Presented by Michael Golden (GlaxoSmithKline) 21 October 2003 Meeting of the Advisory Committee for Pharmaceutical Scien

1. Summary and Status of IPAC-RS Proposal for Improved Control of Delivered Dose Uniformity (DDU) of Orally Inhaled and Nasal Drug Products (OINDP) Presented by Michael Golden (GlaxoSmithKline) 21 October 2003 Meeting of the Advisory Committee for Pharmaceutical Science

2. Presented Position Reflects Consensus of All IPAC-RS Companies: • Aradigm • AstraZeneca • Aventis • Boehringer Ingelheim • Eli Lilly • GlaxoSmithKline • IVAX • Kos Pharmaceuticals • Nektar Therapeutics • Novartis • Novo Nordisk • Pfizer • Schering-Plough

3. Presentation Outline • Review • History • Time for Resolution • Recap • DDU Tests • Limiting Quality • Status • Areas of Alignment • Unresolved Issues • Future Plans • Desired Outcomes • Agreement

4. Review

5. Drivers for DDU Initiative • OINDP products currently on the market are of appropriate quality to enhance public health • OINDP cannot routinely meet expectations in draft Guidances, e.g., many products have been approved with exception to DDU tests acceptance criteria in published Guidances • Need a better approach than in the Guidances (not arbitrary one-size-fits-all) • IPAC-RS developed PTI test to provide more suitable control of OINDP that is consistent with the quality of products under development and on the market

6. History of DDU Initiative • History of interaction with FDA • Draft Guidances (1998-99), industry comments • IPAC and Inhalation Technology Focus Group of AAPS collected and analyzed data base (2000), showing that specifications in draft Guidances are not suitable • IPAC-RS formed (2000) • IPAC-RS developed and submitted statistical proposal (2001) • Presentations to Advisory Committee meetings: April 2000, November 2000, July 2001, March 2003 • Multiple meetings with FDA to review details • Additional work and reports to answer questions from FDA

7. Time for Constructive Resolution • IPAC-RS appreciates Agency’s time, attention and feedback to date, but is requesting a renewed vigor on the part of the Agency and a timely, constructive resolution of the dialogue • written unified position of FDA • commitment to find mutually agreeable quality standard in next 6 months • draft guidance on DDU testing for OINDP by end of 2004

8. Recap of the IPAC-RS 2001 Proposal

9. Current FDA DDU Tests • Non-parametric limit tests • counts the number of determinations in a sample within and outside certain pre-fixed limits • includes zero tolerance criterion • Too stringent to encompass all product types • prolonged reviews • high potential for failing good batches

10. PTI Test • Parametric test • simultaneously controls mean and standard deviation • no zero tolerance • Suitable for all OINDP product types

11. What IPAC-RS PTI Test Achieves • Maintains/improves consumer protection • IPAC-RS PTI test provides the same or better guarantee to reject a bad batch compared to current FDA Draft Guidance • Reduces producer risk • Lower risk to reject a good batch

12. Additional Benefits • Product-specific sample size • Different products can have different sample sizes • Same consumer protection for all sample sizes • Simple design • Same test for single and multi-dose products • For multi-dose products, addresses within- and between-container uniformity in one test

13. How PTI Test Achieves Its Goals • More efficient use of information from sample • uses parametric approach • More information per test • on average increases sample size per test compared to Draft Guidance

14. Target Interval Target Interval Emitted Dose Emitted Dose Define Batch Quality With Coverage Coverage = Proportion of doses in the batch that are within target interval Batches having same coverage of given target interval are considered to be of equal quality

15. Limiting Quality • Limiting Quality: Equals quality at which 95% of batches will be rejected (5% accepted) • PTI limiting quality in terms of coverage • 85% coverage of 75 - 125% of label claim (same as implied by FDA Draft Guidance)

16. Assumptions Made to Develop PTI Test • IPAC-RS assumed (and FDA confirmed) that consumer protection of 1998-99 Draft Guidances DDU test is appropriate • For statistical work, the distribution of delivered dose was assumed normal

17. Relationship between Assumption of Normality and Practical Applications • Evaluation of industry data demonstrated that assumption of normality is reasonable • The proposed test was shown to be robust and conservative for a wide range (but not all) non-normal distributions • IPAC-RS statisticians are currently considering options for improving robustness of PTI test to a broader (than in 2001) range of non-normal distributions • As with all tests, the sponsor will have to demonstrate during drug product development that the PTI test is applicable to particular product

18. Status of Industry-Agency Discussions

19. Intention • IPAC-RS recommended a PTI test with a limiting quality of 85% coverage of 75-125% LC for adoption by the FDA as the standard for control of DDU in OINDP • For each application, the suitability of the test and proposed acceptance criteria would be justified by clinical and CMC development data • Based on each product’s indication and data, more stringent or less stringent acceptance criteria may be suitable, as determined by regulators and individual companies

20. Areas of Alignment • Parametric approach is suitable to assess quality of the batch (not sample) • Quality must be built in during development • Tested sample should be representative of the batch • Investigate the possibility of increasing robustness to non-normality

21. Main Unresolved Issues • Agreement on technologically achievable default quality standard • standard for Limiting Quality (“hypothesis testing”) • standard for Acceptable Quality (“confirmatory testing”) • “Gap” - existence of a “gap,” and width of the “gap” • Final agreement that zero tolerance is unnecessary with the parametric approach • Degree of robustness to non-normal distributions

22. Difficulty with Setting Single Acceptable Quality Standard • Broad range of performance for approved products • Acceptable Quality level as implied by test in FDA Draft Guidances is too tight • numerous exceptions to the guidance were necessary for the currently marketed products • FDA questions whether Acceptable Quality implied by PTI test of 2001 is too loose

23. Producer Risk: Risk to reject high quality batches 100 0 90 10 80 20 70 30 60 40 50 50 Consumer Risk: Risk to accept low quality batches Rejection probability Acceptance probability 40 60 30 70 20 80 10 90 0 100 Batch variability increasing standard deviation, decreasing coverage Limiting Quality When batch variability increases, probability to pass decreases Operating Characteristic (OC) Curve

24. Comparison of Operating Characteristic Curves “Gap” LQ FDA test: as in Draft MDI/DPI Guidance • Consumer protection (Limiting Quality, LQ) same • “Gap”: Fewer rejections does not mean lower quality of accepted batches (see simulated production illustration)

25. Examples of Effect of Deviations on Current FDA OC Curve FDA DCU & TCL test as in Draft MDI/DPI Guidance • Many of OINDP products approved by FDA in 1990-2001 have DDU test or acceptance criteria or both that deviate from draft Guidances (IPAC-RS 2001 survey) • The ”gap” between FDA and PTI OC curves decreases with such deviations, and consumer protection is eroded • PTIT provides reduction of producer risk without compromising consumer protection

26. Illustration: What Different DDU Tests Mean Practically • Next two slides contain results of simulated* production • in order to answer the question “which test makes better decisions?” it is customary to use simulations because only in simulations true batch characteristics (mean, standard deviation, type of distribution, coverage, etc. ) are known precisely • need a simulation because no real data available for unacceptable quality • very limited data that was tested to PTI test plan * Used 5000 simulations, normal distributions

27. Unacceptable Quality Batch Mean ~10014, Batch SD ~ 203 Batch SD, s (%LC) Batch SD, s (%LC) Batch SD, s (%LC) Batch SD, s (%LC) 1.2% Accepted by FDA test (median cov= 80.3%) 98.8% Rejected by FDA test (median cov= 76.5%) 0.3% Accepted by PTI test (median cov= 81.2%) 99.7% Rejected by PTI test (median cov= 76.6%)

28. Acceptable Quality Batch Mean ~1009, Batch SD ~103 Batch SD, s (%LC) Batch SD, s (%LC) Batch SD, s (%LC) Batch SD, s (%LC) 65% Accepted by FDA test (median cov= 98.6%) 35% Rejected by FDA test (median cov= 96.5%) 95% Accepted by PTI test (median cov= 98.1%) 5% Rejected by PTI test (median cov= 91.5%)

29. Summary of Simulation Production Illustration • PTI test is more accurate at indicating the correct disposition for the batches • Unacceptable quality product: FDA and PTI tests reject similar numbers of batches • Acceptable quality product: PTI test rejects fewer acceptable batches than FDA test

30. Future Plans

31. Desired Outcome of DDU Effort for IPAC-RS • Agree that PTI test approach is the default standard • Parametric (no Zero Tolerance) • Coverage as quality definition • Allow product-by-product justification of sample size • multiple sampling plans, e.g., 12/36 to 30/90 • Agree on a quality standard that is acceptable for FDA and industry • Have published Guidance reflecting these agreements

32. Plan for Going Forward: To Do by End of 2003 • IPAC-RS and FDA present status update to ACPS (21 October 2003) • Since March 2003 ACPS meeting, little progress on resolving the main issue (“gap”) • IPAC-RS and FDA to co-author a joint paper explaining that ZT is not needed • IPAC-RS currently interprets FDA feedback as indicating that 2001 proposal is not fully acceptable, therefore IPAC-RS companies will consider Agency’s feedback and review options for addressing FDA comments

33. Plan for Going Forward (cont’d) • IPAC-RS would like to continue dialogue with Agency with the goal of agreeing on technologically justified default quality standard • Present outcome at future ACPS meeting • IPAC-RS would like Agency to publish a draft guidance on DDU in OINDP by end of 2004

34. Concluding Message • IPAC-RS has approached the DDU initiative in the spirit of scientific collaboration and partnership • IPAC-RS needs FDA to become unified and constructive in their position with regard to PTI test for DDU in OINDP • IPAC-RS looks forward to an equitable and responsible resolution of this issue by the Agency in 2004

35. Acknowledgements • Kos Pharmaceuticals • Nektar Therapeutics • Novartis • Novo Nordisk • Pfizer • Schering-Plough • FDA / CDER / OPS • IPAC-RS Members • Aradigm • AstraZeneca • Aventis • Boehringer Ingelheim • Eli Lilly • GlaxoSmithKline • IVAX • Members of IPAC-RS DDU Working Group • IPAC-RS Secretariat