Document ID: EPA-HQ-ORD-2006-0384-0075
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-12T04:00Z

Summary
of
Presentation
°
Brief
Outline
of
the
EPA
Final
Rule
°
Challenge
of
Intentional
Dosing
Studies
°
Application
of
Subpart
K
(
Subpart
A)

°
Selected
NAS
Recommendations
°
Some
Questions
for
Consideration
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

The
Final
Human
Studies
Rule
Effective
April
7,
2006,
expands
the
protections
for
subjects
of
"
third­
party"
human
research
and:

1.
Extends
protections
of
the
Common
Rule
to
intentional
dosing
pesticide
research
submitted
to
the
EPA;

2.
Prohibits
new
research
involving
intentional
exposure
of
pregnant
women
or
children
to
EPA­
regulated
compounds;

3.
Requires
submission
of
protocols
for
covered
human
research
prior
to
study
initiation;
and
4.
Establishes
an
independent
Human
Studies
Review
Board
to
review
the
scientific
and
ethical
aspects
of
research
proposals
and
reports
of
completed
research
with
human
subjects
submitted
to
and
by
the
EPA.
The
Final
Human
Studies
Rule
(
2)

Forbids
EPA
relying
on
human
research
data
that
would
be
prohibited
or
considered
unethical
for
regulatory
decision
making,

except
for
narrowly
defined
circumstances.

 
e.
g.,
if
children
were
at
risk
from
exposure
to
a
substance.

 
e.
g.,
if
data
collected
from
an
otherwise
unethical
study
justified
setting
a
more
restrictive
standard
for
pesticide
tolerance.
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

40
CFR
26:
EPA
Final
Rule
°
Research
supported
or
conducted
by
EPA
 
Subpart
A
(
all
research)

 
Subpart
B
(
intent.
exposure:
preg.
woman,
fetus,
child)

 
Subpart
C
(
observational
research:
preg.
woman,
fetus)

 
Subpart
D
(
observational
research:
children)

°
Third
Party
Research
(
submitted
to
EPA)

 
Subpart
K
(
intentional
exposure
to
pesticides,
after
4­
7­

06:
non­
pregnant
adult)

 
Subpart
L
(
intentional
exposure
to
pesticides:
pregnant
woman,
fetus,
child)

 
Subpart
M
(
after
4­
7­
06,
reports
of
any
human
research)

 
Subpart
O
(
EPA
administrative
action
for
noncompliance)

 
Subpart
P
(
EPA
review
of
protocols
under
Subpart
K)

 
Subpart
Q
(
EPA
use
of
data
from
intentional
exposure)
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

Subpart
A
(
40
CFR
§
26.1xx)

°
Subpart
A
applies
to
all
research
that
is
supported
or
conducted
by
the
EPA.

°
There
are
no
differences
between
the
EPA
Subpart
A
and
Subpart
A
of
45
CFR
§
46
(
HHS),
thus
"
The
Common
Rule."
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

Subpart
B
(
40
CFR
§
26.2xx)

°
Prohibits
EPA
from
supporting
or
conducting
any
research
involving
intentional
exposure
of
pregnant
woman
(
and
her
fetus)
or
child.

°
Two
definitions
worth
noting:

 
"
Intentional
human
exposure"
­
"
exposure
to
the
substance 
would
not
have
occurred
but
for
the
human
subject's
participation
in
the
study."

 
"
Child"
is
"
a
person
who
has
not
attained
the
age
of
18
years."
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

Subpart
K
(
40
CFR
26.11xx)

°
Research
(
after
4­
7­
06):
intentional
exposure
of
non­
pregnant
human
adult
to
pesticides
 
Exemption
for
existing
data,
40CFR
§
26.1101(
b)

°
Differences
(
3)
between
Subparts
K
and
A
 
IC:
"
informed
of
the
identity
of
the
pesticide
and
the
nature
of
its
pesticidal
function"

 
Subpart
K
does
not
contain
a
waiver
of
written
documentation
of
informed
consent.
continued
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

Subpart
K
(
40
CFR
26.11xx)

°
Differences:
Subparts
K
and
A
(
continued)

 
Submit
to
EPA
after
IRB
review/
approval
and
before
initiating
research
(
40CFR
§
26.1125)

°
Discussion
of:
(
1)
risks;
(
2)
measures
to
minimize
risks;
(
3)

benefits,
and
to
whom
they
accrue;
(
4)
alternative
means
of
obtaining
data;
and
(
5)
balance
of
risks
and
benefits.

°
All
subject
information;
written
consent
agreements
°
Subject
recruitment;
any
advertisements
to
be
used
°
How
information
presented
to
potential
human
subjects
°
All
correspondence
between
IRB,
investigators
or
sponsors
°
IRB
notification
that
research
reviewed
and
approved
Federal
Register
71(
24):
6138­
76;
February
6,
2006;
Effective
April
7,
2006.

Subpart
L
(
40
CFR
26.12xx)

°
Prohibits
third
parties
from
supporting
or
conducting
research
(
after
4­
7­
06)
intended
for
submission
to
EPA
involving
intentional
exposure
to
pesticides
of
pregnant
woman
(
and
her
fetus)
or
child
Summary
of
Presentation
°
Brief
Outline
of
the
EPA
Final
Rule
°
Challenge
of
Intentional
Dosing
Studies
°
Application
of
Subpart
K
(
Subpart
A)

°
Selected
NAS
Recommendations
°
Some
Questions
for
Consideration
Intentional
Dosing
Studies
The
conduct
of
intentional
dosing
studies
has
broad
implications
for:

1)
The
EPA's
regulatory
decision­
making
process;
and
2)
Non­
therapeutic
research
involving
human
participants
in
general.
Intentional
Dosing
Studies
(
2)

°
The
risk­
benefit
analysis
of
intentional
dosing
studies
is
challenging
in
part
because
when
studies
are
conducted
by
third
parties
it
is
important
to
distinguish
between
"
potential
benefits"
that
will
improve
public
health
and
safety
and
those
that
are
purely
for
commercial
interest.
Intentional
Dosing
Studies
(
3)

°
In
some
cases
human
dosing
studies
are
needed
to
ensure
the
quality
and
accuracy
of
the
EPA's
decision­
making
process.

°
However,
they
may
also
be
initiated
for
strictly
commercial
interests
to
produce
a
new
competitive
product
or
to
revise
regulatory
standards.
Intentional
Dosing
Studies
(
4)

°
Intentional
dosing
studies
may
share
many
of
the
same
characteristics
as
phase
I
clinical
trials
 
the
goal
of
an
intentional
dosing
study
is
to
assess
a
pesticide's
safety
and
toxicity
at
various
dosage
levels.

°
Even
though
intentional
dosing
experiments
may
not
be
designed
to
diagnose,
treat,
or
prevent
disease,
they
could
yield
knowledge
with
social
and
scientific
import.
Summary
of
Presentation
°
Brief
Outline
of
the
EPA
Final
Rule
°
Challenge
of
Intentional
Dosing
Studies
°
Application
of
Subpart
K
(
Subpart
A)

°
Selected
NAS
Recommendations
°
Some
Questions
for
Consideration
40
CFR
26.1111
Subpart
K:
Criteria
for
IRB
Approval
°
Risks
to
subjects
are
minimized
 
By
using
procedures
which
are
consistent
with
sound
research
design
and
which
do
not
unnecessarily
expose
subjects
to
risk,
and
°
Risks
to
subjects
are
reasonable
in
relation
to
anticipated
benefits,
if
any,
to
subjects,

and
the
importance
of
the
knowledge
that
may
reasonably
be
expected
to
result.
continued
40
CFR
26.1111
Subpart
K:
Criteria
for
IRB
Approval
°
Selection
of
subjects
is
equitable.

°
Informed
consent
from
each
prospective
subject.

°
Informed
consent
appropriately
documented.

°
If
appropriate,
adequate
provision
for
monitoring
the
data
collected
to
ensure
the
safety
of
subjects.

°
If
appropriate,
adequate
provisions
to
protect
subject
privacy
and
maintain
data
confidentiality.

°
If
some
or
all
subjects
vulnerable
to
coercion
or
undue
influence,
include
additional
safeguards
to
protect
rights
and
welfare
of
these
subjects.
Summary
of
Presentation
°
Brief
Outline
of
the
EPA
Final
Rule
°
Challenge
of
Intentional
Dosing
Studies
°
Application
of
Subpart
K
(
Subpart
A)

°
Selected
NAS
Recommendations
°
Some
Questions
for
Consideration
Selected
NAS
Recommendations
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes:

Scientific
and
Ethical
Issues
2004
3­
1
Scientific
Validity
of
Intentional
Human
Dosing
Studies
°
Important
scientific
or
policy
question
not
answered
by
animal
study
or
human
observational
study.

°
Meets
current
scientific
standards
 
Address
research
question;

 
Appropriate
sample
for
study
endpoint;
and
 
Adequate
statistical
power.

°
Good
clinical
practice,
safety
monitoring.

°
Report
all
documents
and
data
to
EPA.
4­
1
Studies
to
Improve
Accuracy
of
EPA's
Decisions
Without
Public
Health
or
Environmental
Benefit
°
Human
dosing
study
intended
to
reduce
interspecies
uncertainty
factor
has
societal
benefit
ONLY
if
it
improves
scientific
accuracy
of
EPA's
animal
to
human
extrapolation.

°
Studies
that
are
to
be
used
only
to
improve
the
accuracy
of
an
RfD,
and
that
otherwise
provide
no
health
or
environmental
benefit,
can
be
justified
only
if
they
pose
no
identifiable
risk
or
have
reasonable
certainty
of
no
harm.
4­
2
Studies
for
Potential
Public
Health
or
Environmental
Benefit
°
IRB
review
for
potential
health
or
environmental
benefit.

°
Can
have
somewhat
higher
level
of
risk.

°
Cannot
cause
lasting
harm
to
subjects.
Examples
of
Public
Health
or
Environmental
Benefits
°
More
stringent
regulatory
standard.

°
New
public
health
measure
adopted.

°
New
product
that
protects
public
health.

°
Improved
scientific
accuracy
of
risk
assessment.
5­
1
Criteria
for
Scientific
and
Ethical
Acceptability
°
Highest
Scientific
and
ethical
standards
 
Prior
animal
&
human
observational
studies;

 
Need
knowledge
from
human
intentional
dosing
studies;

 
Design
&
analysis
(&
power)
to
detect
effects;

 
Balance
risks
$
benefits;
minimize
risks;

 
Equitable
subject
selection;

 
Free
and
informed
consent;
and
 
IRB
review.
5­
2
Participant
Selection
Criteria
°
Equitable
subject
selection.

°
Vulnerable
populations
justified,
with
added
measures
for
protection.

°
Populations
at
increased
risks
justified,

with
added
measures
to
decrease
risks.

°
Subpart
D
requirements.

 
Note:
Research
on
children
less
than
18
years
of
age
prohibited
by
EPA
Final
Rule.
5­
3
Payment
for
participation
°
Payments
not
so
high
as
to
be
undue
inducement.

°
Payments
not
so
low
that
only
attractive
to
economically
disadvantaged
subjects.

°
Payments
reviewed
for
principles
of
justice
and
respect
for
persons.

°
EPA
should
make
guidelines
re:
payment
 

for
risk,
as
well
as
time
&
inconvenience?
5­
4
Best
Practices
in
Informed
Consent
°
EPA
to
develop,
disseminate,
encourage
or
require
adoption
of
best
practices
for
informed
consent.
5­
5
Compensation
for
Research­
Related
Injury
°
Subjects
should
receive
needed
medical
care
for
research­
related
injuries
at
no
cost
to
subjects.

°
EPA
should
study
if
broader
compensation
for
research­
related
injuries
is
needed.
Summary
of
Presentation
°
Brief
Outline
of
the
EPA
Final
Rule
°
Challenge
of
Intentional
Dosing
Studies
°
Application
of
Subpart
K
(
Subpart
A)

°
Selected
NAS
Recommendations
°
Some
Questions
for
Consideration
Some
Questions
for
Consideration
1.
What
is
the
research,
and
what
is
standard
practice?

°
Pesticide
handlers
 
are
pesticide
appliers
doing
their
regular
jobs
and
being
monitored
or
is
the
application
process
or
pesticide
used
different
from
their
standard
job?

°
Insect
repellents
used
by
many,
but
not
all,
campers,

hikers,
etc.

2.
Minimal
risk
definition
°
Does
HSRB
want
to
use
the
current
OHRP
interpretation
or
should
we
re­
visit
this?
Some
Questions
for
Consideration
(
continued)

3.
Minimizing
risks
 
Is
follow
up
post
exposure
or
post
monitoring
a
long
enough
duration
to
see
adverse
events
if
they
are
to
occur?

4.
Societal/
scientific
value
 
Without
sample
size
,
difficult
to
determine
the
value/
validity
of
the
resultant
data.

 
Is
appropriate
control
used
for
the
study's
design?
Some
Questions
for
Consideration
(
continued)

5.
Informed
consent
process
 
What
measures
are
in
place
to
avoid
coercion
or
undue
influence?

 
What
is
relationship
between
researcher
and
subjects?

 
Bilingual
researchers
vs.
interpreters
(
co­
workers?)

 
Comprehension
of
risks
and
discomforts
6.
Informed
consent
form
 
What
is
literacy
rate
in
English
or
other
languages
among
intended
research
subjects?

 
Is
consent
process
more
than
reading
the
form?
Some
Questions
for
Consideration
(
continued)

7.
Remuneration
 
How
much
is
too
much?
(
undue
influence?)

 
How
little
is
too
little?
(
Respect
vs
Justice)