1
EPA
Human
Studies
Review
Board
Chair's
Comments
June
27,
2006
Celia
B.
Fisher,
Ph.
D.

Fordham
University
Chair
HSRB
2
Responsibilities
°
The
Human
Studies
Review
Board
shall
comment
on
the
scientific
and
ethical
aspects
of
research
proposals
and
reports
of
completed
research
with
human
subjects
submitted
by
EPA
for
its
review
and,
on
request,
advise
EPA
on
ways
to
strengthen
its
programs
for
protection
of
human
subjects
of
research.
26.1603
(
b)
3
Charter
3.
Objectives
and
Scope
of
Activities
°
HSRB
will
provide
advice,
information
and
recommendations
on
issues
related
to
scientific
and
ethical
aspects
of
human
subjects
research.

°
The
major
objectives
are
to
provide
advice
and
recommendations
on:

 
Research
Proposals
and
Protocols
 
Reports
of
completed
research
with
human
subjects;
and
 
How
to
strengthen
EPA's
programs
for
protection
of
human
subjects
of
research.
4
Board
Process
Board
members
assigned
as
primary
and
secondary
discussants
will
begin
each
board
discussion
1.
Answer
questions
posed
by
EPA
2.
If
applicable
raise
significant
issues
that
were
not
posed
by
EPA
5
Board
Process
Science
Evaluation
followed
by
Ethics
Evaluation
Rationale:

°
To
be
of
benefit
a
study
must
be
scientifically
valid
(
Nuremberg
Code)

°
Risk­
benefit
ratio
can
only
be
calculated
if
there
is
benefit
6
Scientific
Aspects
of
Research
°
Did
the
research
design
and
implementation
meet
scientific
standards?

°
Do
the
data
generated
by
the
protocol
have
implications
for
the
Agency's
Weight
of
the
Evidence
(
WOE)
determination
and
when
applicable
aspects
of
the
risk
assessment.
7
Scientific
Standards
for
Human
Dosing
Studies
8
Justification

Is
scientific
question
worthwhile?


Are
human
subjects
necessary
to
answer
the
question?


Is
potential
risk
serious
or
irreversible?
9
Dose
Selection

Sufficient
to
test
the
question?
(
single
dose
in
most
cases
is
not
sufficient)


Based
on
appropriate
data
(
e.
g.
preclinical;

previous
studies)
10
Endpoint
Selection

Consistent
with
aim
of
the
study?


Appropriate
to
answer
question
about
human
responses
(
e.
g.,
sensitivity,
accuracy,
validity,

replicability)?


Measured
accurately
and
reliably
with
good
quality
assurance?
11
Participants

Characteristics
generalizable
to
question
asked?


Appropriate
inclusion/
exclusion
criteria?
12
Method

Is
sample
size
sufficient?


Is
selection
of
control
and
experimental
groups
appropriate?


Is
the
staging
of
dose
intervals,
dose
amounts,

and
type
of
exposure
sufficient
to
answer
the
question?


Is
there
quality
assurance
for
observations,

instruments
and
data?
13
Statistical
Analyses

Can
data
be
statistically
analyzed?


Is
the
statistical
method
appropriate
to
answer
the
question?
14
SINGLE
DOSE
LEVEL
STUDIES
15
Single
Dose
Level
Study
Definition
°
Individual
study
that
uses
one
dose
level
irrespective
of
the
number
of
subjects,
frequency
of
dosing
or
inclusion
of
a
control
or
placebo.
16
I.
In
general
single
dose
level
studies
have
limited
utility
°
Such
studies
cannot
be
used
in
isolation
to
establish
a
NOAEL
or
LOAEL
°
In
rare
instances
they
may
have
utility
if
interpreted
within
the
context
of
one
or
more
supplementary
studies
that
provide
information
at
other
dose
levels
under
analogous
conditions.
17
II.
Single
dose
level
studies
may
be
able
to
answer
a
very
focused
question
°
However
in
such
instances
its
utility
will
depend
upon
the
robustness
of
study
design,

the
rationale
for
the
study
and
whether
the
study
design
was
consistent
with
the
rationale.

°
Evaluation
of
robustness
will
include
questions
of:
Control,
relevant
endpoints,
evidence
that
measures
can
identify
an
adverse
effect
or
detect
a
change,
use
of
a
surrogate
marker
that
is
quantifiable
and
recognized
as
an
established
function
of
the
compound
and
other
criteria
for
scientific
validity.
18
III.
A
single
dose
level
study
may
have
utility
if
it
provides
evidence
of
adverse
effects
observed
at
lower
levels
than
other
studies
have
indicated.
19
Ethics
Evaluation
1.
Did
the
study
fail
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted?

Examples
°
FIFRA
Section
12(
a)
2(
P)

°
Declaration
of
Helsinki
or
other
International
Code
of
Conduct
for
Research
or
other
well­
established
International
Ethics
Code
°
1991
Common
Rule
40CFR26
(
after
1991
International
Codes
must
be
at
least
equivalent
to
Common
Rule
standards)
20
If
the
study
did
If
the
study
did
not
not
fully
meet
ethical
fully
meet
ethical
standards
prevalent
at
the
time:

standards
prevalent
at
the
time:
21
2.
Was
the
conduct
of
the
study
Fundamentally
Unethical?

There
is
clear
and
convincing
evidence
that
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent
(
Final
Rule
26.104)
22
3.
Was
the
conduct
of
the
study
Significantly
Deficient
relative
to
the
ethical
standards
prevailing
at
the
time?

Is
there
is
clear
and
convincing
evidence
that:

a.
The
deficiencies
identified
could
have
resulted
in
serious
harm
(
based
on
knowledge
available
at
the
time
the
study
was
conducted);
or
b.
The
information
provided
to
participants
could
seriously
impair
informed
consent
