Document ID: EPA-HQ-ORD-2006-0187-0086
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

1
Summary
of
Summary
of
EPA
Ethics
Reviews
EPA
Ethics
Reviews
Cass,
L.
(
1992)
T­
344,
Amitraz:
Report
of
a
Double
Blind
Tolerance
Study
of
Amitraz
in
Six
Adult
Healthy
Volunteers:
Lab
Project
Number:
RD
197/
20170.
Unpublished
study
prepared
by
Simbec
Research
Ltd.
136
p.
MRID
43283101.

Langford,
H.
(
1998)
Amitraz
(
Code
AE
B049974):
Human
Volunteer
Double­
Blind
Dermal
Tolerance
Study:
Lab
Project
Number:
C00350:
TOX
97228:
RD
197/
21690.
Unpublished
study
prepared
by
Simbec
Research
Ltd.
243
p.
MRID
44639401
2
Amitraz
92
Oral
Study
Amitraz
92
Oral
Study

Conducted
in
1991­
92
at
Simbec
Research,
Ltd.,
in
UK

6
adult
male
volunteers

Cross­
over
design
3
Amitraz
92
Oral
Amitraz
92
Oral
"
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
Amitraz
92
Oral
Amitraz
92
Oral
"
Framework
Framework"­­

­­
2
4.
Risk­
Benefit
Ratio

Subjects
were
told
 
Man
has
received
twice
the
highest
dose
to
be
given
in
this
study
with
some
drowsiness
seen
.
.
.
.
Animals
have
tolerated
doses
several
times
higher.


Main
side
effects
include
drowsiness,
slurred
speech,
dry
mouth,

disorientation
and
a
slight
drop
in
blood
pressure
and
pulse
rate.


Subjects
were
told
the
study
would
be
of
no
medical
benefit
to
them.


The
study
design
ensured
that
no
subject
received
the
high
dose
before
having
demonstrated
tolerance
to
the
lower
dose;
otherwise
risk
minimization
was
not
addressed.


Expected
societal
benefits
are
not
addressed
in
the
report
or
in
the
ethics
committee s
approval.


Subjects
were
compensated
£
350
5
Amitraz
92
Oral
Amitraz
92
Oral
"
Framework
Framework"­­

­­
3
5.
Independent
Ethics
Review

Amended
protocol
approved
by
the
Chair
of
the
Simbec
Independent
Ethics
Committee

No
record
of
full
committee
review
or
comments

Membership
of
the
ethics
committee
and
their
independence
from
the
investigators,
the
performing
laboratory,
and
the
sponsor
was
not
addressed
6
Amitraz
92
Oral
Amitraz
92
Oral
"
Framework
Framework"­­

­­
4
6.
Informed
Consent

Informed
consent
was
obtained
from
all
participants.


A
"
subject
information
sheet"
covered
the
procedure
and
possible
physical
effects
adequately,
but
was
less
complete
with
respect
to
other
topics.


It
was
silent
about
who
would
benefit
from
the
study,
but
clear
that
the
subjects
would
not

IC
materials
contained
potentially
confusing
references
to
drugs
7
Amitraz
92
Oral
Amitraz
92
Oral
"
Framework
Framework"­­

­­
5
7.
Respect
for
Subjects

Subjects'
privacy
was
protected

Subjects
were
free
to
withdraw
without
penalty
8
Amitraz
92
Prevailing
Standard
Amitraz
92
Prevailing
Standard

Conducted
in
UK
in
1991­
92

Cited
and
asserted
compliance
with
Declaration
of
Helsinki
1989

Asserted
compliance
with
the
recommendations
of
the
Royal
College
of
Physicians
on
Healthy
Volunteers
(
1986)
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:
Documentation
of
the
membership
and
independence
of
the
Simbec
Independent
Ethics
Committee
was
inadequate.
10
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
principle
#
9
"
In
any
research
on
human
beings,
each
potential
subject
must
be
adequately
informed
of
the
aims,
methods,
anticipated
benefits
and
potential
hazards
of
the
study
and
the
discomfort
it
may
entail."

EPA
Comment:
The
confusing
references
to
drug
testing,
medical
regulatory
agencies,
and
standards
for
investigation
of
new
therapeutic
agents
in
the
subject
information
sheet
and
consent
document
may
have
misled
subjects
into
thinking
they
were
participating
in
a
drug
trial.
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
substantive
discussion
of
ethical
considerations
in
the
protocol
12
Amitraz
92
Oral
Summary
Amitraz
92
Oral
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
1989
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
13
Amitraz
98
Dermal
Study
Amitraz
98
Dermal
Study

Conducted
in
conducted
in
the
U.
K.
in
1997­
98
at
Simbec
Research,
Ltd.

8
adult
male
volunteers

Cross­
over
design

Split
dose,
four
times
a
day
14
Amitraz
98
Dermal
Amitraz
98
Dermal
"
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
15
Amitraz
98
Dermal
Amitraz
98
Dermal
"
Framework
Framework"
­
2
4.
Risk­
Benefit
Ratio

Risks
characterized
as
drowsiness,
slurred
speech,

dry
mouth,
disorientation
and
a
slight
drop
in
blood
pressure
and
pulse
rate.


highest
dose
was
half
the
animal
NOEL
 
slim
margin,
since
humans
most
sensitive

Silent
about
benefits,
and
about
weighing
benefits
and
risks

Subjects
compensated
£
1075
16
Amitraz
98
Dermal
Amitraz
98
Dermal
"
Framework
Framework"
­
3
5.
Independent
Ethics
Review

Approved
by
the
Chair
of
the
Simbec
Independent
Ethics
Committee

No
record
of
full
committee
review
or
comments

Membership
of
the
ethics
committee
and
their
independence
from
the
investigators,
the
performing
laboratory,
and
the
sponsor
was
not
addressed
17
Amitraz
98
Dermal
Amitraz
98
Dermal
"
Framework
Framework"
­
4
6.
Informed
Consent

Informed
consent
was
obtained
from
all
participants.


A
"
subject
information
sheet"
covered
the
procedure
and
possible
physical
effects
adequately,
but
was
less
complete
with
respect
to
other
topics.


It
was
silent
about
who
would
benefit
from
the
study,
but
clear
that
the
subjects
would
not

IC
materials
contained
potentially
confusing
references
to
drugs

Included
separate
consent
for
HIV
testing
18
Amitraz
98
Dermal
Amitraz
98
Dermal
"
Framework
Framework"
­
5
7.
Respect
for
Subjects

Subjects'
privacy
was
protected

Subjects
were
free
to
withdraw
without
penalty
19
Amitraz
98
Prevailing
Standard
Amitraz
98
Prevailing
Standard

Conducted
in
UK
in
1997­
98

Cited
and
asserted
compliance
with
Declaration
of
Helsinki
1996

Cites
"
ABPI
Guidelines
for
Medical
Experiments
in
Non­
Patient
Human
Volunteers
­
1988,
amended
May
1990"

and
"
ICH
Harmonised
Tripartite
Guideline
for
Good
Clinical
Practice"
20
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
1:
"
Biomedical
research
involving
human
subjects
.
.
.
should
be
based
on
adequately
performed
laboratory
and
animal
experimentation
and
on
a
thorough
knowledge
of
the
scientific
literature."

EPA
Comment:
The
narrow
margin
between
the
high
test
dose
and
the
reported
animal
NOEL
(
and
the
failure
to
acknowledge
it,
either
by
the
investigators
or
by
the
reviewing
ethics
committee)
raises
concern
over
how
thoroughly
a
knowledge
of
the
literature
was
reflected
in
the
design
of
this
study.
21
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

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:
Documentation
of
the
membership
and
independence
of
the
Simbec
Independent
Ethics
Committee
was
inadequate.
22
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

Basic
principle
#
9
"
In
any
research
on
human
beings,
each
potential
subject
must
be
adequately
informed
of
the
aims,
methods,
anticipated
benefits
and
potential
hazards
of
the
study
and
the
discomfort
it
may
entail."

EPA
Comment:
The
confusing
references
to
drug
testing,
medical
regulatory
agencies,
and
standards
for
investigation
of
new
therapeutic
agents
in
the
subject
information
sheet
and
consent
document
may
have
misled
subjects
into
thinking
they
were
participating
in
a
drug
trial.
23
Comparison
to
Comparison
to
DoH
DoH
­­

­­
4

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

EPA
Comment:
There
is
no
substantive
discussion
of
ethical
considerations
in
the
protocol
24
Amitraz
98
Dermal
Summary
Amitraz
98
Dermal
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.