1. Clinical and Surrogate Endpoints for Evaluating Efficacy of Alpha 1 - Proteinase Inhibitor (Human) Augmentation Therapy Topic II - Introduction Blood Products Advisory Committee 95 th Meeting 20 July 2009 Ross Pierce, M.D. Clinical Review Branch, HFM-392 Div. of Hematology/OBRR/CBER/FDA

2. Rationale for Discussing Alpha 1 -Proteinase Inhibitor (Human) (A 1 -PI) Clinical Trial Endpoints Data accumulated since the original approval of the first A 1 -PI product in 1987 leads us to reconsider whether there is an adequate basis to continue to use the historical serum trough target level to assess efficacy of augmentation therapy in emphysema due to AAT deficiency. Epidemiology data question whether the postulated historical target of 11 microM is an optimal protective threshold. Severely AAT deficient patients have abnormally high lung neutrophils and neutrophil elastase concentrations.

3. Questions for BPAC 1.CBER has identified serial high resolution computerized tomography (HRCT) lung density measurements as an appropriate clinically meaningful endpoint to assess the efficacy of augmentation therapy with IV A 1 -PI products on emphysema disease progression. Does the committee agree that the rate of change of lung density as measured by serial HRCT could potentially be used as a primary endpoint in pivotal studies of efficacy of A 1 -PI augmentation for inhalation therapy?

4. Questions (cont.) 1(a) Before embarking on pivotal studies, should sponsors first establish to what extent CT density measurements are confounded by (1) inhalation therapy and (2) exacerbations?

5. Questions (cont.) 1(b) Does the committee recommend any additional information regarding HRCT lung density measurements be obtained prior to sponsors initiating pivotal studies of efficacy of A 1 -PI augmentation for inhalation therapy?

6. Questions (cont.) 2. Does the committee recommend that FDA reconsider the use of biochemical surrogate endpoints of serum and ELF antigenic and functional A 1 -PI levels to provide substantial evidence of efficacy pre-licensure of new I.V. therapy products, in favor of more clinically meaningful endpoints, i.e., HRCT lung density, FEV 1, pulmonary exacerbations, or mortality?

7. Questions (cont.) 3. Does the committee recommend any other alternatives as primary endpoints for A 1 -PI product pre-marketing clinical trials a) for inhalation therapy? b) for new submissions of I.V. therapy?

8. Questions (cont.) 4. Does the committee recommend studies of I.V. A 1 -PI augmentation therapy include higher doses than previously approved (assuming adequate safety)?

9. Regulatory Background 1985: FDA-NHLBI workshop participants recommended the use of biochemical surrogate endpoints, serum and lung (epithelial lining fluid, ELF) A 1 -PI levels, to evaluate the efficacy of A 1 -PI augmentation therapy products.

10. 1987: Prolastin, the first product in this class, was licensed using biochemical surrogate endpoints, including the theoretical “protective threshold” serum A 1 -PI level proposed by Gaduk and Crystal, as well as ELF A 1 -PI levels.

11. 1998: The majority of BPAC members voted to recommend that the FDA continue to accept the biochemical surrogate endpoints of serum and ELF concentrations of antigenic and functional A 1 -PI to provide substantial evidence of efficacy to support product licensure of new A 1 -PI intravenous products. (11 votes yes, 3 no, 1 abstention).

12. 1999: Alpha One Foundation workshop Opinion: Licensure of aerosol A 1 -PI would require clinical trials evaluating clinically meaningful endpoints rather than biochemical surrogates, because the latter were deemed inadequate for aerosol products.

13. 2001: Alpha One Foundation Workshop on Lung CT recommended the density corresponding to the 15th percentile of lung voxels (three dimensional pixels) as the primary endpoint for HRCT clinical trials evaluating products for emphysema.

14. 2005: BPAC Evaluation of biochemical heterogeneity among licensed A 1 -PI products. Designs of phase 4 randomized studies of newer A 1 -PI products using clinically meaningful endpoints (HRCT, FEV 1, pulmonary exacerbations, and/or mortality) discussed. BPAC members supported FDA’s plan for PMC studies of clinically meaningful endpoints for licensed A 1 -PI products.

15. 2008: A workshop on Lung CT sponsored by Alpha One Foundation discussed use of HRCT as a possible study endpoint, study methods, and future applications.

16. 2009: An FDA Workshop co-sponsored with the Alpha One Foundation and HHS was held to discuss “Improving Endpoints, Improving Care: Alpha 1 - Proteinase Inhibitor (A 1 -PI) Augmentation Therapy and Clinical Trials.”

17. 3/09 FDA-AOF-HHS Workshop (cont.) Workshop participants agreed that HRCT lung density was a sensitive and clinically meaningful endpoint to evaluate the efficacy of therapeutic products for emphysema due to severe AAT deficiency. Information regarding a number of older and newer surrogate biochemical endpoints was presented. These biochemical endpoints need further evaluation and may be used to help with dose selection of new products.

18. Topics Considered at 3/09 FDA-AOF-HHS Workshop Whom to Enroll in Clinical Trials? Clinical Trial Endpoints Experience Current and Potential Endpoints for Clinical Trials: Functional Endpoints Radiological Endpoints Biochemical Endpoints

19. Selected Questions Considered at 3/09 FDA-AOF-HHS Workshop How should disease severity and rate of progression impact patient subset selection for enrollment [in augmentation therapy trials]? What have been the major challenges to development of endpoints for clinical trials of A 1 PI augmentation therapy, and how might these be ameliorated? How strong is the need for dose-ranging studies in evaluating A 1 PI augmentation therapies?

20. Selected Questions Considered at 3/09 FDA-AOF-HHS Workshop (cont.) What are thought to be the most useful currently available functional predictors of clinical efficacy in A 1 PI deficiency? What are the disadvantages and advantages of these measurements? What has been learned from ongoing and recently completed studies that is useful for future HRCT endpoint trials?