Document ID: EPA-HQ-ORD-2006-0187-0110
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-06T04:00Z

1
Summary
of
Summary
of
EPA
Ethics
Review
EPA
Ethics
Review
McFarlane,
P.;
Sanderson,
J.;
Freestone,
S.
(
1998)
A
Randomised
Double
Blind
Ascending
Oral
Dose
Study
with
Methomyl
to
Establish
a
No
Adverse
Effect
Level:
Lab
Project
No.
HLO­
1998­
00969.
Unpublished
study
prepared
by
Inveresk
Clinical
Research.
468
p.
MRID
44721401.
2
Methomyl
Oral
Study
Methomyl
Oral
Study

Conducted
at
Inveresk
in
1998,
among
the
first
post­

FQPA
human
studies
of
ChEI

Designed
as
6­
level
escalating­
dose
protocol,
with
no
further
escalation
after
 
40%
ChEI

Subject
receiving
lead
dose
in
session
2
experienced
>
40%
ChEI

Investigators
proceeded
with
session
3,
omitting
the
lead
dose;
later
amended
protocol
to
add
intermediate
(
lower)
dose
3
Methomyl
Methomyl
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports
2.
Scientific
Validity:
Defer
to
others
3.
Subject
Selection

Adult
male
volunteers
from
pool
at
laboratory

No
evidence
of
use
of
vulnerable
groups
4
Methomyl
Methomyl
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
adequately
described
to
subjects

Risk
minimization
not
discussed;
narrow
margin
between
planned
doses
and
reported
animal
NOELs

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed
5
Methomyl
Methomyl
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

Protocol
approved
by
Inveresk
Independent
Ethics
Committee

Committee
members
named,
but
independence
from
investigators
and
freedom
from
conflicts
of
interest
not
addressed
6
Methomyl
Methomyl
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Consent
was
obtained
from
all
subjects

Volunteer
information
covered
procedure
and
possible
physical
effects
adequately,
but
was
less
complete
on
other
topics,
especially
the
nature
and
distribution
of
benefits

potentially
confusing
references
to
the
 
supervising
doctor 
and
 
the
company ,
neither
of
whom
was
identified
7
Methomyl
Methomyl
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Subjects'
privacy
was
protected

Subjects
were
free
to
withdraw
without
penalty
8
Methomyl:
Prevailing
Standard
Methomyl:
Prevailing
Standard

Conducted
in
UK
in
1998­
9

Cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1996)

Cites
and
asserts
compliance
with
"
guideline
for
Good
Clinical
Practice
(
CPMP/
ICH/
135/
95)"
9
Comparison
to
Comparison
to
DoH
DoH

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."

EPA
Comment:
If
a
careful
assessment
was
conducted
it
was
not
reported.
10
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

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
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

Non­
Therapeutic
Principle
#
3.
 
The
investigator
or
the
investigating
team
should
discontinue
the
research
if
in
his/
her
or
their
judgment
it
may,
if
continued,
be
harmful
to
the
individual. 

Non­
Therapeutic
Principle
#
4.
 
In
research
on
man,
the
interest
of
science
and
society
should
never
take
precedence
over
considerations
related
to
the
well­
being
of
the
subject. 
12
Comparison
to
Comparison
to
DoH
DoH
­­

­­
4

EPA
Comment:
The
investigators
and
sponsor
decided
to
proceed
with
Session
3,

dosing
four
additional
subjects
at
the
level
which
had
already
caused
ChEI
>
40%
in
another
subject,
without
consultation
with
the
reviewing
ethics
committee.
Their
choice
to
eliminate
the
leading
dose
from
Session
3,

deviating
from
but
not
amending
the
protocol,
suggests
that
they
knew
they
were
working
near
the
threshold
at
which
continuation
of
the
research
might
be
harmful
to
the
subjects.
13
Methomyl
Summary
Methomyl
Summary

There
are
some
gaps
in
the
record,
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
1996
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.