Document ID: EPA-HQ-ORD-2006-0187-0100
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

How
OPP
Conducts
Ethics
Reviews
of
How
OPP
Conducts
Ethics
Reviews
of
Human
Studies
Human
Studies
John
M.
Carley
April
4,
2006
2
December
2001
Moratorium
December
2001
Moratorium

EPA
asked
the
NAS
for
advice,
and
announced
it
would
not
rely
on
third­
party
human
toxicity
studies
until
their
review
was
complete
and
regulations
were
issued

This
announced
moratorium
was
challenged
by
CropLife
America
and
others,
and
was
overturned
by
the
court
3
CropLife
Decision
CropLife
Decision
"
The
agency's
previous
practice
of
considering
third­
party
human
studies
on
a
case­
by­
case
basis,
applying
statutory
requirements,
the
Common
Rule,
and
high
ethical
standards
as
a
guide,
is
reinstated
and
remains
in
effect
unless
and
until
it
is
replaced
by
a
lawfully
promulgated
regulation."
4
EPA
Human
Studies
Work
Group
EPA
Human
Studies
Work
Group

EPA
staff
were
charged
with
developing
guidance
to
ensure
consistent
interpretation
and
implementation
of
the
CropLife
decision

Assigned
a
subcommittee
to
develop
guidance
for
ethics
reviews
applying
"
statutory
requirements,
the
Common
Rule,
and
high
ethical
standards"
5
HSWG
Ethics
Subcommittee
HSWG
Ethics
Subcommittee

Conducted
literature
search

Focused
on
Emanuel
et
al.
article
from
JAMA,
"
What
makes
clinical
research
ethical?"

Supplemented
it
with
Miller
article
"
Clinical
Research
with
Healthy
Volunteers:
An
Ethical
Framework"
6
Emanuel
Requirements
Emanuel
Requirements

Social
or
Scientific
Value

Scientific
Validity

Fair
Subject
Selection

Favorable
Risk­
Benefit
Ratio

Independent
Review

Informed
Consent

Respect
for
Potential
and
Enrolled
Subjects
7
1.
Value
1.
Value
e.
What
organization
funded
the
research?

d.
Will
society
benefit
from
the
knowledge
gained
from
the
research?

c.
Does
it
test
a
hypothesis
that
can
generate
important
knowledge?

b.
Does
it
evaluate
a
diagnostic
or
therapeutic
intervention?

a.
What
was
the
stated
purpose
of
the
research?
8
2.
Scientific
Validity
2.
Scientific
Validity
e.
To
what
purpose
is
the
study
used,
or
proposed
for
use,
in
the
Agency?

d.
Did
the
research
design
have
sufficient
power
to
definitively
test
the
objective?

c.
How
were
human
subjects
exposed?
What
endpoints
were
measured?

b.
Was
the
research
designed
using
accepted
principles,
methods,
and
reliable
practices?

a.
Did
the
research
have
a
clear
scientific
objective?
9
3.
Fair
Subject
Selection
3.
Fair
Subject
Selection
b.
Were
any
susceptible
groups
used
in
the
study,
such
as
children,
prisoners,
the
infirm
or
impoverished?
Did
the
burden
of
participation
fall
disproportionately
on
a
particular
group?

a.
Were
the
groups
and
individuals
recruited
and
enrolled
determined
solely
on
the
basis
of
the
scientific
goals
of
the
study?
10
4.
Risk
4.
Risk­
Benefit
Ratio
Benefit
Ratio
c.
What
compensation
was
paid
to
the
participants
in
the
study?

b.
If
the
research
presents
no
health­
related
benefits
to
individual
subjects,
what
are
the
societal
benefits
.
.
.
,

and
do
these
justify
the
excess
risk
to
individual
subjects?

a.
How
were
the
risks
to
individual
subjects
minimized?
11
5.
Independent
Ethics
Review
5.
Independent
Ethics
Review
e.
Was
the
research
conducted
in
compliance
with
another
ethical
standard?

d.
Did
the
research
institution
hold
an
FWA
during
the
period
of
the
study?

c.
Was
the
research
conducted
in
compliance
with
the
Common
Rule?

b.
Was
ethics
review
by
individuals
unaffiliated
with
the
clinical
research?

a.
Was
the
research
reported
to
have
been
overseen
by
an
ethics
review
body?
12
6.
Informed
Consent
6.
Informed
Consent
b.
How
and
under
what
circumstances
was
informed
consent
obtained?

a.
Does
the
research
assert
that
informed
consent
was
obtained
from
participants?
13
7.
Respect
for
Subjects
7.
Respect
for
Subjects
b.
Were
subjects
free
to
withdraw
from
the
research
without
penalty?

a.
Was
information
about
individual
subjects
managed
so
as
to
ensure
their
privacy?
14
Early
Lessons
Early
Lessons

Published
articles
rarely
include
more
than
cursory
mention
of
IC
and
IRB
review.

The
matrix
was
useful
to
organize
the
more
extensive
information
often
available
in
unpublished
studies
submitted
to
the
Office
of
Pesticide
Programs

Emanuel
framework
cannot
be
applied
in
sequence
to
reports
of
completed
work
15
Review
Experience
Review
Experience

We
have
applied
this
framework
to
several
hundred
human
studies

Most
studies
evaluated
have
been
of
exposure
of
pesticide
handlers
or
of
workers
who
enter
a
site
treated
with
a
pesticide

Others
have
included
studies
of
repellent
efficacy,
metabolism,
skin
irritation
or
sensitization,
and
toxicity
16
Steps
in
Ethics
Review
Steps
in
Ethics
Review

Scan
study;
find
all
the
pieces

Figure
out
what
happened

Highlight
everything
relevant
to
review

Complete
unshaded
cells
in
matrix

Develop
summaries
in
shaded
cells

Transfer
topic
summaries
to
narrative

Compare
to
applicable
prevailing
standard

Develop
conclusions
17
Summary
of
Experience
to
Date
Summary
of
Experience
to
Date

Reporting
is
better
on
the
procedural
aspects
of
study
conduct
(
informed
consent,
IRB
review)

Reporting
is
weak
on
the
substantive
aspects
of
ethical
study
conduct,
especially:


Societal
or
scientific
value
of
the
research

The
nature
and
distribution
of
the
anticipated
societal
benefits
of
the
research

How
those
benefits
were
weighed
against
risks
to
individual
subjects
18
The
Dilemma:

The
Dilemma:

Without
a
clear
presentation
of
the
societal
or
scientific
value
of
the
research,
or
a
frank
array
and
discussion
of
its
risks
and
benefits,
it
is
very
difficult
to
conclude
that
research
is
justified.
19
Criteria
for
Acceptance
of
Completed
Criteria
for
Acceptance
of
Completed
Research
Research

NAS
recommendation,
the
2/
05
FR
Notice,
and
the
final
rule
are
essentially
the
same:

Do
not
rely
on
completed
research
"
if
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundament­
ally
unethical,
.

.
.

or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted."
20
No
Clear
Evidence
of
Fundamentally
No
Clear
Evidence
of
Fundamentally
Unethical
Research
Unethical
Research

We
have
not
found
clear
and
convincing
evidence
to
suggest
that
any
of
the
research
we're
presenting
to
you
this
week
is
fundamentally
unethical
21
Comparison
to
Prevailing
Standards
Comparison
to
Prevailing
Standards

To
apply
this
criterion
we've
had
to
answer
many
subordinate
questions:


What
ethical
standards
prevailed
where
and
when
the
research
was
conducted?


Do
all
published
ethical
standards
apply
to
all
subsequent
research?


How
strictly
should
standards
be
applied?
22
Rules
of
Thumb
Rules
of
Thumb

Since
1964
some
version
of
The
Declaration
of
Helsinki
applies
to
human
clinical
research
in
all
countries

Since
1972
FIFRA
12(
a)(
2)(
P)
applies
to
all
human
research
with
a
pesticide
in
the
US

Since
1991
the
Common
Rule
applies
to
human
research
in
the
US

Other
standards
may
apply
in
specific
circumstances
23
Generic
Questions
for
HSRB
Generic
Questions
for
HSRB

For
each
study
presented:


Have
we
identified
the
appropriate
standard
of
ethical
conduct?


Is
there
clear
and
convincing
evidence
of
deficiency
in
research
conduct?


Is
the
deficiency
significant?


Is
the
study
ethically
acceptable
under
26
CFR
26.1704?