# Presentation: 062435

## 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- Does the IPAC-RS proposal address the issues raised regarding the FDA draft guidance?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?

##  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:

## 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.

## 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

## 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***

## What Does IPAC-RS Do?

- Proposal specifies an acceptable batch as --at least 85% of the batch falls within 75%/125% of labeled claim

## Slide 8

## 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

## Slide 10

## 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

## Slide 12

## 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- By specifying the sample size, the draft guidance denies the sponsor the opportunity to control their own producer risk(the probability that a batch that is acceptable will not pass)

## 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)

## 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

## Issue #3

- Test by value (parametric tolerance intervals) makes better use of the data than test by attributes (current approach)

## 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.]

## 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

## 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

## Issues, Summary

- Yes, the IPAC-RS proposal does address issues raised regarding the criterion in the FDA draft guidance and of other proposed criteria

## IPAC-RS Claim

- Consumer risk is retained or improved compared to the FDA draft criterion while ***at the same time*** reducing producer risk

## Slide 22

## IPAC-RS Delivers?

- YES.  How is this possible?
- Parametric tolerance intervals will reduce producer risk relative to nonparametric approaches for a given sample size and allowed level of consumer risk
- Elimination of zero tolerance criterion
***Larger sample sizes***

## 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

## 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

## Slide 26

## Slide 27

## 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

## Bottom Line

**85% within 75%/125% can now be the focus of discussion ****(as it should be)**