Document ID: EPA-HQ-ORD-2006-0187-0114
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.;
Freestone,
S.
(
1999)
A
Randomised
Double
Blind
Ascending
Oral
Dose
Study
with
Oxamyl:
Lab
Project
No.
HLO­
1998­

01505.
Unpublished
study
prepared
by
Inveresk
Clinical
Research.
624
p.
MRID
44912301.
2
Oxamyl
Oral
Study
Oxamyl
Oral
Study

Conducted
at
ICR
in
1999,
following
earlier
Methomyl
study

Designed
as
a
5­
level
escalating­
dose
protocol,

with
no
further
escalation
after
 
40%
ChEI
or
 
25%
at
two
successive
time­
points

After
original
five
dose
levels
were
well
tolerated,
a
sixth
higher
dose
was
added.
3
Oxamyl
Oxamyl
"
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
Oxamyl
Oxamyl
"
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

Protocol
states
no
information
on
incidents
available;

sponsor
submitted
12
incident
reports
to
EPA
before
this
study
5
Oxamyl
Oxamyl
"
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

Committee
expressed
concern
about
how
little
was
known
about
oxamyl,
and
its
"
alarming"

toxicity
6
Oxamyl
Oxamyl
"
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
Oxamyl
Oxamyl
"
Framework
Framework"
­­

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

Conducted
in
UK
in
1999

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
#
1:
 
Biomedical
research
involving
human
subjects
.
.
.

should
be
based
.
.
.
on
a
thorough
knowledge
of
the
scientific
literature. 

EPA
Comment:
Protocol
statement
that
 
no
data
on
accidental
or
incidental
exposure
of
people
to
oxamyl
is
available 
is
inconsistent
with
the
twelve
incident
reports
previously
submitted
to
EPA.
10
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

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.
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

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
12
Oxamyl
Summary
Oxamyl
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.
13
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
Methomyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation.
The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,

multi­
route)
risk
assessment
of
methomyl.
At
the
present
time,
the
Agency
is
considering
the
use
of
the
methomyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
used
in
the
cumulative
risk
assessment
of
the
NMCs.
14
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
WOE
document
and
DER
for
methomyl
describe
the
study
design
and
results
of
the
methomyl
acute
oral,
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
methomyl,
the
Agency
has
concluded
that
the
human
toxicity
study
supports
a
10X
inter­
species
uncertainty
factor
for
methomyl
in
the
cumulative
risk
assessment
of
the
NMCs.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
15
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

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


Whether
the
investigators'
decision
to
administer
a
dose
to
additional
subjects
in
session
3,
when
one
subject
receiving
that
dose
in
session
2
displayed
RBC
ChEI
greater
than
40%,
a
response
that
triggered
the
protocol's
anti­
escalation
provision,
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
16
Methomyl
Methomyl
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
timing
of
the
investigators'
report
to
the
ethics
committee
of
the
adverse
effects
observed
in
one
subject
during
session
2
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
17
Methomyl
Methomyl
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
failure
of
the
investigators
to
request
approval
from
the
ethics
committee
for
certain
amendments
to
the
approved
protocol,
as
required
by
the
protocol,
when
the
changes
were
administrative
and
had
no
effect
on
the
safety
of
the
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
18
Methomyl
Methomyl
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
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
19
Methomyl
Methomyl
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
20
Oxamyl
Oxamyl
Charge
to
the
HSRB
Charge
to
the
HSRB
Similar
to
aldicarb
and
methomyl,
oxamyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation
and
is
thus
included
in
the
NMC
cumulative
risk
assessment.

The
Agency
has
previously
completed
the
acute,

aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
oxamyl.
The
Agency
is
now
considering
the
use
of
the
oxamyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
in
the
cumulative
risk
assessment
of
the
NMCs.
21
Oxamyl
Oxamyl
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
WOE
document
and
DER
for
oxamyl
describe
the
study
design
and
results
of
the
oxamyl
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
oxamyl,
the
Agency
has
concluded
that
the
human
toxicity
study
is
sufficiently
robust
for
reducing
the
10X
inter­
species
(
ie,
animal
to
human)
uncertainty
factor
in
the
cumulative
risk
assessment.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
22
Oxamyl
Oxamyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

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


Whether
inclusion
in
the
protocol
submitted
to
the
ethics
committee
of
a
factually
inaccurate
statement
regarding
unavailability
of
data
on
accidental
or
incidental
exposure
to
oxamyl
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
23
Oxamyl
Oxamyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

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


Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
24
Oxamyl
Oxamyl
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/
each]
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