1
Summary
of
Summary
of
EPA
Ethics
Review
EPA
Ethics
Review
MRID
44400401
Russell,
M.,
Rush,
T.
(
1996)
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation.
Unpublished
study
performed
by
Sensory
Testing
Laboratory,
School
of
Medicine,
Univ.
of
California,
Davis,
and
Zeneca
Ag
Products
Western
Research
Center,
Richmond
CA.
Project
numbers
MITCUCD
1A­
1993
and
MITC­
UCD­
1B­
1994;
Report
no.
RR
96­
049B.

136
p.
Supplemented
by
MRIDs
46546601,
46558201,
and
46584901
2
MITC
Study
Summary
MITC
Study
Summary

Two
entirely
independent
studies
covered
by
a
single
report

Odor
threshold
study
conducted
at
UC­
Davis
in
1992­
93

Eye
irritation
study
conducted
at
UC­
Davis
in
1994­
95

The
studies
differ
sharply
in
their
ethical
conduct,
and
are
reviewed
separately
3
MITC
Odor
Study
MITC
Odor
Study
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports
2.
Scientific
Validity:
Defer
to
others
3.
Subject
Selection

38
adult
male
and
female
volunteers
from
university
community

Recruitment
methods
not
reported;
no
evidence
of
use
of
vulnerable
groups
4
MITC
Odor
Study
MITC
Odor
Study
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
characterized
to
IRB
first
as
"
no
risk",
and
later
as
"
minimal
risk"


Risk
minimization
not
discussed

No
record
of
how
risks
were
characterized
to
subjects

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed
5
MITC
Odor
Study
MITC
Odor
Study
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

Approved
by
UC­
Davis
Human
Subjects
Review
Committee,
initially
in
1989
and
annually
thereafter

Initial
approval
was
for
"
scratch­
and­
sniff"
mail­
out
survey

MITC
was
first
use
of
"
olfactometer"


No
documentation
of
IRB
approval
for
period
of
MITC
study

No
documentation
of
protocol
or
informed
consent
materials
for
MITC
study

IRB
failed
to
respond
to
investigator's
request
for
waiver
of
written
informed
consent
until
3
years
after
MITC
work
was
completed
6
MITC
Odor
Study
MITC
Odor
Study
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Primary
report
silent
about
consent

Supplement
asserts
oral
information
and
oral
consent,
through
note
to
file
of
telephone
call

No
documentation
of
IRB
waiver
of
Common
Rule
requirement
for
written
consent

No
documentation
of
what
subjects
were
told
7
MITC
Odor
Study
MITC
Odor
Study
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Subject
privacy
was
protected

Subject
freedom
to
withdraw
was
not
addressed
8
MITC
Odor
Study:
Prevailing
Standards
MITC
Odor
Study:
Prevailing
Standards

Conducted
in
US
in
1992­
3
at
UC­
Davis

Cites
and
asserts
compliance
with
Declaration
of
Helsinki

UC­
Davis
held
federal
Multi­
Project
Assurance
at
time
of
research,
promising
full
compliance
with
Common
Rule
9
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
2:
".
.
.
Each
experimental
procedure
.
.
should
be
clearly
formulated
in
an
experimental
protocol,
which
should
be
transmitted
.
.
to
a
specially
appointed
committee
.
.
."


EPA
Comment:
Protocol
was
not
clearly
formulated.
MITC
work
was
unrelated
to
mail
survey
work
described
in
protocol
reviewed
and
approved
by
IRB
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
 
3a
3a

Basic
Principle
#
9:
"
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.
.
.
[
and]
should
be
informed
that
.
.
.
he
or
she
is
free
to
withdraw.
.
.
at
any
time.
The
[
investigator]
should
then
obtain
the
subject's
freely­
given
informed
consent,
preferably
in
writing."
12
Comparison
to
Comparison
to
DoH
DoH
 
3b
3b

EPA
Comment:
The
primary
report
was
silent
about
consent.
The
information
provided
to
the
IRB
was
irrelevant
to
the
work
with
MITC.

There
is
no
documentation
of
the
context,

procedure,
or
content
of
the
asserted
oral
consent
process.
13
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
such
statement
in
the
protocol
14
Comparison
to
Common
Rule
Comparison
to
Common
Rule

§
111(
a)(
2):
[
to
approve
research
.
.
.
The
IRB
shall
determine
that]
"
risks
to
subjects
are
reasonable
in
relation
to
anticipated
benefits,
if
any,
to
subjects,
and
the
importance
of
the
knowledge
that
may
be
reasonably
expected
to
result."


EPA
Comment:
IRB
records
indicate
no
discussion
of
either
risks
or
benefits
15
Comparison
to
Common
Rule
Comparison
to
Common
Rule
­­

­­
2

§
111(
a)(
4):
[
to
approve
research
.
.
.
The
IRB
shall
determine
that]
"
informed
consent
will
be
sought
from
each
prospective
subject.

.
."


EPA
Comment:
IRB
records
do
not
reflect
any
discussion
of
informed
consent
16
Comparison
to
Common
Rule
Comparison
to
Common
Rule
­­

­­
3

§
111(
a)(
5):
[
to
approve
research
.
.
.
The
IRB
shall
determine
that]
"
Informed
consent
will
be
appropriately
documented,
in
accordance
with,
and
to
the
extent
required
by
Sec.
26.117"


EPA
Comment:
IRB
records
do
not
indicate
the
board
noticed
or
discussed
the
investigator's
request
for
waiver
of
written
consent
17
Comparison
to
Common
Rule
Comparison
to
Common
Rule
­­

­­
4

§
115:
IRB
Records

EPA
Comment:
IRB
records
fall
well
short
of
the
requirements
of
the
CR

§
116:
General
Requirements
for
Informed
Consent

EPA
Comment:
Compliance
of
undocumented
oral
consent
process
with
these
requirements
cannot
be
assessed
18
Comparison
to
Common
Rule
Comparison
to
Common
Rule
­­

­­
5

§
117:
Documentation
of
Informed
Consent

EPA
Comment:
The
failure
to
document
consent
or
to
waive
the
requirement
falls
short
of
Common
Rule
standards
19
MITC
Odor
Study
Summary
MITC
Odor
Study
Summary

Gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence"


No
evidence
that
the
research
was
fundamentally
unethical

No
evidence
that
subjects
included
children
or
pregnant
women

Many
clear
deficiencies
relative
to
the
cited
Declaration
of
Helsinki
and
the
Common
Rule

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies
20
MITC
Eye
Study
MITC
Eye
Study
"
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
and
female
volunteers
from
university
community;
number
unclear

Recruitment
methods
suggest
some
subjects
may
have
been
students
or
colleagues
of
investigators
21
MITC
Eye
Study
MITC
Eye
Study
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
characterized
to
subjects
as
"
transient
irritation
and
tearing"


Risk
minimization
not
discussed

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed

Subjects
compensated
$
60­
250
depending
on
duration
of
study
phase
22
MITC
Eye
Study
MITC
Eye
Study
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

Initial
approval
by
UC­
Davis
Human
Subjects
Review
Committee
and
annual
renewals
with
protocol
revisions
are
documented

IRB
discussion
not
documented
23
MITC
Eye
Study
MITC
Eye
Study
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Consent
materials
are
brief,
but
clear

Consent
materials
include
all
elements
required
by
Common
Rule
§
116
7.
Respect
for
Subjects

Subject
privacy
was
protected

Subjects
were
free
to
withdraw
24
MITC
Eye
Study:
Prevailing
Standards
MITC
Eye
Study:
Prevailing
Standards

Conducted
in
US
in
1994­
5
at
UC­
Davis

Cites
and
asserts
compliance
with
Declaration
of
Helsinki

UC­
Davis
held
federal
Multi­
Project
Assurance
at
time
of
research,
promising
full
compliance
with
Common
Rule
25
Comparison
to
Prevailing
Standards
Comparison
to
Prevailing
Standards

Documentation
of
risk
reduction
is
weak

Documentation
of
societal
benefit
is
weak

Possibility
of
undue
influence
in
recruiting
students
of
investigator

General
compliance
with
Declaration
of
Helsinki
and
Common
Rule
26
MITC
Eye
Study
Summary
MITC
Eye
Study
Summary

Minor
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence"


No
children;
no
pregnant
females;
no
evidence
that
the
research
was
fundamentally
unethical

No
noteworthy
deficiencies
relative
to
the
cited
Declaration
of
Helsinki
or
the
Common
Rule
