Document ID: EPA-HQ-ORD-2006-0187-0081
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

1
Summary
of
Summary
of
EPA
Ethics
Review
EPA
Ethics
Review
Wyld,
P.;
Watson,
C.;
Nimmo,
W.;
et
al.
(
1992)
A
Safety
and
Tolerability
Study
of
Aldicarb
at
Various
Dose
Levels
in
Healthy
Male
and
Female
Volunteers:

Lab
Project
No.
003237.
Unpublished
study
prepared
by
Inveresk
Clinical
Research.
372
p.

(
MRID
42373001)
2
Aldicarb
Oral
Study
Aldicarb
Oral
Study

Conducted
in
1992
at
Inveresk
Clinical
Research

The
first
human
toxicity
study
submitted
to
EPA
since
mid­
1970s

Extensively
supplemented
with
additional
documentation
of
ethical
conduct
of
the
research
3
Aldicarb
Aldicarb
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports
2.
Scientific
Validity:
Defer
to
others
3.
Subject
Selection

Adult
volunteers
from
pool
at
laboratory

All
females
surgically
sterile;
5
used
twice

No
evidence
of
use
of
vulnerable
groups
4
Aldicarb
Aldicarb
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
incompletely
described
to
subjects

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed

Compensation
of
subjects
not
addressed
5
Aldicarb
Aldicarb
"
Framework
Framework"
 
3
5.
Independent
Ethics
Review

Phases
1
and
2
(
males)
and
3
(
females)
conditionally
approved
by
the
Inveresk
Independent
Ethics
Committee

Ethics
committee
charter
provided

Committee
members
reported
to
be
free
from
individual
conflicts
of
interest

Organizational
conflicts
of
interest
not
addressed

Directions
of
the
committee 
for
expanded
lay
summary,
a
second
review
of
the
revised
information,
and
modification
of
the
standard
letter
to
volunteers'
physicians 
were
not
carried
out
6
Aldicarb
Aldicarb
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Consent
was
obtained
from
all
subjects

Aldicarb
was
misleadingly
characterized
as
a
drug

Risks
to
subjects
were
incompletely
described

Male
subjects
were
not
told
doses
to
be
administered
7
Aldicarb
Aldicarb
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Subjects'
privacy
was
protected

Marginally
protective
stopping
rule
(>
70%
RBC
ChEI)


Subjects
free
to
withdraw
8
Aldicarb:
Prevailing
Standard
Aldicarb:
Prevailing
Standard

Conducted
in
UK
in
1992

Cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1989)

Cites
and
asserts
compliance
with
"
principles
of
Good
Clinical
Practice"
9
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
2:
"[
The]
experimental
protocol
.
.
.
should
be
transmitted
for
consideration,
comment
and
guidance
to
a
specially
appointed
committee
independent
of
the
investigator
and
the
sponsor.
.
.
."

EPA
Comment:
The
independence
of
the
reviewing
ethics
committee
is
called
into
question
by
the
investigators'
failure
to
respond
to
conditions
the
committee
placed
on
their
approvals
of
the
research
10
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
Principle
#
4:
"
Biomedical
research
involving
human
subjects
cannot
legitimately
be
carried
out
unless
the
importance
of
the
objective
is
in
proportion
to
the
inherent
risk
to
the
subject."

EPA
Comment:
The
protocol
and
study
report
are
silent
with
respect
to
the
nature
and
distribution
of
benefits
of
the
research,

and
incomplete
in
describing
the
risks
to
the
subjects.
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

Basic
Principle
#
5:
"
Every
.
.
.
project
.
.
.
should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
with
foreseeable
benefits
to
the
subject
or
to
others.
Concern
for
the
interests
of
the
subject
must
always
prevail
over
the
interests
of
science
and
society."

EPA
Comment:
If
a
careful
assessment
of
risks
and
benefits
was
conducted,
it
was
not
reported.
The
protocol
rule
permitting
dosing
to
continue
up
to
a
level
of
70%
ChE
inhibition,
and
the
re­
use
of
five
female
subjects,
suggest
that
the
interests
of
the
subjects
may
not
always
have
prevailed.
12
Comparison
to
Comparison
to
DoH
DoH
­­

­­
4

Basic
Principle
#
9:
".
.
.
each
potential
subject
must
be
adequately
informed
of
the
aims,
methods,

anticipated
benefits
and
potential
hazards
of
the
study.
.
."

EPA
Comment:
The
adequacy
of
the
lay
summary
and
informed
consent
materials
to
support
fully
informed
consent
is
questionable.
13
Comparison
to
Comparison
to
DoH
DoH
­­

­­
5

Basic
Principle
#
12:
"
The
research
protocol
should
always
contain
a
statement
of
the
ethical
considerations
involved
.
.
.
."

EPA
Comment:
There
is
no
such
statement
in
the
protocol
14
Aldicarb
Summary
Aldicarb
Summary

Because
of
the
supplemental
submissions,
more
is
known
about
this
study
than
most.

Some
gaps
remain,
but
gaps
are
not
"
clear
and
convincing
evidence".

There
is
no
evidence
that
the
research
was
fundamentally
unethical.

Some
deficiencies
are
apparent
relative
to
the
cited
1989
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
15
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
Aldicarb
is
a
N­
methyl
carbamate
(
NMC)
pesticide
whose
primary
toxic
effect
is
neurotoxicity
caused
by
the
inhibition
of
the
enzyme,
acetylcholinesterase,

via
carbamylation
followed
by
rapid
recovery.

Aldicarb
can,
at
sufficiently
high
doses,
lead
to
a
variety
of
clinical
signs.
The
Agency
is
conducting
an
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
aldicarb.
In
addition,
aldicarb
is
a
member
of
the
N­
methyl
carbamate
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
NMCs.
16
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
"
Weight
of
the
Evidence"
(
WOE)
document
and
Data
Evaluation
Records
(
DERs)
for
aldicarb
describe
the
study
design
and
results
of
the
aldicarb
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
acute,
aggregate,
single
chemical
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
NMCs.
Regarding
the
aldicarb
human
study,
the
Agency
has
concluded
that
the
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
aggregate
and
the
cumulative
risk
assessments.
17
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

Please
comment
on
the
scientific
evidence
that
supports
whether
the
aldicarb
human
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.,
animal
to
human)

uncertainty
factor
in:

a.
single
chemical,
aggregate
risk
assessment
and
b.
cumulative
risk
assessment.
18
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


In
light
of
the
ethics
committee's
instruction
that
the
lay
summary
be
"
greatly
expanded,"
and
the
fact
that
the
materials
used
to
obtain
informed
consent
listed
a
limited
range
of
symptoms
of
carbamate
toxicity
(
excluding
some
reported
as
adverse
effects
in
the
study),
included
multiple
references
to
the
test
material
as
a
drug,
and
failed
to
identify
dose
levels
to
be
administered
to
male
subjects,
whether,
the
materials
used
to
obtain
informed
consent
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted
19
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

a.
cont'd.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


Whether
the
absence
from
the
protocol
of
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1989
Declaration
of
Helsinki,
Principle
#
4,
with
which
the
research
asserted
compliance)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
20
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:


OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.


Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted