Transcript Document 7927108

An Assessment of IPAC-RS’
Proposal
Walter W. Hauck, Ph.D.
Biostatistics Section
Division of Clinical Pharmacology
Thomas Jefferson University
Philadelphia, PA, USA
How Assessed
• Does the IPAC-RS proposal address
the issues raised regarding the FDA
draft guidance?
• Do the details of the IPAC-RS proposal
support their claims?
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FDA Draft Content Uniformity
Standard (in part)
Tier 1, N=10 containers, one dose per
container
• Accept if :
0 or 1 outside 80%-120% of
labeled claim (LC)
none outside 75%-125% of LC
• If not accepted after Tier 1:
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FDA Draft Content Uniformity
Standard (in part), cont.
• Tier 2, N=20 additional containers (30 total),
one dose per container
• Accept if:
0-3 outside 80%-120% of LC
none outside 75%-125% of LC
• Also requires sample mean within 85%115% of LC at each tier.
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Structure of Criterion
• An inner interval with a count on
maximum allowable number of units
outside the interval (test by attributes)
• An outer interval with a “zero tolerance”
criterion (“safety net”)
• Additional criteria; i.e. limits on the
sample mean
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Issue #1
• Acceptance criteria are of the form of a
statistical hypothesis test, but there are
no hypotheses
• i.e., there is no specification of what
constitutes an acceptable batch, only of
what constitutes an acceptable sample
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What Does IPAC-RS Do?
• Proposal specifies an acceptable batch
as -at least 85% of the batch falls within
75%/125% of labeled claim
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Standard Deviation (% LC)
Means and Standard Deviations
85% Coverage, 75%/125% Target Interval
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Batches
NOT
acceptable
20
16
12
Batches
acceptable
8
4
0
65
75
85
95 105 115 125 135
Mean (% LC)
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Some Clarification
• Consumer risk (false positive decision)
here refers to passing a batch that lies
outside the specifications of an acceptable
batch.
• Producer risk here refers to failing to pass
a batch that is as good or better than the
specifications of an acceptable batch
• Both depend strongly on the specification
of 85% within 75%/125% of labeled claim
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Standard Deviation (% LC)
Means and Standard Deviations
IPAC-RS and Two Alternatives
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20
85% in 75%/125%
16
90% in 75%/125%
12
8
4
0
65
85% in 80%/120%
75
85
95 105 115 125 135
Mean (% LC)
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Comments
• Setting an acceptance criterion such as
85% within 75%/125% of labeled claim
should mean that any batch that
actually falls in the region is acceptable
• Batch failure rate for acceptable
batches is in control of sponsor
• Need to distinguish properties of batch
from properties of sample
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Standard Deviation (% LC)
Means and Standard Deviations
At Least 85% of Batch Within 75%/125%
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Acceptable
batches
20
16
12
Acceptable
samples
(2nd tier,
N=30)
8
4
0
65
75
85
95 105 115 125 135
Mean (% LC)
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Issue #2
• By specifying the sample size, the draft
guidance denies the sponsor the
opportunity to control their own
producer risk
(the probability that a batch that is
acceptable will not pass)
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What Does IPAC-RS Do?
• Proposal provides a choice of two-tier
designs of varying sample sizes, all
intended to control false positive rate at
5%
• Restriction to two tiers is not necessary;
their approach for tolerance intervals
could also apply with alternate choices
of number of tiers (e.g., 1 or 3)
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Comments
• As long as any batch that meets set
criteria is acceptable, then any sample
size acceptable to the sponsor should
be acceptable to the Agency
• Sample size and number of tiers would
need to be prespecified
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Issue #3
• Test by value (parametric tolerance
intervals) makes better use of the data
than test by attributes (current
approach)
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What Does IPAC-RS Do?
• Based on parametric tolerance intervals
• Modified to reduce a statistical
conservatism present with tolerance
intervals
[by adding the upper limit, 25f/k, on the
sample standard deviation, S, and
decreasing k.]
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Issue #4
• The outer acceptance interval, a “zero
tolerance criterion,” becomes a
substantial producer risk as the sample
size increases
• There is a conflict between presence of
a zero tolerance criterion and flexibility
in choice of sample sizes
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What Does IPAC-RS Do?
• The zero tolerance criterion is dropped
• There is a need to be comfortable with
this, but the zero tolerance criterion
does appear to have offered little extra
protection
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Issues, Summary
• Yes, the IPAC-RS proposal does
address issues raised regarding the
criterion in the FDA draft guidance and
of other proposed criteria
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IPAC-RS Claim
• Consumer risk is retained or improved
compared to the FDA draft criterion
while at the same time reducing
producer risk
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S a m p le S t a n d a rd D e v ia t io n
Acceptance Regions, n=24, 2.5% nominal
14
12
10
8
6
4
2
0
70
80
90
Rule 3
100
Sample Mean
Rule 4 (IPAC)
110
120
130
Rule 6 (IPAC)
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IPAC-RS Delivers?
YES. How is this possible?
1 Parametric tolerance intervals will
reduce producer risk relative to
nonparametric approaches for a given
sample size and allowed level of
consumer risk
2 Elimination of zero tolerance criterion
3 Larger sample sizes
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How Possible, cont.
• FDA’s draft proposal is more liberal than
it appears
• IPAC-RS shows FDA draft corresponds
implicitly to at least 78% coverage
(single-dose) or 85% (multi-dose) within
75%/125% of LC
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Summary
• IPAC-RS’ report delivers as claimed
• Statistical approach is an improvement
over any other criterion being
considered
• There is a need to be careful in choice
of constants (k’s and f) to be sure that
consumer risk is properly controlled
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Alpha Levels of Tests, Nominal 2.5%, N=24
0.05
0.04
0.03
Level
Power3
Pow4(IPAC)
Pow6(IPAC)
Ideal
0.02
0.01
0
0.7
0.8
0.9
1
1.1
1.2
1.3
Mean
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Alpha Levels of Tests, Nominal 2.5%, N=24
0.05
0.04
0.03
Level
Pow4(.8)
Pow4(.9)
Pow4(IPAC)
Power3
Ideal
0.02
0.01
0
0.7
0.8
0.9
1
1.1
1.2
1.3
Mean
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Costs to Sponsors
• Increased by larger sample sizes
• Reduced for multi-dose products by
combining through-container-life
criterion into dose uniformity criterion
• Reduced, potentially, for all by giving
control of study design (and hence of
producer risk) to sponsor
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Bottom Line
• 85% within 75%/125% can
now be the focus of
discussion
(as it should be)
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