Document ID: EPA-HQ-ORD-2006-0187-0097
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
Reese,
W.
H.,
Jr.
(
1972)
Final
Report 
Phase
II:
Evaluation
of
Ethrel
in
Human
Volunteers:
BRL
Project
No.
7223.
Unpublished
study
prepared
by
Litton
Bionetics
Inc.
(
MRID
36510)

Weir,
R.
J.
(
1977)
Final
Report:
Evaluation
of
Ethephon
in
Human
Volunteers:
LBI
Project
No.
2416.
Unpublished
study
prepared
by
Litton
Bionetics
Inc.
MRID
66931.
2
Ethephon
1972
Oral
Study
Ethephon
1972
Oral
Study

Conducted
at
Litton
Bionetics
(
USA)
in
1971

28­
day
duration

Close
observation
only
for
first
8
hours

Self­
administration
on
weekends

Self­
reporting
of
effects
3
Ethephon
72
Ethephon
72
"
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
unknown
pool

Reproductive
status
of
females
not
reported

Subjects
may
have
been
lab
employees
4
Ethephon
72
Ethephon
72
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
to
subjects
not
characterized

Risk
minimization
not
discussed

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed

Subject
compensation
not
addressed
5
Ethephon
72
Ethephon
72
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

No
mention
of
ethics
oversight
or
independent
review

No
standard
of
ethical
conduct
cited
6
Ethephon
72
Ethephon
72
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Consent,
oral
or
written,
is
not
mentioned
in
the
report

Subjects
are
reported
to
have
been
"
thoroughly
briefed",
but
what
they
were
told
is
not
documented

Subjects
are
identified
in
the
summary
as
"
volunteers"
7
Ethephon
72
Ethephon
72
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Privacy
of
subjects
was
not
compromised
in
the
report

Freedom
of
subjects
to
withdraw
from
the
research
is
not
addressed
8
Ethephon
72
Prevailing
Standard
Ethephon
72
Prevailing
Standard

Conducted
in
U.
S.
in
late
1971

No
standard
of
conduct
cited

Declaration
of
Helsinki
(
1964)
assumed
to
have
prevailed
9
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
3:
"
Clinical
research
cannot
legitimately
be
carried
out
unless
the
importance
of
the
objective
is
in
proportion
to
the
inherent
risk
to
the
subject"

Basic
Principle
#
4:
Every
clinical
research
project
should
be
preceded
by
careful
assessment
of
inherent
risks
in
comparison
to
foreseeable
benefits
to
the
subject
or
to
others."

EPA
Comment:
Neither
risks
nor
benefits
were
discussed;
no
careful
assessment
was
reported
10
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Non­
Therapeutic
Principle
#
3a:
"
Clinical
research
on
a
human
being
cannot
be
undertaken
without
his
free
consent
after
he
has
been
informed."

Non­
Therapeutic
Principle
#
3c:
Consent
should,
as
a
rule,
be
obtained
in
writing."

EPA
Comment:
Report
is
silent
with
respect
to
consent,
although
it
does
report
that
subjects
were
"
thoroughly
briefed"
and
refers
to
them
as
"
volunteers".
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

Non­
Therapeutic
Principle
#
4b:"
At
any
time
during
the
course
of
clinical
research
the
subject
.
.
.
should
be
free
to
withdraw.
.
.
."

EPA
Comment:
Report
is
silent
with
respect
to
the
subjects'
freedom
to
withdraw.
12
Ethephon
72
Summary
Ethephon
72
Summary

There
are
many
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence".

Although
silent
as
to
consent,
report
states
subjects
were
"
thoroughly
briefed"
and
calls
them
"
volunteers".

There
is
no
evidence
that
the
research
was
fundamentally
unethical.

Some
deficiencies
are
apparent
relative
to
the
cited
1964
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
13
Ethephon
77
Oral
Study
Ethephon
77
Oral
Study

Conducted
at
Litton
Bionetics
(
USA)
in
1973;
not
reported
until
1977

14­
day
dosing;
1
week
pre­
dose
and
4
weeks
post­
dose
observation

Self­
administration
on
weekends

Self­
reporting
of
effects
14
Ethephon
77
Ethephon
77
"
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
unknown
pool

Reproductive
status
of
females
not
reported
15
Ethephon
77
Ethephon
77
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
to
subjects
not
characterized

Risk
minimization
not
discussed

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed

Subject
compensation
not
addressed
16
Ethephon
77
Ethephon
77
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

No
mention
of
ethics
oversight
or
independent
review

No
standard
of
ethical
conduct
cited
17
Ethephon
77
Ethephon
77
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

"
Subjects
were
thoroughly
informed
on
the
nature
and
present
use
of
the
test
substance,
the
animal
toxicity
data,

potential
pharmacological
side
effects,

and
the
results
of
the
prior
study
in
human
volunteers"


"
Consent
documents
were
obtained
from
all
subjects"
18
Ethephon
77
Ethephon
77
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Privacy
of
subjects
was
not
compromised
in
the
report

Freedom
of
subjects
to
withdraw
from
the
research
is
not
addressed
19
Ethephon
77
Prevailing
Standards
Ethephon
77
Prevailing
Standards

Conducted
in
U.
S.
in
mid­
1973

No
standard
of
conduct
cited

Declaration
of
Helsinki
(
1964)
assumed
to
have
prevailed

FIFRA
§
12(
a)(
2)(
P)
applied
20
Comparison
to
FIFRA
Comparison
to
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

The
Standard:
"
It
shall
be
unlawful
for
any
person
.
.
.
to
use
any
pesticide
in
tests
on
human
beings
unless
such
human
beings
(
i)
are
fully
informed
of
the
nature
and
purposes
of
the
test
and
of
any
physical
and
mental
health
consequences
which
are
reasonably
foreseeable
therefrom,
and
(
ii)
freely
volunteer
to
participate
in
the
test."

EPA
Comment:
Subjects
were
"
thoroughly
informed"
and
signed
consent
forms.
There
is
no
clear
evidence
that
the
study
fell
short
of
the
FIFRA
requirement
21
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
3:
"
Clinical
research
cannot
legitimately
be
carried
out
unless
the
importance
of
the
objective
is
in
proportion
to
the
inherent
risk
to
the
subject"

Basic
Principle
#
4:
Every
clinical
research
project
should
be
preceded
by
careful
assessment
of
inherent
risks
in
comparison
to
foreseeable
benefits
to
the
subject
or
to
others."

EPA
Comment:
Neither
risks
nor
benefits
were
discussed;
no
careful
assessment
was
reported
22
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Non­
Therapeutic
Principle
#
4b:"
At
any
time
during
the
course
of
clinical
research
the
subject
.
.
.
should
be
free
to
withdraw.
.
.
."

EPA
Comment:
Report
is
silent
with
respect
to
the
subjects'
freedom
to
withdraw.
23
Ethephon
77
Summary
Ethephon
77
Summary

There
are
many
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence".

IC
materials
not
available,
but
report
states
subjects
were
"
thoroughly
informed"
and
signed
consent
forms.

There
is
no
evidence
that
the
research
was
fundamentally
unethical.

Some
deficiencies
are
apparent
relative
to
the
cited
1964
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
24
Ethephon
Ethephon
Charge
to
the
HSRB
Charge
to
the
HSRB
Ethephon
is
an
organophosphorus
compound
that,

upon
absorption
into
plants,
forms
ethylene
gas
which
is
an
important
component
of
the
plant
hormone
complex.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
ethephon.
25
Ethephon
Ethephon
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
WOE
document
and
DERs
for
ethephon
describe
the
study
design
and
results
of
the
ethephon
repeat
dose,
oral,
human
toxicity
studies.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
studies
in
the
aggregate,
single
chemical
risk
assessment.
The
Agency
has
concluded
that
the
28­
day
human
study
is
sufficiently
robust
to
establish
a
point
of
departure
for
extrapolating
acute
and
chronic
dietary
risk.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
26
Ethephon
Ethephon
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

In
its
ethics
review
of
this
research,
EPA
documented
that
the
study
reports
contained
very
little
information
concerning
the
ethical
conduct
of
the
research
and
that
the
available
information
raised
no
ethical
concerns.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,

taking
into
account
all
that
is
known
about
the
ethical
conduct
of
each
study:
27
Ethephon
Ethephon
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

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