Document ID: EPA-HQ-OPP-2003-0132-0660
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-02-06T05:00Z

26
January
2006
MEMORANDUM
TO
THE
FILE
SUBJECT:
Consistency
of
EPA's
Final
Human
Studies
Rule
with
the
Principles
of
the
Nuremberg
Code
and
the
2004
Report
of
the
National
Academy
of
Sciences
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes
On
August
2,
2005,
the
President
signed
into
law
the
Department
of
Interior,
Environment,
and
Related
Agencies
Appropriations
Act,
2006,
Pub.
L.
No.
109­
54
(
Appropriations
Act),
which
provides
appropriated
funds
for
the
Environmental
Protection
Agency
and
other
Federal
departments
and
agencies.
Section
201
of
the
Appropriations
Act
addresses
EPA
activities
regarding
intentional
dosing
human
toxicity
studies
for
pesticides
as
follows:

None
of
the
funds
made
available
by
this
Act
may
be
used
by
the
Administrator
of
the
Environmental
Protection
Agency
to
accept,
consider
or
rely
on
third­
party
intentional
dosing
human
toxicity
studies
for
pesticides,
or
to
conduct
intentional
dosing
human
toxicity
studies
for
pesticides
until
the
Administrator
issues
a
final
rulemaking
on
this
subject.
The
Administrator
shall
allow
for
a
period
of
not
less
than
90
days
for
public
comment
on
the
Agency's
proposed
rule
before
issuing
a
final
rule.
Such
rule
shall
not
permit
the
use
of
pregnant
women,
infants
or
children
as
subjects;
shall
be
consistent
with
the
principles
proposed
in
the
2004
report
of
the
National
Academy
of
Sciences
on
intentional
human
dosing
and
the
principles
of
the
Nuremberg
Code
with
respect
to
human
experimentation;
and
shall
establish
an
independent
Human
Subjects
Review
Board.
The
final
rule
shall
be
issued
no
later
than
180
days
after
enactment
of
this
Act.

This
memorandum
discusses
the
basis
for
EPA's
conclusion
that
the
final
rule,
Protections
for
Subjects
in
Human
Research,
is
consistent
with
the
principles
of
both
the
Nuremberg
Code
and
the
2004
report
of
the
National
Academy
of
Sciences
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes.
This
memorandum
addresses
first
the
rule's
consistency
with
the
ten
principles
of
the
Nuremberg
Code
and,
second,
its
consistency
with
the
principles
of
the
NAS
Report.

The
Nuremberg
Code
A
brief
historical
perspective
of
the
development
of
the
norms
of
medical
ethics
is
presented
in
T.
Hope,
J.
McMillan,
Challenge
studies
of
human
volunteers:
ethical
issues,
J.
Med.
Ethics
2004;
30:
110­
116:
2
Ethical
Regulation
of
Medical
Research:
Historical
Perspective
There
are
historical
reasons
why
medical
research
is
more
tightly
regulated
that
most
other
human
activities
and
its
regulation
differs
from
that
of
normal
clinical
practice.

It
was
the
appalling
experiments
conducted
by
some
doctors
under
the
Nazi
regime
that
led
to
the
first
internationally
agreed
guidelines
on
research
involving
people,
the
Nuremberg
Code
(
1946).
This
consisted
of
ten
principles
and
these
were
interpreted
by
the
World
Medical
Association
in
their
Declaration
of
Helsinki,
first
published
in
1964
and
last
updated
in
2000.
The
declaration
provides
an
internationally
agreed
ethical
framework
for
the
conduct
of
medical
research
involving
humans.
It
is
the
basis
for
the
various
more
detailed
national
and
international
guidelines
that
have
been
developed.

The
values
incorporated
into
the
various
guidelines
can
be
justified
by
a
number
of
different
traditions
in
moral
and
political
philosophy.
Most
guidelines
emphasize
respect
for
the
autonomy
of
the
potential
participants,
the
risk
of
harm,
and
the
value
and
quality
of
the
research.
Two
related
aspects
that
run
through
all
guidelines
are
worthy
of
note:
first,
that
there
are
strict
limits
to
the
risk
of
harm
that
participants
in
research
can
be
subjected
to,
even
if
they
are
adult,
fully
competent,
and
voluntarily
agree
to
take
those
risks;
second,
that
in
weighing
up
the
potential
good
that
the
research
might
bring
to
people
in
the
future
against
the
potential
harm
to
participants,
concern
about
the
welfare
of
participants
is
given
very
much
weight.
Because
of
the
origins
of
the
Nuremberg
Code,
the
central
concern
of
research
guidelines
is
to
ensure
that
the
interests
of
society,
or
the
enthusiasm
of
the
researcher,
do
not
override
the
interests
of
the
individual
participants.

Id.
at
110.
We
note,
however,
that
historical
analysis
demonstrates
that
the
Nuremberg
Code
was
not
the
first
exposition
of
ethical
principles
meant
to
apply
to
intentional
manipulation
of
the
health
of
research
subjects.
As
discussed
in
Vollman
and
Winau,
Nuremberg
Doctors'
Trials
Informed
consent
in
human
experimentation
before
the
Nuremberg
Code,
Brit.
Med.
Journal
1996;
313:
1445­
47
(
7
December),
in
response
to
intentional
dosing
experiments
by
Albert
Neisser
(
the
discoverer
of
gonococcus
bacteria),
in
which
he
dosed
unsuspecting
prostitutes
with
cell
free
serum
from
syphilis
patients,
the
Prussian
Minister
for
Religious,
Educational,
and
Medical
Affairs
issued
a
directive
in
1900
stating
that
all
medical
research
interventions
other
than
for
diagnosis,
healing,
or
immunization
were
to
be
prohibited
under
all
circumstances
if
"
the
human
subject
was
a
minor
or
not
competent
for
other
reasons",
or
if
the
researcher
had
not
obtained
the
"
unambiguous
consent"
of
the
test
subject
after
a
"
proper
explanation
of
the
possible
negative
consequences"
of
the
research
intervention.
Under
Prussian
law
at
the
time,
however,
this
directive
was
not
legally
binding.
In
1931,
the
Reich
Minister
of
the
Interior
issued
guidelines
for
"
new
therapy
and
human
experimentation":
these
guidelines
"
clearly
distinguished
between
1
Taken
from
313
Brit.
Med.
Journal
1448
(
7
Dec.
1996).

3
therapeutic
(`
new
therapy')
and
nontherapeutic
research
(`
human
experimentation')
and
set
out
strict
precautions"
based
on
the
principles
of
beneficence,
nonmaleficence,
patient
autonomy,
and
informed
consent.
Id.
((
Vollman
and
Winau
do
note,
however,
that
the
German
guidelines
of
1931
were
not
annulled
during
the
period
of
the
Nazi
regime
­
they
were
simply
ignored.
It
is
unfortunate
that,
"[
t]
hough
no
other
nation
seem
to
have
had
such
ethically
and
legally
advanced
regulations
at
the
time,
these
did
not
prevent
crimes
against
humanity
by
part
of
the
German
medical
profession.").
We
note
that,
as
ethical
principles
evolved
during
the
last
century
and
became
more
refined,
the
concept
of
a
strict
prohibition
against
the
participation
of
minors
as
research
subjects
gave
way
to
the
realisation
that
informed
consent
could
be
obtained
on
behalf
of
minors
through
parents
or
legal
guardians.

Thus,
these
historical
analyses
demonstrate
that
the
central
tenets
of
the
Nuremberg
Code,
all
ethical
guidelines
developed
subsequently,
and,
for
that
matter,
ethical
guidelines
developed
prior
to
the
Nuremberg
Code,
are
respect
for
the
autonomy
of
the
potential
participants;
minimisation
of
the
risk
of
harm,
and
assessment
of
the
value
and
quality
of
the
research
when
viewed
against
the
potential
risks
to
subjects.
Both
the
Common
Rule
and
EPA's
Protections
for
Subjects
in
Human
Research
final
rule
incorporate
these
central
tenets
of
ethical
standards.

This
analysis
demonstrates
how
EPA's
final
rule,
which,
in
large
part,
applies
standards
and
requirements
derived
from
the
Common
Rule,
is
wholly
consistent
with
the
principles
of
the
Nuremberg
Code.
Below,
the
Agency
quotes
each
of
the
ten
principles
in
the
Nuremberg
Code
(
in
italics),
and
then
sets
forth
its
analysis
of
how
the
final
rule
is
consistent
with
the
stated
principle.

The
Nuremberg
Code
(
1947)
1
Permissible
Medical
Experiments
The
great
weight
of
the
evidence
before
us
is
to
the
effect
that
certain
types
of
medical
experiments
on
human
beings,
when
kept
within
reasonably
well­
defined
bounds,
conform
to
the
ethics
of
the
medical
profession
generally.
The
protagonists
of
the
practice
of
human
experimentation
justify
their
views
on
the
basis
that
such
experiments
yield
results
for
the
good
of
society
that
are
unprocurable
by
other
methods
or
means
of
study.
All
agree,
however,
that
certain
basic
principles
must
be
observed
in
order
to
satisfy
moral,
ethical
and
legal
concepts:

EPA
ANALYSIS
Although
this
introductory
material
does
not
express
a
"
principle,"
it
does
reflect
a
viewpoint
with
which
EPA
agrees
 
that
it
is
possible
to
conduct
some
types
of
research
with
4
humans
ethically,
and
that
when
research
is
ethically
conducted,
observing
certain
basic
moral,
ethical,
and
legal
principles,
it
may
contribute
valuable
information
for
the
good
of
society
that
is
unprocurable
by
other
means.
The
final
rule
incorporates
these
concepts.
We
note,
in
particular,
that
section
26.1111(
a)(
1)
implicitly
incorporates
the
concept
of
"
unprocurable
by
other
methods
or
means
of
study."
If
the
information
may
be
procured
by
means
other
than
the
conduct
of
human
research,
failure
to
use
those
other
means
is
not
consistent
with
the
minimization
of
risk,
or
with
the
directive
not
to
"
unnecessarily
expose
subjects
to
risk".

1.
The
voluntary
consent
of
the
human
subject
is
absolutely
essential.
This
means
that
the
person
involved
should
have
legal
capacity
to
give
consent;
should
be
so
situated
as
to
be
able
to
exercise
free
power
of
choice,
without
the
intervention
of
any
element
of
force,
fraud,
deceit,
duress,
overreaching,
or
other
ulterior
form
of
constraint
or
coercion;
and
should
have
sufficient
knowledge
and
comprehension
of
the
elements
of
the
subject
matter
involved
as
to
enable
him
to
make
an
understanding
and
enlightened
decision.
This
latter
element
requires
that
before
the
acceptance
of
an
affirmative
decision
by
the
experimental
subject
there
should
be
made
known
to
him
the
nature,
duration,
and
purpose
of
the
experiment;
the
method
and
means
by
which
it
is
to
be
conducted;
all
inconveniences
and
hazards
reasonably
to
be
expected;
and
the
effects
upon
his
health
or
person
which
may
possibly
come
from
his
participation
in
the
experiment.

The
duty
and
responsibility
for
ascertaining
the
quality
of
the
consent
rests
upon
each
individual
who
initiates,
directs,
or
engages
in
the
experiment.
It
is
a
personal
duty
and
responsibility
which
may
not
be
delegated
to
another
with
impunity.

EPA
ANALYSIS
The
final
rule
extends
the
requirements
of
the
Common
Rule
to
covered
research;
these
requirements
include
an
obligation
on
researchers
to
obtain
fully
voluntary
and
fully
informed
consent
from
subjects.
The
Common
Rule
addresses
issues
relating
to
legal
capacity
to
consent,
voluntariness,
the
range
of
information
sufficient
to
make
consent
"
informed,"
and
who
has
responsibility
for
obtaining
such
voluntary
consent.
See
40
C.
F.
R.
§
26.116.
The
final
rule
codifies
these
requirements
at
40
C.
F.
R.
§
26.1116.
We
note
that
the
concept
of
"
legal
capacity
to
consent"
does
not
preclude
the
conduct
observational
research
with
children
under
the
final
rule.
As
noted
above,
as
ethical
principles
evolved
during
the
past
century,
the
concept
that
parents
(
and
other
legally
recognized
guardians)
are
capable
of
giving
consent
on
behalf
of
children
and
that
the
parent's
permission
is
the
legal
and
ethical
equivalent
of
the
child's
consent
is
widely
accepted.
5
Where
the
Nuremberg
Code
calls
for
explaining
the
"
nature,
duration,
and
purpose
of
the
experiment"
the
final
rule
at
40
C.
F.
R.
§
26.1116(
a)(
1)
requires
"[
a]
statement
that
the
study
involves
research,
an
explanation
of
the
purposes
of
the
research
and
the
expected
duration
of
the
subject's
participation,
a
description
of
the
procedures
to
be
followed,
and
identification
of
any
procedures
which
are
experimental."
Where
the
Nuremberg
Code
calls
for
explaining
"
all
inconveniences
and
hazards
reasonably
to
be
expected;
and
the
effects
upon
his
health
or
person
which
may
possibly
come
from
his
participation
in
the
experiment"
the
final
rule
at
40
C.
F.
R.
§
26.1116(
a)(
2)
requires
"[
a]
description
of
any
reasonably
foreseeable
risks
or
discomforts
to
the
subject."
Thus,
these
requirements
are
consistent
with
principle
1
of
the
Nuremberg
Code.

2.
The
experiment
should
be
such
as
to
yield
fruitful
results
for
the
good
of
society,
unprocurable
by
other
methods
or
means
of
study,
and
not
random
and
unnecessary
in
nature.

EPA
ANALYSIS
The
final
rule
at
40
C.
F.
R.
§
26.1111(
a)(
2)
provides
that
an
Institutional
Review
Board
(
IRB)
shall
not
approve
proposed
research
unless
"
Risks
to
subjects
are
reasonable
in
relation
to
anticipated
benefits,
if
any,
to
subjects,
and
the
importance
of
the
knowledge
that
may
reasonably
be
expected
to
result."
As
the
National
Academy
of
Sciences'
2004
report
makes
clear,
the
benefits
to
be
considered
by
an
IRB
(
and
also
by
EPA
and
the
independent
Human
Studies
Review
Board
(
HSRB)
during
protocol
review
under
40
C.
F.
R.
§
26.1125
and
26.1601(
d))
include
results
that
benefit
society
at
large,
as
well
as
benefits
(
if
any)
to
the
individual
research
subjects.
See
generally,
NAS
report,
chapter
4.
EPA
will
approve
proposals
for
research
with
human
subjects
and
accept
reports
of
such
research
only
if
it
determines
that
the
research
is
likely
to
yield
fruitful
results
for
the
good
of
society.
Thus,
the
final
rule
is
consistent
with
principle
2
of
the
Nuremberg
Code.

3.
The
experiment
should
be
so
designed
and
based
on
the
results
of
animal
experimentation
and
a
knowledge
of
the
natural
history
of
the
disease
or
other
problem
under
study
that
the
anticipated
results
justify
the
performance
of
the
experiment.

EPA
ANALYSIS
While
Common
Rule
requirements
do
not
address
principle
3
directly,
the
protocol
review
process
established
by
40
C.
F.
R.
§
26.1125
and
26.1601(
d)
includes
review
of
research
proposals
by
both
EPA
and
the
HSRB.
In
this
review
both
EPA
and
the
HSRB
would
have
access
to
all
available
laboratory
animal
studies
on
the
potential
toxicity
of
the
pesticide,
since
such
information
is
required
to
be
submitted
to
the
Agency
in
support
of
regulatory
actions
affecting
pesticides.
See
e.
g.,
FIFRA
sections
3(
c)(
1)
and
6(
a)(
2).
EPA
and
the
HSRB
would
then
consider
these
data
in
determining
whether
the
proposed
research
meets
the
requirement
in
the
Common
Rule
to
minimize
risks
to
subjects
and,
consistent
with
principle
3
of
the
Nuremberg
6
Code,
whether
the
proposed
experiment
was
so
designed
and
based
on
prior
data
or
information
that
the
anticipated
results
of
the
study
justify
its
conduct.

4.
The
experiment
should
be
so
conducted
as
to
avoid
all
unnecessary
physical
and
mental
suffering
and
injury.

EPA
ANALYSIS
The
final
rule
at
40
C.
F.
R.
§
26.1111(
a)(
1)
provides
that
an
IRB
shall
not
approve
proposed
research
unless
"
risks
to
subjects
are
minimized."
Both
EPA
and
the
HSRB
will
determine
whether
they
concur
with
the
determination
of
the
IRB
that
risks
to
potential
subjects
of
research
are
minimized.
Thus,
the
final
rule
is
consistent
with
principle
4
of
the
Nuremberg
Code.

5.
No
experiment
should
be
conducted
where
there
is
an
a
priori
reason
to
believe
that
death
or
disabling
injury
will
occur;
except,
perhaps,
in
those
experiments
where
the
experimental
physicians
also
serve
as
subjects.

EPA
ANALYSIS
While
neither
the
Common
Rule
nor
the
final
rule
have
a
provision
corresponding
exactly
to
this
prohibition
of
research
that
is
likely
to
lead
to
death
or
disabling
injury
(
for
good
reason
­
it
going
without
saying
that,
in
the
late
20th
century,
there
was
no
need
to
incorporate
such
a
provision
explicitly
in
ethical
standards
applicable
to
research
in
the
United
States),
such
a
prohibition
is
implicit
in
two
of
the
provisions
of
the
final
rule.
These
provisions
state
that
an
IRB
shall
not
approve
proposed
research
unless
"
risks
to
subjects
are
minimized"
and
"
risks
to
subjects
are
reasonable
in
relation
to
anticipated
benefits."
See
40
C.
F.
R.
§
§
26.1111(
a)(
1)
and
26.1111(
a)(
2).
EPA
cannot
conceive
of
any
societal
benefit
that
could
justify
undertaking
research
for
pesticides
when
there
was
an
a
priori
reason
to
believe
death
or
disability
would
result.
EPA
would
not
approve
research
involving
such
risks
under
any
circumstances.
Thus,
the
final
rule
is
consistent
with
principle
5
of
the
Nuremberg
Code.

6.
The
degree
of
risk
to
be
taken
should
never
exceed
that
determined
by
the
humanitarian
importance
of
the
problem
to
be
solved
by
the
experiment.

EPA
ANALYSIS
The
final
rule
at
40
C.
F.
R.
§
26.1111(
a)(
2)
provides
that
an
IRB
shall
not
approve
proposed
research
unless
"
Risks
to
subjects
are
reasonable
in
relation
to
anticipated
benefits."
As
the
NAS
report
makes
clear,
the
benefits
to
be
considered
by
an
IRB
(
and
also
by
EPA
and
the
HSRB
during
protocol
review)
include
results
that
benefit
society,
as
well
as
benefits
to
individual
research
subjects.
See
generally,
NAS
report,
chapter
4.
EPA
considers
the
phrase
"
the
humanitarian
importance
of
the
problem
to
be
solved
by
the
experiment"
in
Nuremberg
principle
6
7
to
be
equivalent
to
the
phrase
"
for
the
good
of
society"
in
Nuremberg
principle
2,
and
regards
the
final
rule
requirement
to
consider
"
anticipated
benefits,
if
any,
to
subjects,
and
the
importance
of
the
knowledge
that
may
reasonably
be
expected
to
result"
as
capturing
the
intent
of
both
phrases.

7.
Proper
preparations
should
be
made
and
adequate
facilities
provided
to
protect
the
experimental
subject
against
even
remote
possibilities
of
injury,
disability
or
death.

EPA
ANALYSIS
This
principle
is
reflected
in
both
the
requirements
of
40
C.
F.
R.
§
26.1111(
a)(
2),
quoted
above,
and
40
C.
F.
R.
§
26.1111(
a)(
6),
which
provides
that
an
IRB
shall
not
approve
proposed
research
unless
it
includes
"
adequate
provision
for
monitoring
the
data
collected
to
ensure
the
safety
of
subjects."
Thus,
the
IRB
(
and
both
EPA
and
the
HSRB,
when
they
review
proposals
for
research
with
human
subjects)
will
not
approve
the
proposed
research
design
unless
it
would
ensure
appropriate
medical
oversight
of
the
research,
include
"
stopping
rules"
to
ensure
the
safety
of
subjects,
and
collect
information
needed
for
an
investigator
to
determine
that
research
subjects
were
experiencing
unanticipated
adverse
effects
that
might
indicate
potential
for
more
serious
harm.
Thus,
the
final
rule
is
consistent
with
principle
7
of
the
Nuremberg
Code.

8.
The
experiment
should
be
conducted
only
by
scientifically
qualified
persons.
The
highest
degree
of
skill
and
care
should
be
required
through
all
stages
of
the
experiment
of
those
who
conduct
or
engage
in
the
experiment.

EPA
ANALYSIS
The
discussion
above
concerning
principle
7
also
applies
to
principle
8.
During
the
course
of
review
of
proposals
for
research
with
human
subjects,
established
by
40
C.
F.
R.
§
26.1125
and
26.1601(
d),
EPA
and
the
HSRB
will
evaluate
the
qualifications
of
the
researchers
who
will
conduct
the
proposed
research
to
ensure
that
they
are
competent
to
carry
out
the
study
in
a
manner
that
will
adequately
protect
the
research
subjects.
Thus,
the
final
rule
is
consistent
with
principle
8
of
the
Nuremberg
Code.

9.
During
the
course
of
the
experiment
the
human
subject
should
be
at
liberty
to
bring
the
experiment
to
an
end
if
he
has
reached
the
physical
or
mental
state
where
continuation
of
the
experiment
seems
to
him
to
be
impossible.

EPA
ANALYSIS
The
final
rule
at
40
C.
F.
R.
§
26.1116(
a)(
8)
requires
that
the
informed
consent
materials
provided
to
research
subjects
contain
"
a
statement
that
participation
is
voluntary,
refusal
to
participate
will
involve
no
penalty,
or
loss
of
benefits
to
which
the
subject
is
otherwise
entitled,
8
and
the
subject
may
discontinue
participation
at
any
time
.
.
.
."
Thus,
the
final
rule
is
consistent
with
principle
9
of
the
Nuremberg
Code.

10.
During
the
course
of
the
experiment
the
scientist
in
charge
must
be
prepared
to
terminate
the
experiment
at
any
stage,
if
he
has
probable
cause
to
believe,
in
the
exercise
of
the
good
faith,
superior
skill
and
careful
judgment
required
of
him,
that
a
continuation
of
the
experiment
is
likely
to
result
in
injury,
disability,
or
death
to
the
experimental
subject.

EPA
ANALYSIS
The
discussion
above
concerning
principle
7
also
applies
to
principle
10.
During
the
course
of
review
of
proposals
for
research
with
human
subjects,
established
by
40
C.
F.
R.
§
26.1125
and
26.1601(
d),
EPA
and
the
HSRB
will
evaluate
the
adequacy
of
proposed
"
stopping
rules"
that
would
govern
when
to
terminate
the
research
because
of
risks
to
research
subjects.
EPA
would
not
approve
any
research
unless
it
contained
safeguards
sufficient
to
ensure
that
the
experiment
did
not
cause
injury,
disability
or
death.

The
2004
NAS
Report
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes
What
are
the
underlying
principles
of
the
2004
NAS
report
of
the
NAS
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes?

Based
on
a
careful
review
of
the
NAS
report,
EPA
concludes
that
the
underlying
principles
intended
by
the
NAS
committee
to
be
reflected
in
its
recommendations
are
the
three
"
fundamental
ethical
principles"
identified
by
the
National
Commission
for
the
Protection
of
Human
Subjects
of
Biomedical
and
Behavioral
Research
(
National
Commission)
in
its
report,
Ethical
Principles
and
Guidelines
for
the
Protection
of
Human
Subjects
of
Research
(
the
"
Belmont
Report").
The
three
fundamental
principles
identified
by
the
National
Commission
are:
respect
for
persons,
beneficence,
and
justice.
See
NAS
Report
at
49­
50,
98,
and
113­
14.
The
final
rule
is,
in
its
entirety,
wholly
consistent
with
these
principles
of
the
NAS
Report.

The
NAS
committee
makes
the
point
repeatedly
that
"
the
committee
was
not
required
to
invent
the
basic
standards
that
govern
human
research
in
the
United
States.
These
standards
are
already
embodied
in
the
Federal
Policy
for
the
Protection
of
Human
Subjects
(
the
Common
Rule.)"
NAS
Report
pp.
4,
33.

The
NAS
committee
stated
plainly
and
repeatedly
that
the
fundamental
principles
articulated
in
the
Belmont
Report
both
undergird
and
are
made
operational
by
the
procedural
requirements
of
the
Common
Rule.
The
following
quotations
express
this
view:
9
"
Federal
regulations
incorporate
the
obligation
of
beneficence
by
requiring
IRBs
to
ensure
that
risks
are
minimized
to
the
extent
possible,
given
the
research
question,
and
are
reasonable
in
relation
to
potential
benefits
to
the
participant
or
to
the
importance
of
the
knowledge
to
be
gained
through
the
research
(
40
C.
F.
R.
26.111(
a)(
1)­(
2))."
NAS
Report
at
56.

"[
D]
etermining
whether
the
principle
of
beneficence
has
been
satisfied
requires
balancing
the
anticipated
risks
to
study
participants
against
the
anticipated
benefits
of
the
study
to
society.
The
risks
to
participants
must
be
reasonable
in
relation
to
the
societal
benefit.
In
the
words
of
the
Common
Rule,
the
risks
must
be
reasonable
in
relation
to
the
importance
of
the
knowledge
that
may
reasonably
be
expected
to
result
(
40
C.
F.
R.
26.111
(
a)
(
2))."
NAS
Report
at
107.

"
According
to
the
Common
Rule,
IRBs
should
not
approve
a
research
protocol
involving
humans
unless
`
selection
of
subjects
is
equitable'
(
40
C.
F.
R.
26.111[
a](
3)).
This
requirement
derives
from
the
principle
of
justice
identified
in
the
Belmont
Report."
NAS
Report
at
114.

"
Voluntary,
informed
consent
by
research
participants
.
.
.
is
a
major
element
in
the
system
of
protection
of
research
participants.
The
consent
requirement
expresses
the
principle
of
respect
for
persons,
including
respect
for
and
promotion
of
autonomous
choices.
The
Common
Rule
stresses
this
requirement,
as
do
other
codes
of
research
ethics,
including
the
Nuremberg
Code
(
1949),
the
Declaration
of
Helsinki,
and
the
GCP
guidelines."
NAS
Report
at
120.

These
provisions
of
the
Common
Rule
have
been
incorporated
into
EPA's
final
rule:
40
C.
F.
R.
26.111(
a)(
1)­(
2))
is
incorporated
at
40
C.
F.
R.
§
26.1111(
a)(
1)­(
2);
40
C.
F.
R.
26.111(
a)(
3)
is
incorporated
at
40
C.
F.
R.
§
26.1111(
a)(
3);
and
the
importance
of
the
concept
of
freely
voluntary,
fully
informed
consent
is
incorporated
into
the
final
rule
at,
inter
alia,
40
C.
F.
R.
§
26.1116.
Thus,
as
do
the
Common
Rule,
the
Nuremberg
Code,
the
Declaration
of
Helsinki,
the
Belmont
Report,
and
Section
12(
a)(
2)(
P)
of
FIFRA,
the
final
rule
stresses
the
requirement
of
fully
informed,
freely
voluntary
consent.

Accordingly,
EPA
concludes
that
the
"
principles
proposed
in
the
2004
report
of
the
National
Academy
of
Sciences
on
intentional
human
dosing"
are,
in
fact,
the
"
three
fundamental
principles"
of
respect
for
persons,
beneficence,
and
justice
articulated
in
the
Belmont
Report,
and
that
the
final
rule
is
entirely
consistent
with
those
principles.