Massach
usetts
Massachu
setts Ins
Institute of Technolo
Technology
Harva
Harvarrd Me
Medical
dical School
hool
Brig
ham
m an
Brigha
and Women
men’s Ho
Hospital
VA Bo
thca
are Sy
Boston Heal
Healthc
System
2.782J/
J
82J/3.961J
.961J//BEH.451
BEH.451J/HST524
HST524J
SUMMARY OF FEDERAL REGULATORY ISSUES
AND CLINICAL TRIALS
M. Spect
Spector, Ph.D.
FDA
• Name of device
• Descriptio
Description of device
– Indica
d use
Indication and intende
intended
– Performanc
Performance claims
claims
• FDA classi
fica
ation
classific
tion
• Precli
onal
al and biol
ogiical test
Preclinical test
testing: functi
function
biolog
testing
– Tests
– Which
ents
ts of the
Which compon
componen
the de
device to be evalua
evaluated by each test
test method
method
– Form of the
onen
entt to be
the comp
compon
be tested
• IDE prot
protocol
ocol
–
–
–
Inclus
lled in the
clusion criter
criteria for patients
tients to be enro
enrolled
the st
study
Controls?
Number of patients; statistics-pow
statistics-poweer ca
calculation
lculation
(http://calculat
ors.stat.ucla..edu
(http://calculators.stat.ucla
edu/)
– Outcome varia
bles
variab
– Informed cons
consent
ent form
• Benefit/ris
k ratio
Benefit/risk
Page 1
Biocompatibility
Flow Chart for the
Section of Toxicity
Tests for 510(k)s
Source: U.S. FDA
Page 2
Source: U.S. FDA
Page 3
Source: U.S. FDA
Page 4
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2001
This guidance represents the Food and Drug Administration's
(FDA's) current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statutes and
regulations.
Source: U.S. FDA
Page 5
FDA CLINICAL TRIAL GUIDANCE
Purpose of Control Group
Control groups have one major purpose: to allow
discrimination of patient outcomes (for example, changes
in symptoms, signs, or other morbidity) caused by the
test treatment
treatment from outcomes caused by other factor
factors,
such as the natural prog
progression of the disease, observer
or patient expectations, or other treatment. The control
control
group experience tells us what
what wo
would have happened
happened to
patients if they had not received
received the
the test treatment
treatment or if
they had received a different
different treatment known to be
effective.
effective.
FDA CLINICAL TRIAL GUIDANCE
• Purpose of Control Group
– Randomization
Randomization
– Blinding
• Types of Control
– Placebo Concurrent Control
– NoNo-treatment Concurrent Control
– DoseDose-response Concurrent
Concurrent Control
– Active (Positive)
(Positive) Concurrent Control
– External Control (Including
(Including Historical Control)
– Multiple
Multiple Control Groups
Groups
Page 6
FDA CLINICAL TRIAL GUIDANCE
Purposes of Clinical Trials and Related
Issues
• Evidence of Efficacy
• Comparative Efficacy and Safety
• Fairness of Comparisons
– Dose
– Patient Population
– Selection and Timing of Endpoints
FDA CLINICAL TRIAL GUIDANCE
Guidance for Industry
E6 Good Clinical Practice:Consolidated Guidance
Guidance
• Good clinical
al et
clinical practice
practice (G
(GCP) is an internation
internationa
ethical
hical and
and
scientific quality standard for designing, conducting, recording,
recording,
and reporting trials that
that involve the participation
participation of human
subjects.
• Compliance with this standard provides public assurance that
the rights, safety, and we
wellbeing of trial subjects are protected,
protected,
consistent wi
with the principles that have their origin
origin in the
the
Declaration of Helsinki, and that the clinical
clinical trial
ial data are
are
credible.
credible.
• The objective of this ICH GCP guidance
guidance is to provide a unified
standard for the European Union (E
(EU), Japan, and the United
States to facilita
te the mutual acceptance of clinical data by the
facilitate
the
regulatory authorities in these jurisdictions.
Page 7
POWER CALCULATION
SAMPLE SIZE DETERMINATION
Type
Type I Err
Error (False Positive)
Positive)
• Alpha (α
(α) is the probability
probability that
that the test will lead
lead to the rejec
rejection
tion of the
the hy
hypothesi
esis
tested when that
that hypothesis
hypothesis is true.
– Hypothesis
Hypothesis:: The medical
dical devi
device results
results in an im
improved outcom
outcome. α=0.05 me
means that there
there
is only a 5%
5% probability
probability that this is wrong; i.e.,
i.e., low
low chance of a false
lse positive.
– There could be di
es if
dire consequenc
consequences
if we are wrong because the ne
new device would be used
use
even though it is no bett
re, we
better than the
the control.
control. Therefo
Therefore,
we have
have to be confident
confident that
that we are
right (i.e
i.e., a 95%
95% probability
probability that the new
new device is better than the contro
controll).
Type
Type II Err
Error (False Negative
Negative))
• Beta (β
(β) is the pr
probability
obability that th
the test will
will rejec
reject the hy
hypothesis
pothesis tes
tested when a
specific altern
ative hy
alternative
hypothesis is true; 1-β
1-β is the “power.”
wer.”
– Hypothesis
Hypothesis:: The medical
dical devi
device results
results in no im
improvem
ovement in outcom
outcomee. β=0.2
=0.2 means th
that
there is a 20%
20% probability
probability that the new
new device is show
shown by th
the study
study to be the
the sam
same as the
control,
e.
control, when it is actually
actually bet
better;
er; i.e
i.e., a 20%
20% chance of a false negativ
negative.
– Not as much a proble
m if we are wrong, because the
problem
the new
new device wo
would just
just not
not be used.
used
Therefore
Therefore we
we can accept
accept only an 80%
80% probabili
probability (i.
(i.ee., power)
power) that
that there
there is no dif
difference
rence
between
een
the
de
e
vice
e
and
control.
rol.
betw
d vic
cont
• In meeting
ility
y (95%)
meeting the
the criterion
criterion of α≤ 0.05 it is sho
shown that
that there
there is a hi
high probab
obabilit
(95%)
that
that the
the ne
new de
device is better
tter than
than the
the cont
control.
rol. The
The st
study shoul
ould have a sufficient
number of pa
ts in each grou
gh)) su
patien
tients
group (i.e.,
i.e., a su
sufficien
fficientt po
power; 80%
80% is enou
enough
such that
that
if ther
theree were
were no differe
fference it woul
would have been
been detected.
tected.
Page 8