1
EPA
EPA
Human
Studies
Review
Board
Human
Studies
Review
Board
(
HSRB)

(
HSRB)

Public
Meeting
Public
Meeting
April
4,
2006
2
HSRB
Charter
HSRB
Charter
"
HSRB
will
provide
advice,
information,
and
recommendations
on
issues
related
to
scientific
and
ethical
aspects
of
human
subjects
research."


The
major
objectives
are
to
provide
advice
and
recommendations
on:

a.
Research
Proposals
and
Protocols;

b.
Reports
of
completed
research
with
human
subjects;
and
c.
How
to
strengthen
EPA's
programs
for
protection
of
human
subjects
of
research
3
EPA
&
Human
Research
EPA
&
Human
Research
Issues
involving
human
research
may
arise
in
three
areas:


When
EPA
plans
and
carries
out
human
research

When
EPA
reviews
proposals
from
third
parties
to
conduct
human
research

When
EPA
considers
the
results
of
human
research
under
its
statutory
mandates
to
protect
human
health
and
the
environment
4
Order
of
Overview
Presentations
Order
of
Overview
Presentations

Summary
of
EPA's
Protections
for
Subjects
of
Human
Research
­
Mr.
William
Jordan

OPP
Approach
to
Assessing
Human
Health
Risks
of
Pesticides
Using
Data
From
Human
Studies
 

Mr.
Michael
Metzger

OPP
Assessment
of
Ethical
Conduct
of
Human
Studies
 
Mr.
John
Carley

OPP
Assessment
of
Individual
Human
Studies
 

Ray
Kent,
Ph.
D.


Summary
of
Human
Studies
for
Consideration
by
the
HSRB
 
Louis
Scarano,
Ph.
D.
5
EPA
Requirements
for
Protection
EPA
Requirements
for
Protection
of
Subjects
in
Human
Research
of
Subjects
in
Human
Research
William
Jordan
EPA
Office
of
Pesticide
Programs
6
Overview
Overview

History
of
EPA
efforts
to
provide
protections
for
subjects
of
human
research

History
of
EPA's
Human
Studies
rulemaking

Provisions
of
EPA's
final
Human
Studies
Rule

Introduction
to
Pesticide
Regulation
7
Protections
for
Subjects
of
EPA
Protections
for
Subjects
of
EPA'
s
1
s
1st
st
and
and
2nd
nd
Party
Human
Research
Party
Human
Research

In
1991
EPA
adopted
the
Common
Rule

Common
Rule
applies
to
all
human
research
conducted
or
supported
by
EPA

Prior
approval
by
an
Institutional
Review
Board

Informed
consent
8
Protections
for
Subjects
of
EPA
Protections
for
Subjects
of
EPA'
s
1
s
1st
st
and
and
2nd
nd
Party
Human
Research
(
2)

Party
Human
Research
(
2)

As
a
matter
of
policy,
EPA
has
gone
beyond
the
requirements
of
the
Common
Rule:


EPA
has
followed
the
rules
in
HHS'

Subparts
B
and
D

After
IRB
review
and
approval,
all
human
research
conducted
or
supported
by
EPA
has
undergone
review
by
EPA's
Human
Subjects
Research
Review
Official
(
HSRRO)
9
Protections
for
Subjects
of
Human
Protections
for
Subjects
of
Human
Research
by
Research
by
"
Third
Parties
Third
Parties"


FIFRA
section
12(
a)(
2)(
P)
makes
it
unlawful
for
any
person
"
to
use
any
pesticide
in
tests
on
human
beings
unless
such
human
beings
(
i)
are
fully
informed
of
the
nature
and
purposes
of
the
test
and
of
any
physical
and
mental
health
consequences
which
are
reasonably
foreseeable
therefrom,
and
(
ii)
freely
volunteer
to
participate
in
the
test."
10
History
of
EPA
HS
Rulemaking
History
of
EPA
HS
Rulemaking

FQPA
 
children's
protection
factor
(
1996)


"
The
English
Patients"
(
1998)


SAB/
SAP
Subcommittee
(
2000)


Moratorium
on
Human
Toxicity
Studies;

Initiation
of
NAS
Review
(
2001)


Croplife
decision
(
2003)
11
History
of
EPA
HS
Rulemaking
(
2)

History
of
EPA
HS
Rulemaking
(
2)

Key
NAS
(
2004)
Recommendations:


Adopt
the
Common
Rule
for
third­
party,

intentional
dosing
human
research

Establish
an
HSRB
to
review
the
science
and
ethics
of
proposed
research

5­
6:
Ethics
standard
for
relying
on
"
new"

human
research

5­
7:
Ethics
standard
for
relying
on
"
old"

human
research
12
History
of
EPA
HS
Rulemaking
(
3)

History
of
EPA
HS
Rulemaking
(
3)


Advance
Notice
of
Proposed
Rulemaking
(
2003)


FY
2006
Appropriations
Act
(
2005)


Banned
EPA
acceptance,
consideration,
&
reliance
on
intentional
dosing,
human
toxicity
studies
until
a
final
rule
was
issued

Required
the
final
rule
to
establish
an
HSRB

Required
the
final
rule
to
prohibit
the
use
of
pregnant
women
and
children
as
subjects

Proposed
Rule
(
Sept.
2005)


Final
Rule
(
Jan.
2006)
13
EPA
EPA'
s
HS
Rule:
1
s
HS
Rule:
1st
st
&
2
&
2nd
nd
Parties
Parties
Requirements
for
first­
and
second­
party
research:


Continues
to
require
EPA
to
follow
the
Common
Rule
in
research
it
conducts
or
supports

Categorically
prohibits
any
EPA
research
involving
intentional
exposure
of
human
subjects
who
are
pregnant
women
or
children
to
pesticides
or
any
other
substances

Adapts
HHS
regulations
providing
additional
protections
beyond
those
of
the
Common
Rule
to
pregnant
women
and
children
as
subjects
in
EPA
observational
research
14
HS
Rule:
Third
Parties
HS
Rule:
Third
Parties
Requirements
for
third­
party
research
intended
for
submission
to
EPA
under
the
pesticide
laws:


Bans
all
new
research
involving
intentional
exposure
of
pregnant
women
or
children,


Extends
the
requirements
of
the
"
Common
Rule"
to
other
human
research
involving
intentional
exposure
of
non­
pregnant
adults

Requires
submission
to
EPA
of
protocols
and
related
information
about
covered
human
research
before
it
is
initiated
15
HS
Rule:
Third
Parties
(
2)

HS
Rule:
Third
Parties
(
2)

Requirements
for
third­
party
research
intended
for
submission
to
EPA
under
the
pesticide
laws:


Establishes
the
HSRB
to
review
and
advise
about
both
proposals
for
new
research
and
reports
of
certain
types
of
covered
human
research
on
which
EPA
proposes
to
rely
under
the
pesticide
laws

Once
a
study
is
conducted,
requires
data
submitters
to
provide
detailed
information
describing
how
the
study
met
the
applicable
ethical
standards
16
Comments
on
Section
26.1603
Comments
on
Section
26.1603

Section
26.1603
creates
the
HSRB
and
assigns
it
responsibility
to
"
comment
on
the
scientific
and
ethical
aspects
of
research
proposals
and
reports
of
completed
research
with
human
subjects
submitted
by
EPA
for
its
review."


This
responsibility
allows
the
Board
to
address
EPA
questions
about
how
the
Agency
proposes
to
use
the
data
in
its
risk
assessments
17
HS
Rule:
EPA
Decision
HS
Rule:
EPA
Decision­
Making
Making
Requirements
applicable
to
EPA
as
a
regulator:


Requires
EPA
to
document
its
scientific
and
ethical
assessments
of
completed,
intentional
human
dosing
research,
and
to
obtain
HSRB
review
for
certain
types
studies
on
which
EPA
intends
to
rely
under
the
pesticide
laws:


All
intentional
exposure
toxicity
studies

All
other
intentional
exposure
studies
initiated
after
April
7,

2006

"
Old"
exposure,
insect
repellent
efficacy,
ADME,
&
other
non­
toxicity
tests
not
required
to
go
to
HSRB
18
HS
Rule:
EPA
Decisions
(
2)

HS
Rule:
EPA
Decisions
(
2)

Generally
forbids
EPA
to
rely,
in
its
actions
under
the
pesticide
laws,
on
intentional­
exposure
human
research
that:


Involves
pregnant
women
or
children,
§
26.1703,
or

Is
considered
unethical;
different
standards
for
judging
ethical
acceptability:


"
old"
studies,
i.
e.,
research
initiated
before
4/
7/
06,
§

26.1704

"
new"
studies,
i.
e.,
research
initiated
after
4/
7/
06,
§
26.1705
19
HS
Rule:
Prohibition
against
Reliance
on
HS
Rule:
Prohibition
against
Reliance
on
Data
from
Kids
&
Pregnant
Women
Data
from
Kids
&
Pregnant
Women
Section
26.1703,
standard
of
acceptability
applicable
to
all
intentional
exposure
studies:

"
Except
as
provided
in
§
26.1706,
in
actions
within
the
scope
of
§
26.1701,
EPA
shall
not
rely
on
data
from
any
research
involving
intentional
exposure
of
any
human
subject
who
is
a
pregnant
woman
(
and
therefore
her
fetus)

or
child."
20
Comments
on
Section
26.1703
Comments
on
Section
26.1703

This
prohibition
covers
all
data
from
research
if
any
of
the
subjects
is
a
pregnant
woman
or
child.
EPA
will
not
consider
data
only
on
adult
subjects
extracted
from
a
prohibited
study

Prohibition
is
triggered
by
information
that
pregnant
women
or
kids
were
used
as
subjects

Absence
of
information
on
the
pregnancy
status
or
age
of
subjects
does
not
trigger
the
prohibition
21
HS
Rule:
Prohibition
against
Reliance
on
HS
Rule:
Prohibition
against
Reliance
on
Unethical
Unethical
"
Old
Old"
Research
Research
Section
26.1704
 
Ethical
standard
for
"
old"

studies:

".
.
.
EPA
shall
not
rely
on
data
from
any
research
initiated
before
April
7,
2006,
if
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
(
e.
g.,

the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent),
or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted."
22
Comments
on
Section
26.1704
Comments
on
Section
26.1704
Ethical
deficiencies
must
be
established
by
"
clear
and
convincing
evidence":


Absence
of
documentation
is
not
evidence
that
the
undocumented
behavior
was
ethically
improper

But,
if
a
standard
requires
certain
material
to
appear
in
a
protocol
or
study
report,
the
absence
of
the
material
is
evidence
of
a
deficiency
in
documentation

"
Clear
and
convincing"
evidence
=
more
than
a
"
preponderance
of
the
evidence,"
less
than
"
beyond
a
reasonable
doubt"
23
HS
Rule:
Public
Health
Exception
HS
Rule:
Public
Health
Exception
Notwithstanding
the
prohibitions
on
reliance
on
certain
types
of
data,
under
the
rule
EPA
may
rely
on
otherwise
unacceptable
data
if
to
do
so
is
"
crucial
to
a
decision
that
would
improve
protection
of
public
health",
§
26.1706
Any
such
study
used
for
this
purpose
must
undergo
independent
review
from
the
HSRB,

followed
by
public
comment
24
Pesticide
Regulation
Pesticide
Regulation
EPA
regulates
pesticides
under
two
laws:


FFDCA
 
establish
tolerances
for
pesticide
residues
in
food
and
feed

FIFRA
 
license
(
register)
pesticide
products
sold
or
distributed
in
commerce
25
Pesticide
Regulation
Pesticide
Regulation
Food
Quality
Protection
Act
of
1996
(
FQPA):


Established
a
new
safety
standard
for
tolerance
setting
 
a
"
reasonable
certainty
of
no
harm"


Changed
EPA's
approach
to
risk
assessment:

aggregate
risk,
cumulative
risk,
and
children's
protection
safety
factor

Required
EPA
to
"
reassess"
existing
tolerances
by
August
2006
26
Pesticide
Regulation
Pesticide
Regulation

Proponents
of
pesticide
use
bear
the
burden
of
demonstrating
safety:


Safety
decisions
are
science
based

Applications
for
registration
and
tolerance
petitions
contain
extensive
data
to
support
EPA
risk
assessments

EPA
requires
specific
types
of
data
to
characterize
both
hazard
and
exposure

EPA
also
reviews
other
relevant
data,
including
nonrequired
studies
submitted
by
registrants
and
studies
from
the
public
literature
27
Purpose
of
this
HSRB
Meeting
Purpose
of
this
HSRB
Meeting
As
required
by
the
final
rule,
EPA
is
seeking
HSRB
advice
on
science
and
ethics
issues
involving
human
studies
on
eight
pesticide
active
ingredients,
which
EPA
is
considering
(
and
on
which
EPA
may
rely)
as
part
of
tolerance
reassessment
under
FFDCA:

Aldicarb

Methomyl

Oxamyl

Azinphos
methyl

DDVP

Ethephon

Amitraz

Sodium
Cyanide
28
Order
of
Overview
Presentations
Order
of
Overview
Presentations

Summary
of
EPA's
Protections
for
Subjects
of
Human
Research
­
Mr.
William
Jordan

OPP
Approach
to
Assessing
Human
Health
Risks
of
Pesticides
Using
Data
From
Human
Studies
 

Mr.
Michael
Metzger

OPP
Assessment
of
Ethical
Conduct
of
Human
Studies
 
Mr.
John
Carley

OPP
Assessment
of
Individual
Human
Studies
 

Ray
Kent,
Ph.
D.


Summary
of
Human
Studies
for
Consideration
by
the
HSRB
 
Louis
Scarano,
Ph.
D.
