year period (2000-2002) to determine if there were any associations.
The workplan, funding, and timeline did not anticipate the need for IRB approval or the
development of a Quality  Assurance Project Plan (QAPP).  The applicant was not aware of the
need for IRB approval and did not understand the approval process. As a result, there were
significant difficulties and delays in starting this project.

Dr. Lorenzana pointed out the benefits of an IRB, which is to ensure that the rights and welfare
of HSR subjects are adequately protected.  An IRB has the authority to approve, require
modifications in, or disapprove research.  There are many IRBs throughout the United States.  In
Idaho, an IRB  exists at Boise State University.

Dr. Lorenzana stated that the research for this study qualified for an exemption from the IRB
approval process because  it used an existing collection of health data and that any information
being collected did not identify individuals. The exemption process, however, required a
narrative from the applicant to Dr. Cole, after which he arid the PO submitted a request to NCER.
The exemption approval took 2.5 months.  Generally, the QAPP plans should be submitted and
approved for research projects.  The IRB and QAPP approval process takes time and effort, and
these should be factored in the project timeline and budget for tasks.  Dr. Lorenzana advised
grantees to check with their  grant PO to determine if IRB approval is necessary or if an
exemption is applicable.

Regional Case Studies—Questions and Answers:

A question was asked about the life cycle of the Libby, Montana case. The response was that the
whole life cycle of the study was unclear. A participant added that at  the CDC, protocols  are
given annually. If there is any major changes, the IRB conducts a review. Generally, approvals
take approximately 6-8 weeks; exemptions take about 2-3 weeks.  A question was raised whether
the study should have gone through EPA for approval. At the time of the study, the study
proposal was reviewed by ATSDR through their process. If the study was conducted today, it
would have gone through  Dr. Preuss.

Regarding the  Asian and Pacific Islander Seafood Consumption Study in King County,
Washington, a question was asked whether any attempt was made to contact the people in the
community to  warn them about eating the fish. Dr. Sechena pointed out that there were three
phases involved in the study, and that the third phase involved determining how to reach the
community. A comment was made that with ethnic communities, caution should be taken when
giving out information to the folks in a community. A question was raised whether information


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       72

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should have been given to the community sooner. Dr. Sechena added that the information was
not available any sooner. In addition, she did not think that participation in the study would have
been any different if that had occurred.  An attendee asked if the study was approved by EPA.
Dr. Preuss replied that the study was under the HSR umbrella, and he could not comment on
each study without receiving it. Another question was asked regarding what to do with the
collected data. A response was given that if the quality of the data is good and names are
affiliated with the data, then the data can be used for analysis.  Dr. Preuss pointed out that the
system is set up for POs and Program Officers in the Regions to make the decision whether a
study is HSR or not. Someone asked how POs would obtain funds for the study. Dr. Preuss
replied that EPA would stand behind  the PO in making the determination.  He added that if a line
item grant is being sought, certain things must be  done; a system is in place, the steps are written
down, and they just need to be followed for the grant to be awarded.

Regarding the Human Mercury Biomonitoring Study in Alaska, one attendee asked where the
document with the data was stored. Dr. Cirone replied that it was being kept with the grant.
Another attendee asked if anyone was planning to warn folks not to eat the fish if the study
results showed a high health risk. Dr. Cirone stated that the study design was somewhat flawed,
and she did not anticipate doing so. Another question was raised regarding what incentive
existed to take this study to an IRB when CDC had an exemption for it.  Dr. Cirone replied that
this was a biomonitoring study; there was no CDC documentation, just a CDC reference. The
earliest documentation dates back to 1999. This was a choice likely made early in the program.

Regarding the Children's Asthma Study in Idaho, the question was raised whether this study was
an example of research and public health practice. Dr. Sowell pointed out that CDC and ATSDR
have always been very careful in making the distinction between research and public health
practice, and would consider this case to be research. Setting up a program and collecting
samples for future use does not necessarily constitute research. Some of the work being done by
the states is initially considered public health practice but crosses over into research. The
question was asked about what happens when something is considered public health practice but
then becomes research. The response was that there is no simple answer to that question. From
the outset of a study, it has to be determined if it is going to be research. Thought should be
given to whether the study will go beyond public health practice.

A question was asked whether IRB approval should be sought if EPA receives an HSR
application from a university. Dr. Sechena was not sure if the University of Washington
required the IRB approval or if it was specific to the grant.  Regarding the University of
Washington IRB approval, the question was asked whether the process was smooth and efficient.
Dr. Sechena pointed out that there were no "red flags" identified for the study.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       73

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Report Outs From Breakout Groups:             ;;

Attendees at the workshop were assigned to one of four breakout groups.  The facilitator of each
breakout group was responsible for clarifying the purpose and outcomes for the session.  A group
representative was selected for each breakout group as well as a discussion leader.  Key
questions to be addressed were: (1) What "fatal flaws" do you see in the current model (the
current processes being used)? (2) How might we be more successful? Which suggestions in the
optional model (optional additions to the current model) might improve our processes? (3) What
are some of the challenges we might face if we implement these ideas, and how might we
overcome those challenges? (4) Who are the players that need to be involved in decisionmaking
and where are the major decision points? After the discussions took place, each breakout group
was asked to compile recommendations for management to help everyone to be more successful
in reviewing HSR. Recommendations presented by each group representative included the
following:                               c

Group 1 Recommendations:

•  Change the IGMS requirement so that grants can be awarded prior to human subjects studies
   review.

•  Ask Dr. Preuss to write a memo to the regional RAs requesting an appointment of a
   RHSRRO.
                                             ,--jf

•  Develop a national workgroup of regional HSRROs to identify tracking needs for the
   existing system, including a query capability; develop a consistent human subjects studies
   training plan; have the workshop organizers, Patti Tyler and Roseanne Lorenzana, develop a
   recommendation package and identify one regional person to brief the RAs on the workshop
   recommendations.

Group 2 Recommendations;

 •  Have the Regions consider a human subjects official position (with a non-research ethics
   oversight).

 •  Create a culture where the ultimate goal is protecting human subjects, regardless of whether
   it is research.

 •  Develop and implement a training program.

 •  Develop written guidance, Web site, and list of contacts (subject experts), and publish these
   in the Federal Register for public input/comment.

 •  Identify and publicize the consequences for noncompliance of EPA Order (40CFR26, EPA
   Order 1000.17, Change A-l).

 •  Develop a briefing strategy for upper management.


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        74

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 •  Suggest that EPA develop its own IRB.

 •  Develop a tracking system that is accessible in the Regions on the progress of decisions made
   regarding the HSRRO process.

 •  Develop a straw proposal for new HSRRO that is generated by the workshop and finalized
   by the workshop planning group.

 •  Have a question on human subjects immediately followed by a question on research in two
   parts: If "yes" to human subjects and "no" to research, then require an attachment of the
   regional decision memo; if "yes" to both, then require HSRRO approval.

Group 3 Recommendations:

•  Increase management's focus/attention on HSR and include NRSC recommendations, ID on
   SCOUT, and Dr. Preuss on RA and DRA calls.

•  Identify a point of contact for human subjects (HS Officer) with a regional advisory board.

•  Have a joint decision made between Dr. Hermann and the regional HS Officer to determine if
   a study is HSR.

•  Create a National HSO Council lead by the HSRRO.

•  Maintain communication between the HSRRO and the regional HS Officer.

•  Provide all EPA staff with ethics training.

•  Provide training for all EPA Project Officers.

•  Define HSR and public health practice on the grant solicitation and request the grantee to
   frame the proposal with these definitions.
                                           ^
•  Create a tracking system.                 !

Group 4 Recommendations:

•  Determine a point of contact for the Regions for HSR.

•  Provide training at all levels appropriate to individual responsibilities.

•  Promote awareness of HSR at all levels, including NPMs as national grant RFPs are often
   administered in the Regions.

•  Develop a process like HSR for public health practice, and if necessary, third-party studies.
        Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       75

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Reconcile grant funding timelines or at least make potential grantees aware of the IRB
response prior to funding.

Allow for some room in the process for regional flexibility but maintain overall consistency.

Allow for future revisions and modifications.
      Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       76

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  nORtH
caaoLma
                            ^asti-tma,
                         jpHllDHOOD &
                         ifMRonment
                            "stuDies
                                                Scenario

                                   • You are a parent of a child with asthma
                                   • A couple of days ago, your child had an
                                    appointment with his/her pediatrician
While at the
appointment, your
pediatrician
showed you and
your child this
flyer about an
asthma study that
wants to explore
the role of air
pollution and
asthma
   Are you tMtwewi a end 117 Do you h*V> »«ttirn»?
You miy qualify tor MI m\r pollution raaolich itudy.
     This siiirty I* ml a drag IrM or e cfwmber rtudy


 Skrty require Iww cHnic riMi. During UN Mudy Ooys you wi be oiMd la
inoMor jour ertna lympMim Tta laM taioth of th* sluOy. Induwng tM clivc
       vi tm h ebam A to nh» w»«ki.
   I be prtMdad Win a POrVMoDM phone •» It (Xrt rt ItN Mudy
After seeing this
   ad, you of
   course had
many questions.
 What types of
questions would
  you ask your
     child's
  pediatrician?
   After answering some of your
   clinical questions in regards to
   asthma, your child's pediatrician
   suggests that you contact the
   study number to find out more
   information in regards to this
   study.
                                   You decide to check out the study's
                                        website listed on the ad.
                                       http://www.epastudies.org

-------
                                                           Here is the information you found

                                                              on the website for this study

                                                                            PACES
                                                        The purpose of this study Is to examine the effects of partlculate
                                                         air pollution In the Chapel Hlll/Carrboro area on the pulmonary
                                                          health of moderate and severe asthmatic children ages 8-18
                                                        years old. This study Includes a baseline medical evaluation with
                                                         breathing and allergy tests, optional blood draw, cheek swabs,
                                                          and urine and nasal fluid collections. If the baseline medical
                                                          evaluation finds that the participating child is a moderate or
                                                         severe asthmatic, the child will be asked to enroll In a six-week
                                                         diary study. Each day during the diary study the participant will
                                                          monitor their asthma symptoms using a portable breathing
                                                        monitor and record their medication use with a PDA/mobile phone
                                                              connected to their personal Internet medical diary.
  Just based on the information you
  have so far, what are some of the
  things you might discuss with your
child in deciding whether or not to call
and consider being part of this study?
You and your child decide to call the
number. The recruiter describes the
  study for you and then asks you a
          series of questions.
         Screening Questions
   Name
   Relation to child (parent, guardian, other)
   Phone
   Name of child
   Age of child
   Does your child and you have flexible daytime hours?
   Does your child or you have plans to leave the area within 3
   months?
   Is your child presently in any other studies or ever In EPA
   studies?
   Does your child have asthma?
   Does your child have chronic respiratory disease?
   Does your child have any major medical conditions? Accidents?
   Operations?
   What type of medication is your child receiving?
   Address
  In the end, you decide to make an
   appointment to  enroll your child.
You are sent in the mail, before your
     child's  appointment, a study
     consent form as well as study
               restrictions.

-------
  Restrictions for Appointment

Do not come with an upper respiratory infection -
call and reschedule appointment
For baseline visit have your child:
- Avoid smoky areas
- Drink plenty of fluids 24 hours before appointment
- Not consume any caffeine day of appointment
- Eat a light meal 1 hour before arriving
- No rescue medicines for 6 hours, however, do use the
  medicines if needed - call and reschedule if use
- Bring allergy skin test records if possible,
- Bring all meds and peak flow meter if your child has one
        The Appointment

You bring the consent form
Assent form
Clinical screening for eligibility
             The Forms
             Consent

Completed by parent or guardian
Requirement for this study is to have both
parents signature
"Informed"
Confidentiality
Can refuse to participate in any aspect of
study
Can leave the study at any time
               Assent

 Completed by the child
 Child agrees to participate - parents
 cannot force child to participate if he/she
 does not want to
 Same components as consent form, not
 as detailed

      HIPAA Authorization

"The Health Insurance Portability and
Accountability Act of 1996" (known as
"HIPAA")
Provides permission for researchers to
access information from a participant's
medical records or health insurance
records to use in this research study

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      Consent to Allow Storage of
            Biological Samples
  Separate consent
  Have several choices
  - Agree to allow storage of specimens with
    identifying information which might include
    genetic research
  - Request Identifying code be removed and if
    removed may use as in above
  - Request identifying code removed and
    specimen can be stored but NO genetic testing
  - Request specimens be disposed of
              Screening
 Blood draw
 Urine sample
 Vital signs, pulse, blood pressure, respiratory, SpO2,
 temperature, weight and height
 Skin prick testing for allergies
-  Grass, weeds, trees, mites & Insects, animals, molds
 Spirometry
 Exhaled NO measurement
 Exhaled breath condensate
 Nasal lavage
 Buccal cell collection
                                                                          Urine collection
Vital signs, pulse, blood pressure, respiratory, SpO2,
temperature, weight and height
                       Skin prick testing for
                       allergies:
                          grass, weeds, trees,
                          mites & insects, animals
                          molds

-------
   Nasal lavage
End of screening procedures

• Given phone number to call in
  case of emergency

   •  Receives instructions to
     monitor for signs of
     adverse symptoms

• Receives compensation for
  screening

• Instructed that recruiters will
  call if eligible for second part
  of study

-------
Screening Determined Your Child
 Eligible for Second Part of Study

Receive phone call to schedule follow-up
visit as well as home visit to set up air
monitoring

              Follow-up visit:
 Receive instructions for use of PDA to input daily diary
 (once a day for 6 weeks) and for use of electronic peak
      flow monitor (twice a day for 6 weeks)
                                                    Home air monitor - set up to be in your yard for 1 week
                                                   Your presence not needed for set-up or sample collection
                                                    After 6 weeks,  return to clinic to
                                                    return peak flow meter and PDA
                                                      to receive full compensation

-------
PM Moderators:  Margaret Jones and Bruce Macler

Group 1 Presentation:  Being a Child in an Epidemiological Study
Rebecca Calderon and Danelle Lobdell, ORD-NHEERL

Dr. Lobdell began the presentation by referring to the North Carolina asthma, childhood, and
environment studies conducted by the University of North Carolina (UNC) School of Medicine.
She discussed a typical example of a study in which a flyer was provided to a parent of an
asthmatic child by the pediatrician during a scheduled appointment.  The flyer discussed an
asthma study being conducted to explore the role of air pollution and asthma. The study
involved three clinic visits during a period of 6-9 weeks.  She pointed out that after viewing such
a flyer, there were probably many questions that came to mind. After answering some of the
clinical questions  regarding asthma, the pediatrician suggested that the parent contact the study
number to obtain more information about this study. The parent then browsed the study's Web
site that was listed on the flyer.  One of the major questions included finding out exactly what
types of procedures (skin prick test or other) were to be performed in the study to determine the
severity of asthma in a child. If the parent and child decided to call the number for the study, the
recruiter would describe the study and ask some questions. In the end, the parent would decide
to make an appointment  to enroll the child in the study. A study consent form would be mailed,
along with  study restrictions. For the appointment, the parent would bring the consent form,
assent form, and clinical screening results for eligibility. The consent form would be completed
by the parent or guardian.  The assent form would be completed by the child. Parents cannot
force their child to participate if the child does not wish to participate.

Under HIPAA authorization, permission is given to researchers to access information from a
participant's medical or health insurance records to use in the study. A separate consent form is
needed to allow storage of biological samples. Screening is conducted via blood draw, urine
sample, vital signs, skin  prick testing for allergies, spirometry, exhaled NO measurement,
exhaled breath condensate, nasal lavage, and buccal cell collection.  At the  end of the screening
procedures, a telephone number would be provided in case of an emergency, as well as
instructions to monitor for signs of adverse symptoms.  Compensation for screening would then
be provided, and the study participant .would be informed that recruiters would call if the
participant is eligible for the second part of the study. If screening determines that the child is
eligible for the second part of the study, a follow'-up visit would be scheduled as well as a home
visit to set up an air monitoring device.  During.the follow-up visit,  instructions would be
provided for use of a PDA to input the study participant's daily diary and for use of an electronic
peak flow monitor. After 6 weeks, the study participant would return to the clinic to return the
peak flow meter and PDA  for full compensation.

Dr. Lobdell provided some examples of materials such as the consent form to participate in a
research study provided  to the parents of minors involved in the study; an assent form to
participate  in a research  study provided to minors; UNC School of Medicine/UNC Hospitals
information about storage and use of specimens with identifying information; an addendum to
the consent form for storing blood, tissue, or body fluid with identifying information; and an
addendum to the consent form for participating in a research study.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        83

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Questions and Answers                            :

An attendee asked if the physician involved in such a study was liable in any way.  Dr. Lobdell
replied that the physician was not liable in this case. A comment was made that loyalty to a
physician may coerce some patients to enter the study.  It should be emphasized that the study is
voluntary. Another attendee commented that it might have been less intrusive if the study was
posted on a wall rather than given out as a handout or flyer. Dr. Calderon commented that
postings on a wall are not as  effective in obtaining volunteers. If a physician asks patients to
volunteer, they are more likely to participate.  An attendee suggested doing a mailing to patients.
In addition, caution  has to be used with mailings because of HIPAA rules. A question was raised
regarding how to account for patients without insurance.  Dr. Calderon responded that the study
looked at recruitment in the school system, which was more successful than having
advertisements in the paper or through medical offices. The Education Departments and their
interpretation of the Federal Educational Rights and Privacy Act (FERPA) are preventing
investigators from entering school systems to conduct studies because of societal concerns over
privacy issues.

A question was asked whether parents  calling the recruiter for the study would get their
questions answered  before being asked screening questions.  Dr. Lobdell responded that their
questions would be answered, but that  there could be a couple of key screening questions that
might be asked to determine  if the child qualifies for the study. Someone asked what the
parents' motivation  was for entering their child in the study.  Dr. Lobdell responded that in the
National Children's Study, for example, altruism was a big motivator simply because many
parents who had a child with a medical condition would want to help their child. Dr.  Calderon
added that participation in the study could lead the parent to better doctors or give them the
assurance that they are doing the right thing for their child.

Dr. Calderon pointed out that it was critical to know if the child was involved in any other study.
A simple blood test  was done to screen out those involved in too many studies.  A question was
asked about the grade level of the flyer. Dr. Lobdell replied that the flyer was geared for an 8th
grade reading level. One participant suggested adding a glossary to the end of the consent form
because many parents  would not know the meaning of some of the terms used. Dr. Lobdell
agreed but suggested keeping the consent form very simple.  She added that most people do not
want to take the time to read a long consent form, and in some instances, are willing to just sign
it without reading it. It is important to go over the consent form with the participant to ensure
his/her understanding of the study. In addition, she suggested that the consent form always
include a statement  of confidentiality.  It should be made clear that the patient's level of care
would not change as well.  Finally, payment should be included for participation in the study,
which is a big incentive for the child to participate. Dr. Calderon added that usually the payment
goes to the child.  Dr. Lobdell pointed  out that if parents sign the consent form, there  also must
be an assent form signed by the child.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        84

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                                                                           •  Species of interest for risk assessment purposes

                                                                           *  Many aspects of humans cannot be readily
                                                                              accounted for in animal studies
                                                                               Longevity, diet, lifestyle, d?sess&, gsnstic vatlhiiity

                                                                           •  10x uncertainty factors
               Anlmai Toxicology Studies
                   In Vitro Studies

Species of interest for risk assessment
purposes

Studies humans exposed to "real world"
particles in "real world" scenarios
    acute or chronic affacte

Can examine potentially susceptible
populations

End points are highly relevant
    mortality
    morbidity
Causality difficult to demonstrate

Difficult to eliminate confounders
 (PIW, O,, NO,, air toxics)

Can be difficult to accurately measure exposure, especially
personal exposure

Outcomes usually limited
 Hard to examine biological plausibility, mechanisms

Can be costly and time consuming
 Species of interest for risk assessment
 purposes

 Randomization of treatment (can establish
 causality)

 Control of exposure conditions (single, binary,
 mixtures)

 Susceptible populations can be studied

 Capability of making sophisticated, mildly
 invasive measurements in a laboratory setting

 Use of intervention agents (e.g. anti-
 inflammatory drugs)

 Can form a bridge/link to field studies and
 animal studies

-------
  Ethical issues limit agents to which humans can be
  exposed
   No carcinogens
   Ho agents that sause irreversible damage
  Ethical issues limit who can be exposed
  Small number of subjects studied
  Acute effects primarily studied
  Limitation on kinds of end points that can be used
  Costly to perform
                                    Can use more invasive
                                    procedures

                                    Can study acute as well as
                                    chronic effects

                                    Can study susceptibility
                                    using genetic or other models

                                    Relatively inexpensive to
                                    perform compared with
                                    human studies
                                   Antmal Toxicology Studle!
* Extrapolation to humans must be performed
      short life span
      diet, exercise, housing conditions

* Disease models may not mimic human susceptibility

• Many end points are not comparable to
  measurements made in humans
                                                              an
                                                              k--l I  I
                                                                                1 Air  p 0.4 |}|)m Ozone  D 2.0 pilill O/oi
  Identification of
  underlying
  mechanisms by which
  air pollutants damage
  lung cells

  Rapid screening of
  complex mixtures to
  identify components
  responsible for causing
  adverse health effects
Animal Toxicology studies

      Limitation of In Vitro '  ,


* Cells removed from their normal 3 dimensional
  environment.
   Artificial environment
• No blood supply with potentially important factors.
• Exposure not likely the same as in vivo.

• Hard to measure functional changes in organ
  systems

-------
                    Human
           Animal
                                                                              Amduretal., 1953
                                                                               siuffuf riiojdcfe Jni'miaiion up to 8 ppm eaused ticsus d
                                                                           Frank etal., 1962
                                                                            SisH'ur difiiddft caused mmuv^ed mmay mshtfc'mcft

                                                                           Young etal., 1964
                                                                            «xon£ caus&ii s&oraijmis Jn Sung funcUon b> subj&et?. t
                                                                              and 0.& ppm whHiJ mi rasrt

                                                                           Bates etal., 1972
                                                                            firaS siydy with JnUsfrmtUin?. fixc'S'ciso
                                                                              kw co'nc^n?r?il!onB of ossoruf caused sU^'st.k'jvm irs s
                                                                             iSiimim^mmmffsnxMmr/mmmmfmaimaitmmims
There has been an active human studies program at
EPA since 1973
More than 5000 human volunteers have been studied
with no adverse affects on any volunteer


Human studies done at the EPA have played a key
role in setting and modifying several standards
 O^one 1 hf & 8 hr standards
                                                                           Criteria Air Pollutants
                                                                            Ozone, SO2, NOj, PM, Add Aerosols


                                                                           Water disinfection by-products
                                                                            BDCH

                                                                           Fuel additives
                                                                            iVITBE


                                                                           Air Toxics
                                                                            Toluene, Chlorine

                                                                           Indoor Air
                                                                            VOCs, Bloaerosola
Asthmatics


COPD


Smokers


Diabetics


Metabolic Syndrome


People with Angina
Elderly


Young


Women


Minorities


Athletes


"Responders"
Breath
 blcwiafkars of'exposu
 biomarRers of effect

Skin
 inflammation


Blood
 inflttmmrttkm
 eoagiifmtoo/clutUfig
 lio&i defansa
 ininutns function
 acuto (>hi)Sf! rwitionsf?

Urine
                                                                                                                 Respiratory Tract
                                                                                                                  piiyslokigy
                                                                                                                 Brain/CNS
                                                                                                                  cogtiiticin
                                                                                                                  bahsvior
                                                                                                                 Eyes
                                                                                                                  cell dsmage/frrltstlo^
                                                                                                                  tsar flim stability
                                                                                                                 Heart

-------
     Cardiovascular Physiology
     Respiratory Physiology
     Cellular/Biochemical Changes in Respiratory Tract
     Pharmacokinetics
     Respiratory Tract Dosimetry
     Immune Status
     Neurobehavior Effects
                                                                                  Long Physiology
                                                                             Ozone causes reductions in lung
                                                                              function in healthy volunteers:
                                                                                 Effects at different ages
                                                                                                                         srient
                                                                                  Cardiac Physiology
                                                                               Exposure to PM causes
                                                                               decreased heart rate variability
                                                                               In healthy elderly volunteers
Volunteers are exposed to
concentrated air pollution
particles In the Chapel Hill
air in a unique chamber.
 Average Particle Concenlratlon

Higher concentrations of particles
induce more lung inflammation as
measured by increased  levels of
PMNs.
                    sStililSsswssSEsisBSffl
PM exposure causes a rise      °
   in blood fibrinogen
2.9   47.2     107.3  206.7


 Average Particle Concentration
                  Humans with lung disease
                  have a greater uptake of
                  particles than normal healthy
                  humans.
                   Comparison of blood levels
                   of MTBE following Inhaled,
                   oral, or dermal exposure.
               (B
 *  Increased reliance on human data


 *  Susceptible populations


 '  "omics" technology is changing everything
     Biomarkers of exposure, effect, susceptibility

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The challenge is to make a
convincing case that human
studies done in a safe and
ethical manner can play a key
role in helping the EPA set
standards that will protect the
health of all Americans

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Group 2 Presentation:  Ozone Study—Being in a Clinical Study
Bob Devlin and Don Graff, ORD-NHEERL

Dr. Devlin began the presentation by asking.a few questions such as: What is the benefit of
doing HSR? Should EPA be conducting HSR? What benefit is there to EPA in doing HSR?
With regard to EPA human exposure studies, he pointed out that each study has its own strengths
and limitations. The strengths of epidemiology studies are in species of interest for risk
assessment purposes, in studying humans exposed to "real world" particles in "real world"
scenarios such as asbestos or tobacco smoke, in examining potentially susceptible populations,
and in highly relevant endpoints. The limitations of epidemiology studies lie in that causality is
difficult to demonstrate; confounders are difficult to eliminate such as PM, OB, NOi,  or air toxics;
it can be difficult to measure exposure accurately such as indoor air exposure; biological
plausibility or mechanisms may be hard to examine; and the studies can be costly and time
consuming. The strength of controlled human; exposure studies is in the species of interest for
risk assessment purposes; randomization of treatment; control of exposure conditions (e.g.,
studying children requires a high threshold); studying susceptible populations; having the
capability of making sophisticated, mildly invasive measurements in a laboratory setting; using
intervention agents (e.g., anti-inflammatory drugs); and forming a bridge/link to field studies and
animal studies. The limitations of controlled human exposure studies include the ethical issues
that limit agents to which humans can be exposed (i.e., no carcinogens, no agents that cause
irreversible damage); ethical issues that limit who can be exposed (e.g., children, elderly); small
number of human subjects studies; acute effects being studied primarily; limitation on kinds of
endpoints that can be used; and cost of human  studies, as compared to animal studies.

Dr. Devlin discussed the strengths of animal studies, which include using more invasive
procedures, studying acute as well as chronic effects, studying susceptibility using genetic or
other models, and realizing much lower costs,  as compared to human studies. The limitations of
animal studies, however, includes performing extrapolation to humans, disease models not
mimicking human susceptibility, and having many endpoints that are not comparable to
measurements made in humans. In vitro studies are strong in the identification of underlying
mechanisms by which air pollutants damage lung cells, and in the rapid screening of complex
mixtures to identify components responsible for causing adverse health effects.  The limitations
of in vitro studies, however, is in the fact that cells are removed from their normal three-
dimensional environment; there is no blood supply with potentially important factors; exposure
is not likely the same as in vivo; and it is hard to measure functional changes in organ systems.

Dr. Devlin added that studies should be designed that include all exposures and results should be
extrapolated from them (e.g., combining all studies on current ozone standards).  He pointed out
that there has been an active human studies program at EPA since 1973, and more than 200
different studies have been conducted.  More than 5,000 human volunteers have been studied
with no adverse effects. EPA researchers have studied pollutants such as criteria air pollutants
(ozone, SC>2, NOi, PM, acid aerosols); water disinfection by-products (BDCM); fuel additives
(MTBE); air toxics (toluene, chlorine); and indoor air (VOCs, bioaerosols). Potentially sensitive
subpopulations that  have participated in EPA clinical studies include asthmatics; smokers;
diabetics;  those with COPD, metabolic syndrome, or angina; elderly; young; women; minorities;
athletes; and "responders." In addition, human studies conducted at EPA have been a key factor


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        90

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in setting and modifying several standards.  In controlled human exposure studies, cardiovascular
physiology, respiratory physiology, cellular/biochemical changes in the respiratory tract,
pharmacokinetics, respiratory tract dosimetry, immune status, and neurobehavioral effects are
measured for evidence of pollutant-induced changes.  Expectations for the future include an
increased reliance on human data, susceptible populations, and "omics" technology (e.g.,
biomarkers of exposure, effect, and susceptibility).  EPA's challenge in protecting human health
is to make a convincing case that human studies are conducted in a safe and ethical manner,
which can then be a key factor in helping EPA set standards to protect human health.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        91

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                                                                    Physiologies it,   « ^; in Healthy Young Adults Expo
                                                                                (id  lid   'Wi)&I Hill Coarse Air Parttotes:
                                                                    • What is the research question?
                                                                                            : cause adverse
                                                                    • Who needs the data?
                                                                       EPA Office of Air and Radiation

                                                                    • Why is the data needed?
                                                                       Support the PM NAAQS

Protocol and Consent forms from the 1KB of record

Major sections of the protocol:
 -  Investigators and personnel
 -  Purpose and rationale
 -  Description of study design, methods, and procedures
 -  Benefits to Individuate or society
 -  Sample size calculations and I
 -  Confidentiality and data security
 -  Compensation

Consent form
External review
Internal review prior to IRB
submission
 Branch Chief
 Human Research Ofhs rei
 Informal division review
IRB review
Internal review after IRB
submission
 QA
 Division Director
 HRPO Director
 ADH/E
 HSRRO
  Focused advertisement placement
  depending on the needs of the study
  Some screening can occur over the
  phone to verify study qualifications
  Volunteers who pass the phone
  screening are scheduled to meet with
  the Westat recruiter for a more In-
  depth medical history screening
             '   />                      t

 Medical station staff consists of 3 nurses and 9 EPA and UNO
 physicians
 Medical screening and physical exam
 ••• Review of metdlcai history
   Sriforffiatfon coBscted by Wssiai
 - Evaluates subject's health status
   for study involvement
 - Usually Involves a physical
   Bssessnrteni and blood-work
 If the volunteer passes the
 physical exam Westat schedules
 training or study exposure visits

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 Major sections of consent form:
 Study purpose
 Reasons volunteers should not par
 Step"by"Step description of the volu
    participation
 Possible risks or discomforts
                                    I   '.
 How privacy wiii bs [irotestfid
 What wiM happen if a shidy~r«!aifid injury ccuura
 Questions regarding rights as  a research subject
 Compensstton for parU^Spation
        storage
                       avfsi'i"u• i^^*>*t*3>*33:,t:&4MtC5EJ6»^.fijga^^j'l"j- gsa^gW f-™Jt'.S's
• Always written and explained in layman's terms
• Volunteer and investigator each sign two consent
  forms, one stays in the study file and one goes with
  the volunteer
• Always make it clear that participation is voluntary
  and the participant can withdraw from  the study at
  any point
• Always inform the volunteer of new information
  gained from the study that might influence their
  willingness to continue to participate following
  enrollment



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4

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  •  Present to the HSF at 8 am
  •  Medical assessment by the nursing staff
  *  Pre-exposure blood draw (typically about 80 mL)
  *  Placement of ECG electrodes for telemetry and
    holter monitor (heart rate variability, or HRV)
  *  30 minute rest for pre-exposure HRV measurement
  •  Pre-exposure spirometry to assess lung function
";£x!sssm!iaKmuS
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Dr. Graff discussed protocol preparation for conducting a controlled human exposure study at
EPA's Human Studies Division. He offered three fundamental questions that should be
answered: (1) What is the research question? (2) Who needs the data? (3) Why is the data
needed?  Protocol and consent forms from the IRB are needed. The major sections of the
protocol should include the following:  investigators and personnel; purpose and rationale;
description of the study design, methods, and procedures; benefits to individuals or society;
sample size calculations and methods of data  analysis; confidentiality and data security, which is
increasingly important under the HIPAA rules; and compensation. He added that the Human
Studies Division has a standard set of payments and also tends to pay more as a greater number
of entities are conducting these studies in Research Triangle Park. Dr. Graff stated that an
external review, internal review prior to IRB submission, IRB review, and an internal review
after IRB submission comprise a good protocol review. He then referred to a Westat recruiting
contract that involved focused advertisement placement, which was dependent on the needs of
the study. He indicated that some screening could occur through the telephone to verify study
qualifications. Volunteers who passed the telephone screening were then scheduled to meet with
the Westat recruiter for a more in-depth medical history screening.

With regard to informed consent, Dr. Graff stated that the consent forms should include a study
purpose, reasons the volunteers should not participate, step-by-step description of the volunteer's
participation, possible risks or discomforts, how privacy will be protected, what payment will be
provided for participation, what will happen if a study-related injury occurs, questions about
rights as a research subject, and how the samples collected will be stored.  Consent forms should
be written in layman's terms; both the volunteer and investigator should sign two consent forms
(one for the study file and one that goes with the volunteer).  It should be made clear that
participation is voluntary  and that the participant can withdraw from the study at any point. In
addition, the volunteer should always be informed about new information gained from the study
that might influence their willingness to continue to participate after enrollment.

Questions and Answers

An attendee asked how long it would be before cumulative exposures data would be made
available. Dr. Devlin replied that ORD is preparing this, including regulations with regard to
susceptible populations.  Another attendee asked if there were any adverse events during the
study.  Dr. Devlin responded that there were no ddverse events at the Human Studies Division in
30 years. It was learned that diabetics, however, were more susceptible to ozone, but there were
no adverse effects among 5,000 volunteers. Another attendee inquired how many lives were
saved from the new PM and ozone standards. Dr. Graff pointed out that 500,000 people are
killed by particles world-wide, and 40,000 people are killed in car accidents alone in the United
States. The public health benefits are compelling.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop        97

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 Prolecllon of Human Subjects In EPA's Research and Non-Research Studies
               September 28, 2005
                 Seattle, WA
     The Power of Perception
 A Broader View of Risk Communication
                 Alvln Chun
                 Director
       Center for Risk Communication & Public Involvement
              OSA, ORD, EPA, HQ
               (415)972-3720
                                       Human Study Terms
                                       Human Studies
                                       Payment of Human Subjects
                                       Chemical Exposures Unknown
                                       Potentially High Exposures
                                       Low Income Subjects
                                       Potential Carcinogens
                                       Health Risks
                                       Confidentiality of Data
 Translation into Plain Terms
Govt Experiments
Illegal Bribes

Scary

Death

Helpless Victims
Horrific Deaths
Dangerous
Cover-Up
Human Studies
Payment of Human
Subjects
Chemical Exposures
Unknown
Potentially High
Exposures
Low Income Subjects
Potential Carcinogens
Health Risks
Confidentiality of Data
            The "Story"

There is an illegal top secret government
experiment to kill innocent people.

The government is covering up a
mysterious and dangerous chemical that is
causing cancer in people.
        Outside Inquiries
Why are you killing innocent people?
Do you find that poor people are easier to trick
and lure?
This has the smell of a poorly planned
conspiracy. We're getting different stories
everytime we speak to your office. What else
are you covering up?
Why should we believe anything you say?
You must be in the pocket of big business.
Either you're lying or misleading people?
                                           Some Answers

                                 We have no intentions of killing innocent
                                 poor people. You must be crazy!
                                 You can believe what you want but we
                                 have met all the regulations.
                                 All our studies have strong scientific
                                 justifications.  I don't care what others
                                 have told you. We've gotten approvals
                                 from 3 IRB's as required by our
                                 regulations.

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         The New Story?
         The Problems
                                                     Studies and Good Intentions Aren't Always
                                                     Viewed as Fact... But Perceptions Are


                                                     We Can Create Perceptions Which Can
                                                     Send the Wrong Message About Our
                                                     Studies
      Some Consequences
 (An organizational chart will be developed to illustrate
 how misperoeptions can mobilize outside forces such as
 the media, advocacy groups and politicians to impact a
 study despite all the sound scientific and regulatory
 procedures that were followed.)
Some Solutions To Consider


In addition to the science and regulatory
requirements, think strategically about the
potential perceptions and how they can
influence outside parties.
We work strategically with Management
and Public Affairs to insure that a study is
recognized as a solution to a problem.
 Some Strategic Steps to Consider

• Get the word out about the problem and
 how the proposed study is trying to help
• Be open to outside concerns and address
 them before advancing the study
• Insure that people inside the Agency know
 the facts and where they can get them
• Appoint a point of contact to insure
 consistency

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The Power of Perception:  A Broader Perspective aft Risk Communication
Alvin Chun, ORD, Office of the Administrator

Dr. Bruce Macler, Region 9, introduced Capt. Alvin Chun.  Capt. Chun pointed out that
throughout this workshop, he has been watching and listening to the attendees. His perception of
the group was that attendees were careful, caring, very articulate, and honest people. It was clear
that much work went into organizing the workshop. He asked everyone to think about the
workshop title, "Human Studies by EPA" and commented that the public would perceive this
wording to be a negative thing. The public's perception of the federal government, especially of
EPA, is generally negative.  Those in government are often perceived as bureaucratic, lazy,
secretive, and wasteful. The title was reworked to "Protection of Human Subjects in EPA's
Research and Non-Research Studies" because of fear that someone out in the public would find
out about this workshop. He added that there is a misperception between the public, EPA, and
other attendees. He discussed how human study terms could be translated into plain terms. For
example, the term "human studies" can be translated as government experiments.  "Payment of
human subjects" can be translated as illegal bribes; "chemical exposures unknown" as scary;
"potentially high exposures" as death; and so on.  The "story" then becomes that there is an
illegal top secret government experiment to kill innocent people, and that the government is
covering up a mysterious and dangerous chemical that is causing cancer in people. He showed
how interpretations such as these give wrongful and inaccurate perceptions of human studies. As
a result, there are a lot of questions that arise such as:  Why are you killing innocent people? Do
you find that poor people are easier to trick and lure to these studies? What else are you
covering up?  Why should we believe anything you say? Some of the answers then are that "we
have no intentions of killing innocent poor people"; "you can believe what you want, but we
have met all the regulations"; "all of our studies have strong scientific justifications, and we've
gotten approvals from three  IRB's as required by our regulations."  Although studies and good
intentions are not always viewed as fact, perceptions are viewed as such.

Capt. Chun added that perceptions could be created that send the wrong message about the
studies. Some of the  solutions that can be considered in averting this would be to think
strategically about the potentialperceptions and how they can influence outside parties. Also,
working strategically with management and public affairs can help to ensure that a study is
recognized as a  solution to a problem. Strategic steps could include: getting the word out about
the problem and how the proposed study is trying to help; being open to outside concerns and
addressing them before advancing the study; ensuring that people inside the Agency know the
facts and where they can get them; and appointing a point of contact to ensure consistency. He
advised everyone on being aware of the power  of perception in the things they do and in the
things they write. Human studies are hard to define. Empathy and openness are important to the
public when communicating on this topic.  In addition, it would be a good idea to let people
know of a problem early on  so as to earn their trust. Capt. Chun suggested the development of a
brochure to explain human studies.

Questions and Answers

A suggestion  was made for more information to be disseminated to soften the public's perception
of EPA.  A question was asked on how to motivate people to get a more positive reaction.  Capt.


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      100

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Chun suggested creating doubt about a current situation, which would be dependent on
establishing trust. An attendee asked what to do if the information still is not accepted. EPA has
to listen to what the public is saying. The human subjects issue goes to the heart of the public's
values. If the public hears that something is negative on the television, then they will believe it
no matter what EPA says about it. Capt. Chun suggested establishing good relationships,
acknowledging peoples' concerns, being open with the facts, and negotiating with the public if
their values are different. A comment was made that, from a scientific viewpoint, it is hard to
share the facts with the public. Another attendee asked what could be done to change the
perceptions within EPA.  Capt. Chun observed that most people experience many disruptions
during the day and are distracted with other tasks, which makes it harder to focus on changing
perceptions. Staff in the Regions, however, have more control of their time, so they might be
capable of promoting change.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       101

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Day Four

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      Additional Safeguards for
         Vumei^abli|iSubjeets
            Septerrfber29,"2005
 Ks    ^Vulnerable Subjects -s||sjss;
 ?   -1       Definition    ;    111"
; "Vulnerable"-\>0is not the best word choicf for
   use in the 19S11 NIH and FDA regulations
               IJavid ForsterS       ;is:
     Western Institutional Review Board
 Webster's-           ;v  .,        ;:-
 1. Capable of being physically wounded
 2. Open to attack or damage          ' >
 | *    Vulnerable Jtujtfjects -
       Historical Use of Term
  "The special considerations that should be:it
  given to cliildrenvandanfants Jiare, first, that $
  they are particularlysSglnerable and helpless-
 ^aiicl therefore call;for"ntpre|consideration
 ;thanjdthergroups.";   •;  >*8     fr
      Historical Use of Concent
  : Dr. Rdbert Marston, in a speech at University of ;
  Virginia on November 10, 1972, addressed the  ;rf
  concept; of individuals with "limited civil   v  M
  freedorS," antoped for better protections for ;J||
  them, |:  vj|j;w   ;      ;:         ^ggl
  , ^TUis included prisoners, residents of instirufibris-
  ;forjthe mentally Retarded and mentally ill, an||sP
  min^rs.'^    :« •         •     • : '.":'.  -wKr
  /Hastifigs Center Report 3(2)fl-4, Apr 1973. *
        Vulnerable Subjects -
       Historical Use of Term
"Vuhierable" is not usedjiffi SHIS;
•The Nuremberg CodeivS   ; SSS^
• The Declaration of Helsinki (until 2000 version),
• 1974 NIH regulations on subject protection, or
• The Belmont Report.   .-.;-.:              ''•}:'•'


' Used in the 1981 NIp^iStEIM regulations^
        Vulnerable fubjeeti -
         The Belmont Report
  The Belmont K,eport addressed the concept of
  vulnerability Ss part ;of the pjriiiciple of Respect for
  Persons: ;oS   -;/--yA^K, %:-'?--    :::  S*; :
 "Respect foripersons incorporates at least two
  ethical convictions: first, that individuals should
  :be treated as autonomous agents, :aiid sebpnd, that
  persons with diminished autonorny^ire'erititled to ;
  protection."      \- ^      -x "';   -v      ;S;;

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          Belmont Report quote
                                                  Elements of Autonomy
   '"Not every human being is capable of self-
   determination. The capacity for self-determination
   matures during an individual's life, and some
   individuals lose this capacity wholly or in part ¥ ;
  : because of illness, mental disability, or        ;: I
  .circumstances that severely restrict liberty.
  JRespect for the immature and the'incapacitated
  Smay require protecting them as they mature or
   jvhilethey are incapacitated."   : {'      •---.'
                                           Capacity
                          Voluntariness S^;


                          Freedom from the
                          control or influence
                          of others.
   l|g;  Vulnerable Subjects;   H-,
   (Have Actual or Potential Limitations on Autonomy)
Lack of Capacity
  Temporary; i
  Fluctuating
 Limits on Voluntariness
 (potential for control, coercion,
 undue influence, or     :
 manipulation)       \ S'&
 • Fatal or Incurable Diseas^;/
 • Emergency Situations ^fpv
 • Hierarchical Social Structure
 • Economically Disadvantaged
 • Educationally Disadvantaged
•"• Marginalized Social Groups
                                                         Definitions
 Control - Physical restraints.
/Coercion - Use of a credible threat of harm or force to
 control another.                : :;v
 Undue Influence - Misuse of a position of confidence or
 power to lead anotherto make a decision he would not
 otherwise have mac!e.i;v                   S   '•":•'
• Manipulation - Deliberate management of conditions or
: infoririation in such a way as to lead another to make a-•
^decision he would not otherwise have made. Examples"
Sof information manipulation include lying, withholding ,
 infoitriation, and exaggeration.-:
        Constant Considerations
           about Vulnerability
   ^ithin any population of vulnerable ;subjectSiK;
   individuals wilUiave difl^feiitlevelsiSfiWSS-
   vulnerability.  S/ -;:     ^gly •-.-  '•:- ' y:;f^'-;S-
   The level of vulnerability pfraii individual may
  'change due to changes in capacity or in conditions
  laffecting voluntariness.     I     '          :•••
  •sjfhe IRB considers a hypothetical group of  ';/;£ -,.
   •subjects^whereas the investigator interacts with; ^
   actual subjectsss       :v ..'.-•••  ••_ :W:ji:&fyi-'-
                                         HHS Regulation 45 CFR 46.111(1^) -
                                          Definition of Vulnerable ;Subjects
                                        llaWhen sorrie^di'alliof the subjects, such as      >•
                                        ;; 6hildrepi;:prisoners,;pregnant women,
                                         liandicapped or mentally disabled persons, or;:
                                         economically or educationally disadvantageci:''s
                                         persons, are likely to be vulnerable to coercion pi-
                                         undue influence [,-] additional safeguards have
                                         been included in the study to protect the rights
                                         and welfare of: tjiesei subjects."-       :-:-;:

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       ICH1.61 - Definitiol if
        I Vulnerable Subjects
 Individuals whose willingness to volunteer Jri|;
 a clinical trial may be unduly influenced by  •
 the expectation, whether justified or not, of;
 benefits associatedftwim participation, or oKK;
 retaliatory response from senior members of a
 hierarchy in case of refusal to participate.
      ICH 1|61 2 Definition
 ft    Vulnerable Subjects <«,„«
Examples are members of Kgrcmp withfta
pharmacy, dental, and nursing students, ft;
subordinate hospital andftlaboratory personnel,
employees of ihe pharmaceutical industry,
members of the armedftfbrcesft and persons;
kept in detention.      ftfti       ;:,     S
       ICH 1.6r-Definition pf   f|
      Vulnerable Subjects (cont.)
 Other vulnerable subjects include^§|tients
 with incurable diseases, persons iniiursing    ;
i hpmes,; jinemployed pr/jnlpoverished persons,
 minority ;groups, homeless personSv-nomads,
 refugees, minors, and those incapable of
; giving consent.    ^,v:s
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        Emergency Situations
    Hierarchical Social Structure
   Possible:problems with capacity,   -i
   Potential fofceontrol, coercion, undu
   /influence, or manipulation.    ^&
   IHmits on yoluntaririess due to time %
   constraints.
   Institutional Setting;.
  Potential for control, coercion, undue    ^
  influence, or manipulation.              "A.
  Examples include:;iPrisoners,vrnilitary      -H
 ^personnel, employees, students, hospitalized
  patients, and residents of nursing homes and
  other medical institutions, :;^;    -.^      i
 |Prisonera;are automatically vulnerable by
 ^regulation;                        ™;
   Educationally Disadvantage^
   Economically Disadvaniaged
  Mayjhave limitations on understanding:;
  May^fee illiterate,^    :f   /§j  ;   -
  Potential for undue influence of U
  manipulation. tK;B;   M    ;l£>iv::;::
  MgySiiroll jn research in order to receive
  treatment. ">        VS   :    -"-•
  May em-oil in research solely: for compehsation
  (fbr^xarnple, Phpse;! drug studies).  ';- :
 : OfteiiSducationally Sisadyantaged in addition.
  Potential for  undue influence or manipulation.
 f Marginalizeti Social Groups
          .::       :.':     ' xK-^f"     . V
 ,Have little social pchver. '¥•   .-'v-f J-;  •':
^ftennotjgrantedfultaccess to social?:
 institutions, such as the legal system.v;
 Potential for control, coercion, undue   v
^influence, or manipulation.       ;" »^;:;
 Many possible sources - disease, race;
 •poverty, etc.  ; ''- ;,;&     @;;  :  :^ 6    .;
  Individuals withIpatal Disease
 M|yitake verjy:high risks in desperation fori
 cure.:t    ''•*•       «;C       '- : 'A      1
 Potential for imdue influence or :-     ^;
 manipulation.-?    -'     ••      «ff:        "%:,
 May be problems with, capacity,'permanent-!
 or temporary, caused by disease or drugs*
; Vulnerability magnified in dying subjects, fc

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   Individuals with Incurable Disease
  May takeiyery high risks iff desperation^iBr
  cure. ^«g;i  «3  :      \''        '-.,-.  '•};!'
           :\;^    .   -J  :              •:
  Potential^imdue influence or     S
  manipulatiM.          V-fe?'-     - tfc
  Mayv^ejprQblems with capacity, permaiieht
  or temporary,'caused by disease or drugs.v
        for vulnerable subjects?
  j :Regulationf g- "When some or all of the  si:
  >.subjects areflikely to be vulnerable to    S«i;
   coercion or wdue influence^such as       *
   children, prisoners, pregnant women,
   ttientally disabled persons, or econStm'cally
  ji&r educationally disadvantaged persSns,   j
  ^additional safeguards have beeririncluded inH
  tth|;study toiprotect the rightsitnd welfare;JPi
   •these subjects?'46:1 ll(b);;:vJ*P": -    *;•:"!
  What ti^e additional safeguardis
 ;      for Vulnerable subjects? I
 :^^::         ';iv^   ':       \^?-^    •     ^;^-
 SThe subpart A::regulations dojiSt provide a sg i
  definition.;-  * :;'j^;:.  ••    * ;K          ^?|;-:;
  However, subpafts B, C, and D do provide   : x*;':
 ^examples. -^ vR   •        : >        '"•  •.'/•":.
 BCongress tasked the National :6Sinmission with
 l^vriting reports-bnjesearch withipregnant woitieii,:
 (prisoners, childtejpBnd the institutionalized "-SI:-
  mentally disabled;1 S  -.-..'•.            ?*J
  The first three reports are the basis for subparts B,
 ;;C, and D of theyNIH regulations (45 CFR 46).'.:
 p fFR 5f45 CFR |6-§ibpart g
 §50^51/46.404 Clinical Invesdg!rtfeii| not
  ^Involving greater than minimal risk;
  r grelter than friinimal risk|g|cii>ijdireh is " :.j  ;: il
   presented niaylnvolvechil^jren|S;SubjectsvI&-K
   only if the IllB finds' arid dociiment! that s*Sr;; -•
  sadequate provisions: are;rnade for soliciting : the
  ?sassent- of thejchildren and; the permission of
   then-parents; or guardian§as;Setfbrth in -'•-   -^
   §5S,55/§46.408.  ;; :   jiS^M^   '•• f!..->;V.
21 CFR 50/4^ iSFR 46 - Subpart 1)
 Additional Protections for Children  {>
 Involved as Subjects in Research      '
 Source: 48 FR 9818, March 8, 1983, unless
 otherwise noted.         d        ^ VS:
 21 CFR 50/45 CFR 46 - Subpart D
 §50.52 /46.404 Clinical investigations involving
   greater than minimal risk but presenting the
   prospect of direct benefit to individual subjects,
   Any clinical investigation . v;in wlu'chniorethanU
   minimal risk to'children is presented by an    ,;W
   intervention or procedure that holds out the   ;o"
   prospect of direct benefit for the individual
 .-.  subjec|,;or by^a monitoring procedure that is likely
;;t;,.to coiitribute to^the subject's^vell-beirig, may  '; ,
;-- involve children as subjects'SnjyJiplje IRB finds ;i;
   and documents that^'S* ffi:; - -K-^S'    t' A' ;

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 pi  CFR 50/45 CFR 4% Subpart D
  21 CFR 50/45 CFR 46 - Subpart D
  (a) the risk is justified by the anticipated benefit to
     theisubjects; v « V    ..••.-..
  (b) the relation of the anticipated benefit to the risk is
 i   at least as;iavorable to tlie:subjeots:as that
 ~g   presented;by available alternative approaches;
 %   and      'V£.         i-;;  V  '-^ -t \^:i:  ,,
  (c) adequate provisions are made for solioitingtthe':(.
  r  assent of the^hildren and permission of their':"
 :  ^  parents^ guardians as set forth iii:50.55,  ;
  §50.53/46.404 Clinical investigations involving greater
  than minimal risk and no prospect of direct benefit to
  individual subjects, but likely to yield gelleralizable   ;
  knowledge about the subject's disorder or condition, x ;::
  Any clinical investigation^.: • • in which more than minimal  : :;
  :risk to children :is presented by an intervention or procedure
  •that does not hold out the prospect of direct benefit for the
  individual subject, or by a   monitoring procedure that is not
  likely to contribute to the well-being of the subject, may
  iriyojve children-as subjects only if the 1RB finds and
  documents that: KfcK;^       ,          "
 % 1 CFR J0/4       R 46. -
 (a) the risk represents a riiinor increase over minimal risk;
 (fa) the intervention of "procedurepresents:experiences to
 :  : subjects thai are reasonably commensurate with those
   inherent in their actual orexpected medical, dental,
   psychological, social, coeducational situations;  "'.     «
 (c) the intervention or procedure'is likely to yield generalizable;
  iiinowledge about the subjectsrilisorder or condition which is
  gof vital importance for the understanding or amelioration of
  Etjie subjects' disorder or/condition; and
 (d)'adequate provisions are made for soliciting assent of the
   children and permission of their parents or guardians as set
   forth in 50.55/46.408.   : :K  ':'     -Kf
  21 CFR 50/45 (3FR46 - Subpart JD
 §5();54/46.407 Clinical investigations;!^* otherwise^ 5V •
   approvable that present an opportunity to understand,
;,  prevent, or alleviate a serious probleWf affecting the
:y, health or welfare of children.     VKj::         ^
 y If anjlRB does not believe that a clinical investigation .:•;';. ^
  : involving children meets the requirements of §50.51,
   §50.52, jjir §50.53, the:clinical investigation may proceed
   onlyifSjS:        ""£••>•  K-           ;•••
 (a) The IRBjjjnds that thejclhucal investigation presents a
   reasonable oppoilunityj to :further the understanding,
   prevention, or alleviatioiiibf a serious problem affecting the
   health or welfare of children; and  •--     ,4 :-SLv
 21 CFR 50/45 CFR 46 - Subpart D
 2||CFR 5d/45lCFR 46 - Subpart D
 (b);Tfie%)mmissioner of Food:and Drags! after
:    ^consviltation with a paneljof experts in-pertinent
;;;    disciplines (for example^ science^inedicine^ :   :
•1;    education, ethics, law):and^followirig-/SSSv: ^--^
"^   opportunity for public review and comHeril^has
 •'•   deteriTiined either:     -•;  "'         <;-.-•  W'^'
 (1) that ;the research in fact satisfies the conditions
:•  :v6Q|0.51, §50.52, or §50:^3, as applicable, or  .':
^;(2) that the following conditions are:inet;:|eS ff:-
J(i)  Tlie clinical investigation presents a reasonable
:;g    opportunity to further the understanding,     .K,.,
 ^    prevention, or alleviation of a serieiis problenr i
  ;    affeipting t-he health or welfare of children;     -;
 (ii)  The clinical investigation will be conducted in
      accordance with sound 'ethical principles; andv;
 (iii) Adequate provisioh$;are rnadeibr: solicitingith|:
 5    assent of children and the permission of their ^
 '.:•    parents or guardians as set forth in 50.55.«::?"  S

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 re|[pt|Sgpp6iirtirieiit of an ;advodat|;:fbr
 ea[;lid;wlio is;a wardjjijii additin to

                                                                           Novemb(:ri3,;2001,;Fi|S6^) '.
Pregnant|voni|ti -pjB^f lis^tnay ;be involved in
  )|Whe|i^sci6htiQ9aily appropriate, preclinical ;|r
   itudigfj including studies on pregnant    :  .^
  "vliiiniBli, arid clinical studies, including studies-:
   :pn n6rgpregnant womenj have been ;    'i:   •:'.
   cpiidag|ed and 1 provide;data for assessing    .'• -.
   potential-risks to^regnaiit women and fetusesp
                                                                    45 cfflilliluipf t B
                                                                          ii:ssiSj.vj:: ;y 5V : ".": ™j  ..- ^::*: v-:
: the prosi|ec|gRdi^fct ;benifor:the ;S   I
 woman i|i; tiie|fetiis;;pr, ifth|re;is no^iicH
 prospectigf b6neflt,v|he risl§i:o thie fetuses '
 riot grea^p than minimal atSd thgp\i jgftse
                                                                (3afiiiot be||3btained;by 'any othe§|i:l|ajis

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          45CFR46-SubpartB
          45 CFR 46-Subpart C
 «(h) No inducenieiits, moijetary or otherwise,  :;
 -  ; will be offered/to terminate a pregnancy;
  (i)jlndividuals engaged in the itsearch,wil|
 ;    have no part in any decisions as toiher 1^
 f    timing, methodi:or procedures used to  .'-."A
 ,;   terminate a pregnancy; and v
  (j) Individuals engaged in the research will
     jftave no part in determining the viability of
 V    aineonate. ••-. Z\ ••  K                  %
           Additional DHHSJProtections
      Pertaining to Biomedical and Behavioral
       , ^           Research
       -   Involving Prisoners as Subjectsi; ;S
         45 CFR 41 - Siibpat^ C
        15 GFR 46-Subpart <1
  -.  Inasirtiiidi as prisoners May be under ctjiistraints
  ^because of their incarceration||'hich eould affect
  f ;their ability to make a truly voluntary artd^ •'&:-
  :imcoen;ec|decision whether or not to partimjpfta
    subjeets;Hfrfsearch, it i|'{lie purpose of tliis^  :
    subpart to provide additional safeguards for the
  ^protection of prisoners involved;inactivities tot
  ^JWhiclithis;subpartis applicableiS \    5: Jl*l:.
    §46.304 QompositipTi of Institutional Review
   ^Boards where^prisdners are involved.   ^    t:;  ;
   ';%) A majority of theBoard (exclusive ofpH|bner
    "'.-. members) shall have no association with the
       prison(s) involved, apart ;from:iheir   ''.'-^.~>i
    (b)"^t --least"6i|e;raeniber'of-: the Board shall bela
      prisoner, or a prisoner representative with
      appropriate backgroundj and experience to
         45 (|f 1^46-Subpart C
: • ;t:;;§46.305 Additional duties of^Ilie Institutional , -..'.
  ;;^eview Boarcls where:prisoners are involved.   ;:
 (a) In;addition to alfeptherTesponsibilities prescribed^
 ;   fbr-Institutional^view Boards underlhis part,  :
:••.  thefBoard shall;review researph covered by this  :
 ::   subpart and approve such research:ouly;if it finds
  -^that:       :/i K'.;."-.     '•"     : -^W:  :' ••
    ; f I) The research-'iiiider review represents one of
-.-'-  .-.v-'i-tlie categorfeof research perrrii$slble under
.; ,;    §46.306(a)(2);        :3l  v.l];%     ;
        45 GFR 46-Subpart €
*(2) Any possible advantages accruing to the prisoner
 it: tlirpugh his orhepparticipatiouun the researches, vj
  ; When compared to the generailiving conditions^
    medical care, quality of food, amenities and
    opportunity for eariiings in the prison, 'are not of
    such a-magnitude^that his or .her ability to weigh -
    the :f iskS;Of the research against the value :of such
    advantages in the limited choice environment of
    the prison is impaired;  ,fe;/,-        '••  ' •  -.-•

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       45 CMft 46 - SuKpai|t C
(3)  Theiisfe involved in the research are S;
    commensurate with risks that would be
    accepted;by nonprisonej;;yolunteersj
(4)  Procedures: for the selection of subjects ^
    within the prison are fair to all prison|fs*
    andijmrnune from arbitrary intervention'
    by plnsQii authorities or prisoners.     I;
             Concliisibn
The use of additional safeguards;pf(jvide
extra protections for vulnerable sublets.
They serve a paternalistic ftmction, a'iid
administratively limit the choices open to«
subjects, iigestigatorsvJlRBs, and-agencies;;
in other wb||s, they cuf:c-ff scim'Jtif the v^l!
possible branches of ehoieeijnjglilcisiorf-1
making tree;M  ^     WffWi: :;fl|;.   •  \

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Thursday, September 29, 2005 (Day Four)

AM Moderators: Alicia Alto and Suzanne Wuerthele

Special Protections for Children, Fetus, Elderly, Lower Socioeconomic Groups, English as
a Second Language Groups
David Forster, Western IRB and University of Washington

Mr. Forster began his presentation with identifying that the Western IRB was a "for-profit"
agency, with 80 percent of the board members not on staff.  The Western IRB has completed
many reviews for other institutions (e.g., Johns Hopkins University), and the reviews were
primarily for medical research.  In addition, there are approximately 20-30 private IRBs (out of a
total of 4,000) in comparison to university IRBs.  Mr. Forster expressed that in referring to
vulnerable subjects, the term "vulnerable" w%s not the best choice of word to use in the 1981
NIH and FDA regulations.  In the historical use of the term "vulnerable subjects," it meant that
children and infants are particularly vulnerable and need more consideration than other groups.
Vulnerable subjects also can be regarded as human guinea pigs (M.H. Pappworth, Human
Guinea Pigs, 1967). In a speech at the University of Virginia in 1972, Dr. Robert Marston
addressed the concept of individuals with "limited civil freedom" and called for better protection
of them. This included prisoners, residents of institutions for the mentally retarded and mentally
ill, and minors (see Hastings Center Report 1973;3(2):l-4).  The term "vulnerable" is not used
in the Nuremberg Code, Declaration of Helsinki,  1974 NIH regulations on subject protection, or
the Belmont Report. It was used, however, in the 1981 NIH and FDA regulations.  Mr. Forster
added that the Belmont Report addressed the concept of vulnerability as part of the principle of
Respect of Persons: "Respect for persons incorporates at least two ethical convictions: first, that
individuals should be treated as autonomous agents, and second, that persons with diminished
autonomy are entitled to protection."  Vulnerable subjects have actual or potential limitations on
autonomy.  Those that lack capacity are children and the mentally disabled.  Limits on
voluntariness include a fatal or incurable disease, emergency situations, hierarchical social
structure, economically disadvantaged, educationally disadvantaged, and marginalized social
groups.

Mr. Forster stated that there are constant considerations about vulnerability, and individuals will
have different levels of vulnerability. The level of vulnerability of an individual may change
because of changes in capacity or in conditions affecting voluntariness. The IRB considers a
hypothetical group of subjects, whereas the investigator interacts with the actual subjects. The
definition of vulnerable subjects according to DHHS Regulation 45CFR  46.11 l(b) states that
"when some or all of the subjects, such as children, prisoners, pregnant women, handicapped or
mentally disabled persons, or economically or educationally disadvantaged persons, are likely to
be vulnerable to coercion or undue influence, additional safeguards have been included in the
study to protect the rights and welfare of these subjects." As an additional safeguard for
vulnerable subjects, Congress has asked that reports be written on the impacts of research with
pregnant women, prisoners, children, and the institutionalized mentally disabled. Also, clinical
investigations cannot involve more than minimal risk to vulnerable subjects, and only if the IRB
finds and documents that adequate provisions are made for soliciting the assent of children and
the permission of their parents or guardians as listed in 21CFR50 and 45CFR46, Subpart D.


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Those studies that involve greater than minimal risk and no direct benefit to individual subjects,
but are likely to provide generalizable knowledge about the subject's disorder or condition, can
be conducted only if the IRB finds and documents that the risk is a minor increase over minimal
risk, and the intervention or procedure involves experiences that are commensurate with those
inherent in their actual or  expected medical, dental, psychological, social, or educational
situations. Children who are wards of the state or any other agency, institution, or entity can be
included in research approved under CFR 46.406 or 46.607 if the research is related to their
status as wards or if conducted in schools, camps, hospitals, institutions, or similar settings in
which the majority of children involved as subjects are not wards.  The regulation also states that
the IRB will require appointment of an advocate for each child who is a ward, in addition to any
other individual acting on behalf of the child as guardian or in loco parentis. Pregnant women or
fetuses may be involved in research if "preclinical studies, including those on pregnant animals,
and clinical studies, including those on non-pregnant women, have been conducted and provide
data for assessing potential risks to pregnant women and fetuses."  No inducements, monetary or
otherwise, will be offered to terminate a pregnancy and those engaged in the research will have
no part in determining the viability of a neonate.  In the case of prisoners as vulnerable subjects,
45CFR46 Subpart C states that additional safeguards should be taken for the protection of
prisoners involved in research activities.  The use of additional safeguards must provide extra.
protections for vulnerable subjects and serve to limit the choices open to subjects, investigators,
IRBs, and agencies.

Questions and Answers

A question was asked whether there was a national IRB group.  Mr. Forster replied that ARENA
is a national group that holds meetings at which larger IRBs attend. The smaller IRBs, he added,
do not attend because they do not have enough funds to send people to these meetings. In
general, the IRBs think that there should be more regional IRBs; however, during the past 5
years, there has been more talk about national IRBs or central IRBs. Another question was asked
about the financial outlook for the Western IRB and other "for-profit" IRBs. Mr. Forster
responded that the for-profit IRBs charge on a fee-for-service basis. When some institutions
began closing, these IRBs were facing a more serious problem, but the situation has been
improving. The problem now is teasing out the costs of an IRB. With regard to informed
consent, an attendee asked if there was any reason not to provide information when conducting
research.  Mr. Forster stated that the informed consent process should be followed closely and
that people should be told all the information they need to make an informed decision. He
pointed out that it is standard practice to use deception,  and that at times many ethical issues
arise. A question was asked regarding how the Common Rule, 40CFR46 (EPA counterpart), the
Belmont Report, and other documents or reports fit together.  Mr. Forster pointed out that these
items are Part A of the NIH regulations, which is comprised of pieces added by various agencies.
Another question was asked about whether the FDA screens the ethics of the research studies.
Mr. Forster added that the FDA is now thinking about eliminating the Helsinki regulations and
adopting more ethical considerations.  A comment was made regarding the fact that EPA has not
adopted all of the subparts of the NIH regulations, but that hopefully, Dr. Preuss would affect
some change in this respect.  Another comment was added that EPA Regions might be
conducting research that may involve human subjects but not what would be considered HSR. It
is important to distinguish between HSR and public health practice. Mr. Forster added that it is a


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difficult distinction to make but should be made with the help of an IRB. A question was asked
if an accreditation process was starting to take place for IRBs. Mr. Forster replied that the
accreditation process began about 3 years ago, but it was an expensive process. Eventually, he
added, all IRBs will be accredited.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      114

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Overview of the Proposed Third Party Rule
Anne Lindsay,  EPA Office of Pesticides Programs

Dr. Wuerthele introduced Ms. Lindsay, Deputy Director of the Office of Pesticides Programs
(OPP). Ms. Lindsay pointed out that she spent her entire EPA career in the pesticides program;
she is a policy person, not a researcher or scientist. She stated that OPP makes decisions about
whether pesticides should enter, remain, or be removed from the market.  OPP does not
commission research and essentially is not a scientific research organization.  She added that in
the future, however, opportunities might exist to collaborate and develop better ways of doing
things. OPP is involved in conducting third-party studies. She discussed some of the key
elements of a new proposed rule published in the Federal Register on September 12 that
provides the strongest protections for human subjects proposed by the federal government,
including a categorical ban on any new testing of pesticides that involves intentional dosing of
pregnant women or children. She referred participants to the following Web site for the full
proposal and related materials:  http://www;.e^                                      M.s.
Lindsay described some of the many types of HSR activities with pesticides.  She explained that
many human studies involve collecting data on people who are exposed to pesticides in their
daily activities (e.g., pesticides loaders and applicators).  Approximately 22 third-party toxicity
studies that cover about 14 different pesticides have been submitted to EPA.  These studies were
submitted between 1967 and 2004, the majority of which were generated between 1996 and
2004. Nineteen of the studies were intended to identify or quantify the toxic effects of a
pesticide. These studies do not involve intentional exposure. Other examples of human studies
that do not involve intentional exposure include epidemiologic studies, analyses of accidents or
incidents, and  monitoring and observational studies. There are, however, many types of
intentional dosing studies such as studies to test the effectiveness of mosquito repellents. Dermal
absorption studies can involve a small amount of chemical being placed on the skin of a human
volunteer and researchers determining how much of the chemical is absorbed and how quickly it
infiltrates the individual's blood,  urine, or excrement. This type of absorption study can be very
important in assessing a pesticide's risk in an occupational setting. In addition, there are
intentional dosing studies to identify or measure toxic effects in humans in which volunteers
receive small but  increasing doses of a chemical to ascertain the dose that causes a threshold
adverse reaction.  She added that  the majority of human studies on pesticides received by OPP
come from observational studies  of exposure; most of these studies do not involve intentional
dosing or exposure but rather collect data from subjects engaged in normal daily activities.

Ms. Lindsay provided an overview of the Common Rule and EPA's codification at 40CFR26.
She defined first-, second-, and third-party research. She explained that HSR conducted by a
federal Common Rule agency is "first-party" research. Research conducted by others with the
support of a federal Common Rule agency is "second-party" research.  Research conducted by
others with no support from any federal Common Rule agency is considered "third-party"
research. EPA's Common Rule applies to all of EPA's first- and second-party research.  EPA's
proposed rule would extend the Common Rule to certain regulated third-party research. EPA's
proposed regulation is to protect the welfare of human research participants by setting rigorous
standards to guide how new human research is performed and by defining criteria to judge the
acceptability of the results once such research is completed. Human subjects must be treated
ethically and be fully informed of potential risks. The main focus of EPA's proposed new


         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop       US

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regulation is intentional dosing human studies for pesticides conducted by private researchers
without federal government support (i.e., by third parties).

Ms. Lindsay summarized the substance of EPA's proposed rule. She indicated that the
regulation would establish stringent and enforceable standards for ethical conduct of research
involving intentional dosing of humans with pesticides. The proposal, she added, is based on the
2004 report of the National Academy of Sciences (NAS) and contains even more protective
measures than those recommended by the NAS and goes beyond the requirements of EPA's
FY06 Appropriations Act.  The proposed rule, which was signed by the President of the United
States on August 2, 2005, prohibits conducting new third-party intentional dosing studies on
pregnant women or children under current pesticide laws. This rule is consistent with the
Appropriations Act forbidding the use of pregnant women, infants, or children as subjects and
applies to all intentional dosing studies, not just toxicity studies, and to all substances, not just
pesticides. The proposed rule makes no exceptions, either for EPA or for regulated third parties.
In addition, the proposed rule also forbids EPA from relying on studies that involve intentional
dosing of pregnant women or children in its pesticide decision-making, whether they are based
on the results from new or old intentional dosing studies.  By extending the Common Rule to
third parties who conduct intentional dosing studies intended for submission to EPA, people who
volunteer for third-party intentional dosing pesticide studies will be treated ethically, potential
risks will be fully disclosed to them, and every effort will be made to minimize any additional
risks.

Ms. Lindsay pointed out that although third-party intentional dosing HSR studies with pesticides
currently are not required to undergo any external review, EPA is proposing to establish an
HSRB to review study protocols before the research is conducted and the reports after the
research have been completed. Every new intentional dosing study for a pesticide will undergo
ethical review by a local IRB and then by EPA staff and the HSRB. Recommendations from all
three groups regarding the scientific and ethical aspects of the proposed research will be
provided to investigators before a study begins.  The 90-day comment period on the proposed
rule, as required by the Appropriations Act, will end in early December. A final rule is due
within 180 days of enactment, which will be the end of January. OPP has begun discontinuing
reliance on third-party intentional dosing human  toxicity studies. OPP would like the proposed
rule to be approved by February 2006. She emphasized the value of public input.

Questions and Answers

A comment was made that the OPP program was very rigorous in its review of human studies
data. The question was asked whether human studies would follow the same standards as animal
studies. Ms. Lindsay replied that human studies  are performed incorporating the highest
scientific standards; otherwise, they would not be ethical to conduct. She added that the early
critics of the proposed rule view this as a loophole that would encourage people to violate the
standards in the Rule. She did not think that decisionmakers in the Agency would want to be in a
position where they knew that there was a piece of reliable data showing a need for better
protective regulatory action but that it was forbidden  to use it according to the Rule. Some think
this is wrong.  Another question arose regarding whether OPP receives data from pregnant
women and children non-intentional dosing studies. Ms. Lindsay could not recall ever receiving


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such a study. One comment being considered in the proposed Rule is whether the coverage
should be broadened to include non-intentional dosing studies. There are related ethical
questions that probably should be included in the Rule. Another question was asked whether the
pesticides data and human studies data are readily available.  Ms. Lindsay stated that the best
pesticides data are available and that most or all of the human studies data can be made available
through a FOIA request. A question was asked regarding the fate of data collected on pregnant
women and if such a study would be regarded as unethical. Ms. Lindsay replied that the study
would have to go through the HSRB and would need large public input to decide how the data
should be used. An attendee asked whether a categorical ban would be placed on such a study.
Ms. Lindsay indicated that a categorical ban would be placed on the conduct of data use only,
not on the study. A question was asked whether there were any plans to address classification of
a harmful substance. Ms. Lindsay replied that the Agency needs to hold more discussions on this
topic. Additionally, she stated that the struggle would be to find an effective way to use the
proposed Rule.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      117

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Where To Go for Help—Overview
Jean Zodrow, EPA Region 10

Dr. Lorenzana referred the attendees to the List of Resources in Appendix A. Other materials are
available on QuickPlace.  She added that there definitely would be follow up after this meeting.
She then referred to the next presentation, which would be given by the four discussion leaders
on their group's recommendations. She added that for those involved in the planning group,
there would be a conference call meeting in 2 weeks. At that time, the first priority would be to
review the recommendations and decide how to consolidate the recommendations.

Draft Recommendations and Proposed Next Steps

The following recommendations were compiled by attendees at the end of the workshop:
                                        t!
•   Create a culture where the protection of human subjects in EPA-conducted or -funded studies
    (whether the studies are HSR or public health practice) is the number one priority.

•   Increase management's focus/attention on HSR by: (1) having workshop participants brief
    their DRAs, (2) inviting Peter Preuss to brief DRAs and RAs on HSR requirements,
    (3) identifying HSR on SCOUT, and (4)  developing a briefing strategy for upper
    management.

•   Develop and implement interim guidance and policy for Regions as national efforts evolve.

•   Identify a Human Subjects Officer and associated advisoiy board in each Region.

•   Have the Regional Human Subjects Officer make the final regional determination as to
    whether a study is HSR or public health practice. Dr. Roger Cortesi (ORD/NCER) and
    Dr. Rick Hermann (ORD/NHEERL-Human Research Protocol Office Director) are available
    for consultation.

•   Create a National Human Subjects Officer Council led by a Agency Human Subjects
    Research Review Official that is composed of Human Subjects Officers from each Region
    and National Program Offices to maintain consistency and communication across the Agency
    and to inform with new developments on HSR; develop national guidance and policy for
    HSR; identify additional tracking needs for the existing system that includes query
    capability; and develop an Agency-wide human subjects training plan and program.

•   Make changes to IGMS to reflect the HSR determination and approval process, including:
    (1) enhancing awareness of HSR and its  requirements relevant to the EPA Grants Program by
    coordinating with the 12 Regional Grants Management Officers; (2) reconciling grant
    funding timelines with the HSR approval process and making potential grantees aware of
    IRB review comments prior to funding approval; (3) defining HSR and public health practice
    on grant solicitation (perhaps in consultation with NCER) and request the grantee to meet
    specific requirements if the study is HSR; (4) incorporating HSR training for all Project
    Officers; (5) creating a tracking system for grants that are either HSR or public health

         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      118

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   practice; (6) considering provisional grant awards prior to HSR approval; and (7) modifying
   Question 14 in IGMS that asks whether human subjects are involved to include a corollary
   question as to whether the study is HSR.  If the answer to that question is "yes", require
   approval by the Agency's Human Subjects Research Review Official (Peter Preuss). If "no"
   to research, require attachment of the regional decision memo.

•  Create a tracking system that is accessible to the Regions on the progress of decisions with
   respect to the status of a study within the Human Subjects Research Review Official's review
   process.

«  Develop Agency written guidance, Web site, and list of references and subject experts for
   public input and comment in the Federal Register.

•  Develop a straw proposal for the new Human Subjects Research Review Official generated
   by the workshop and finalized by the workshop planning group.

•  Suggest that EPA create its own IRB, which would be accredited and consist of members
   who are not EPA employees or persons from the regulated community.  Also, possibly
   suggest that IRBs used by the Agency be  accredited.

•  Identify and publicize consequences for noncompliance of EPA Order 1000.17, change 1A,
   (40CFR Part 26) Policies and Procedures  for the Protection of Human Subjects in Research
   Conducted or Supported by EPA.

•  Review and provide comments on the Proposed Rule for Third Party Studies as these
   comments could influence workshop recommendations.

•  Ensure regional participation on the future workgroup that will be determining specifics
   involved with implementing the recommendation provided within the Proposed Rule for
   Third Party Studies for the creation of a Human Subjects Review Board.

•  Set up a conference call with Lee Tyner (OGC) to address legal concerns and questions that
   were developed by the workshop planning group.

•  Have workshop co-leads Patti Tyler and Ros'eanne Lorenzana develop a workshop
   recommendation package.

Ms. Tyler and Dr. Lorenzana agreed to follow up with the recommendations made as a result of
this workshop and adjourned the meeting. Dr. Lorenzana asked attendees to contact her via
e-mail if they had more questions after the workshop.
         Protection of Human Subjects in EPA's Research and Non-Research Studies Workshop      119

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   Appendix A




List of Resources

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            Protection of Human Subjects in EPA's Research
                         and Non-Research Studies

                              LIST OF RESOURCES

Pre-Meeting Materials Available on Quickplace and OSP Intranet:
1.  Code of Federal Regulations, TITLE 45 PUBLIC WELFARE DEPARTMENT OF
   HEALTH AND HUMAN SERVICES PART 46 PROTECTION OF HUMAN SUBJECTS
   (Note: Focus on Subpart A since this is the text of the "Common Rule," which EPA adopted
   as.40CFR26)
2.  EPA Order 1000.17, Change Al, POLICY AND PROCEDURES ON PROTECTION OF
   HUMAN RESEARCH SUBJECTS IN EPA CONDUCTED OR SUPPORTED RESEARCH
3.  HSR Activities Exempt From IRB Review 40 CFR 26.101(b)(l)-(6)
4.  Both seminar slide presentations (Peter Preuss and Rick Hermann/Rebecca Calderon)
5.  NHEERL Human Research Policy
6.  NHEERL Human Research Guidance, July 2005
7.  NERL - Policy and Procedures Guidance for Obtaining Approval of NERL Studies Involving
   Human Subjects, Human Material, or Human Data
8.  Public Health Practice vs. Research: A Report  for Public Health Practitioners Including
   Cases and Guidance for Making Distinctions (Johns Hopkins, May 2004).
   (wwwvepargoy/pppf
9.  Guidelines for Defining Public Health Research and Public Health Non-Research (CDC
   Document)
10. Federal Register Notice - Advanced Notice of Proposed Rulemaldng on 3rd Party Intentional
   Dosing Studies
11. CDC-ATSDR Protection of Human  Subject Procedures
12. NAS Report: Intentional Human Dosing Studies for Regulatory Purposes, Scientific and
   Ethical Issues (VERY LONG DOCUMENT) (http://books.nap.edu/catalQg/10927.html)
13. The Belmont Report (http://ohsr.od.nih.goy/guidelmes/belmont.li
14. Pesticide Testing on Human Subjects: Weighing Benefits and Risks. Environmental Health
   Perspectives, V. 113(7), pp.813-817, 2005.
   15. Review of Procedures for Protecting Human Subjects in Recent Clinical Studies of
   Pesticides. Regulatory Toxicology and Pharmacology, 2003 Oct;38(2):210-23.

Other:
1.  Andrew Schneider and David McCumber. An Air That Kills:  How the Asbestos Poisoning
   of Libby, Montana, Uncovered a National Scandal.

Contacts for Determining Exemptions Covered Under the Paperwork Reduction Act:
1.  Barbara Pace, Office of Cross-Cutting Law Issues
2.  Rick Westlund, Office of Environmental Information
3.  Peter Preuss, Office of Research and Development, National Center for Environmental Assessment
4.  Roger Cortesi, Office of Research and Development, National Center for Environmental Research
5.  Richard Hermann, National Health and Environmental Effects Research Laboratory,
   Human Studies Division
6.  Lee Tyner, Office of General Counsel, ERA Headquarters
                                                                              121

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Helpful Links:
h|lE-//www.hlis.gov/ohr|3/

httji;//www,epastu:dies.org

CHRP Human Subject Assurance Training
            d^
Federalwide Assurances (http;//ww^                                  index,ht;ml)

CITI Training Program (https://ww%^ti|TO
                                                                                      122

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Contacts for Help with Human Subjects Research Issues
ISSUE
Determining if a study is human
subjects research
Determining if a study is exempt
from IRB review
Human subjects research versus
public health practice
Information on IRBs and submitting a
grant proposal
Information on submitting a human
subjects research protocol
NHEERL Human Research Guidance
ERA Grants Management
Communications and Public
Involvement
Ethical considerations for vulnerable
subjects
Proposed Third Party Rule
Research Study Protocols
-Epidemiological studies
-Clinical Studies
Legal responsibilities of project
officer in human subject research
Office of Children's Health
Protection
NAME
Peter Preuss
Roger Cortessi
Peter Preuss
Roger Cortessi
Roger Cortessi
Helen McGough
Richard Hermann
Richard Hermann
Rebecca Calderon
See Regional list of GM contacts on p. 3
*
PHONE
301-564-3322
202-343-9813
301-564-3322
202-343-9813
202-343-9813
206-543-0098
919-966-6217
919-966-6217
919-966-0617

E-Mail
preuss .peter@epa. gov
cortesi.roger(o),epa.gov

preuss.peter@epa.gov
cortesi.roeer@epa.gov

cortesi.roger(o)/epa. gov

hmcgough@ii.washlngton.edu

hermarm.richard(2),epa. gov

hermann.richard(a>,epa. gov
calderon. rebecca@epa.gov

Due to the sensitivity of this topic, all media and public communications should be go through
Ann Brown, Office of Research and Development, 9 1 9-54 1-7818, brown.ann@epa.gov. At
Athe same time be sure to inform your regional public affairs office. Assure that all EPA
parties that should be informed are informed.
David Forster
Anne Lindsay
Rebecca Calderon
Danelle Lobdell
Bob Devlin
Don Graff
Lee Tyner
Michael Firestone
Devon Payne-Sturges
360-252-2428
703-305-7090
919-966-0617
919-843-4434
919-966-6255
919-843-5155
202-564-5524
202-564-2199
202-564-2706
dforster(2),wirb.com

!mdsay,amie@epa.,eov
calderon.rebecca@epa.gov
lobdell.danelle@epa.gov
devlia.robert@epa. gov
grafT.don(5iepa.goY
tyner. lee@epa. gov
firestone.michael(3),epa. gov
payne-sturges.devon@epa.gov
                                                                    123

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Office of Pesticide Programs Regional Contacts for Human Subjects Research Iss

Region
Region 1
Region 2
Region 3
Region 4
Region 5
Region 6
Region 7
Region 8
Region 9
Region 10

Name
Rick Sugatt
Roland Hemmett
Ronald Landy
Tom Baugh
Gilberto Alvarez
Jeffrey Riley
Brenda Groskinsky
Patti Tyler
Brace Macler
Roseanne Lorenzana

Phone
617-918-1415
732-321-6755
410-305-2757
404-562-8275
312-886-6143
214-665-8542
913-551-7188
303-818-3130
415-972-3569
206-553-8002

v.anne(2)epa.gov
ues • ~ "

E-mail
sugatt.rick@epa.gov
hemmett.roland@epa.gov
landy.ronald@epa.gov
baugh.thomasl@epa.gov
alvarez.gilberto@epa.gov
riley .j effrey@epa.gov
groskinsky.brenda@epa.gov
tyler.patti@epa.gov
macler.bruce@epa.gov
lorenzana.roseanne@epa.gov
124

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 Find  the Grant Regional  Office Near You

 RegJonJ. (CT, MA, ME, NH, Rl, VT) Grants and Funding in New England -
 http://www.epa.qov/re3ign01/arants/index.htrril

 community funding sources and environmental education grants program. Pam Ringhoff 617-918-1912

 ReaJorL2 (NJ, NY, Puerto Rico, Virgin Islands) Giants - http://www.epa.gov/region02/grants/

 grants available to the Region 2 community including current issues, application kits, community grants and
 FAQs. Roch Baamonde 212-637-3401

 Region 3 (DE, DC, MD, VA, PA, WV) Grants and Funding in the Mid_-Atlantic States -
 http://www.epa.aov/region03/arants/index.htm

 general grant information and water financing information. Kathleen Blinebury 215-814-5395

 Region 4 (AL, FL, GA, KY, MS, NC, SC, TN) Grant Assistance - http://www.epa.gov/region4/financial/index.htrTil

 grant information and information managing your EPA assistance agreement. Ed Springer 404-562-8410

 Re§ipji5 (ll_, IN, Ml, MN, OH, Wl) Funding Sources: http ://www,e^

 - information on grant funding available in Region 5. Sharon Green 312-353-5661

 Re§iojij3_(AR, LA, OK, NM, TX) Grants and Funding
 http://yosemjte^
                                         #•
 - information about grants, funding and procurement and also minority and women business enterprise
 information. Hattie Brown 214-665-7423

 Region_7 (IA, KS, MO, NE) Regional Grants Information - Mp://www.,erpJa,gQy7reg

 regional and national grant information as well as forms and guidelines. Karen Sherrill 9130551-7461

 RegionJ (CO, MT, ND, SD, UT, WY) Grants and Financial Assistance -
 http://www.epa. gov/region8/community_resources/grants/grants. html
                                               i
 information covering grants available in Region 8. Wayne Anthofer 303-312-6305

 JitgionJ. (AZ, CA, HI,  NV, American Samoa, Guam) fjjndjns^oyices -
 http://wvw.epa.gov/regign09/funding/index,htrnl

 information on Region 9's continuing program and project grants. Carolyn Truong 415-972-3663

 Rteajon_10_(AK, ID, OR, WA) Gjrants - http://yosemite.epa.aov/R10/HOMEPAGE.NSF/webpage/Grants

 information on grants available in Region 10. Armina K. Nolan 206-553-0530

Headquarters - Grants Administration Division (202) 564-5325 (E.S.T. 8:00 a.m. - 4:00 p.m., Monday
thru Friday) Betty Utterback or Mildred Lee
                                                                                       125

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Websites for additional information:

General HSR information:
httrx//www.hhs.gov/ohrp/

Human subjects research flow charts to assist with decision making
          .hhs.ggW
Common Rule:
Ethics training through CITI:        ''
https://www.citiprogra^

HIPPA privacy act information
http ://www.hhs . go v/ocr/hipaa/

Approved federal wide assurances for IRBs
Registration of an IRB
http://www.hhs,gQY/Q^p/asgarances/

IRB Guidebook
http://www.hlis.gov/olirp/irb/irb  guidebook.htm

Informed consent requirements and documents
http://www.hhs.gov/ohrp/r^olicy/index;h.tmMnformed

Use of another institution's IRB
Special protections for children as research subjects
http://www.hhs.goy/olirp/cb.ildren/

Expedited IRB review
http://www.hhs.gov/ohrp/huniansubiects/gui.dance/exT3edJ.ted98.htm
                                                                        126

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  Appendix B




Participants List

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             Protection of Human Subjects in EPA's Research
                          and Non-Research Studies

                              Silver Cloud Hotel - Broadway
                                     1100 Broadway
                                   Seattle, WA 98122

                                 September 26 - 29, 2005

                                    Participants List
Alicia Aalto
U.S. Environmental Protection Agency

Gilberto Alvarez
U.S. Environmental Protection Agency

Marcia Bailey
U.S. Environmental Protection Agency

Thomas Baugh
U.S. Environmental Protection Agency

Debbie Bishop
U.S. Environmental Protection Agency

Rebecca Calderon
U.S. Environmental Protection Agency

Carmen Caldwell
U.S. Environmental Protection Agency

Michael Callahan
U.S. Environmental Protection Agency

Jayne Carlin
U.S. Environmental Protection Agency

Alvin Chun
U.S. Environmental Protection Agency

Patricia Cirone
U.S. Environmental Protection Agency

Roger Cortesi
U.S. Environmental Protection Agency
Dana Davoli
U.S. Environmental Protection Agency

Robert Devlin
U.S. Environmental Protection Agency

David Forster
Western Institutional Review Board

Don Graff
U.S. Environmental Protection Agency

Brenda Grosldnsky
U.S. Environmental Protection Agency

Joel Hansel
U.S. Environmental Protection Agency

Amanda Hasty
U.S. Environmental Protection Agency

Richard Hermann
U.S. Environmental Protection Agency

Ariel  Iglesias
U.S. Environmental Protection Agency

Margaret Jones
U.S. Environmental Protection Agency

Lon Kissinger
U.S. Environmental Protection Agency

Anne Lindsay
U.S. Environmental Protection Agency
                                                                                   128

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Barbara Lither
U.S. Environmental Protection Agency

Danelle Lobdell
U.S. Environmental Protection Agency

Roseanne Lorenzana
U.S. Environmental Protection Agency

Bruce Macler
U.S. Environmental Protection Agency

Helen McGough
University of Washington

Aubrey Miller
U.S. Environmental Protection Agency

Armina Nolan
U.S. Environmental Protection Agency

Solomon Pollard
U.S. Environmental Protection Agency

Peter Preuss
U.S. Environmental Protection Agency

JeffRiley
U.S. Environmental Protection Agency

Ruth Sechena
University of Washington

MaryBeth Smuts
U.S. Environmental Protection Agency

Anne Sowell
Centers for Disease Control and Prevention

Marc Stifelman
U.S. Environmental Protection Agency

Maryann Suero
U.S. Environmental Protection Agency

Richard Sugatt
U.S. Environmental Protection Agency
Kent Thomas
U.S. Environmental Protection Agency

Vivian Turner
U.S. Environmental Protection Agency

Patti Tyler
U.S. Environmental Protection Agency

Dennis Utterback
U.S. Environmental Protection Agency

Ann Williamson
U.S. Environmental Protection Agency

Suzanne Wuerthele
U.S. Environmental Protection Agency

Jeanmarie Zodrow
U.S. Environmental Protection Agency
                                                                                     129

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