# Presentation: 706663

## Postmarketing Clinical Studies of A1PI Products

- L. Ross Pierce, M.D.
- Medical Officer, Clinical Review Branch, Div. of Hematology, FDA

## QUESTIONS FOR THE COMMITTEE:
Based on the differences in primary structure of A1PI..., does the Committee have comments/ recommendations re:

Adequacy of requested/planned post-marketing commitment studies to evaluate the longer-term safety & efficacy of A1PI  products, as measured by specified clinically meaningful endpoints?
Adequacy of proposed safety monitoring programs?

- Based on the differences in primary structure of A1PI..., does the Committee have comments/ recommendations re:
- Adequacy of requested/planned post-marketing commitment studies to evaluate the longer-term safety & efficacy of A1PI  products, as measured by specified clinically meaningful endpoints?
- Adequacy of proposed safety monitoring programs?

## Pre-marketing Clinical Studies of Intravenous A1PI Products

- Pivotal trials (14 -  30 subjects) based on the biochemical surrogate endpoints, antigenic A1PI and neutrophil elastase inhibitory capacity:
- Maintenance of trough steady state serum levels greater than arbitrary threshold and not inferior to that of Prolastin
- Levels in bronchopulmonary lavage (BAL) fluid significantly greater than pre-treatment
- 6 month safety data including anti- A1PI antibodies.

## Sponsors of all 3 US-licensed A1PI products to conduct postmarketing studies to help evaluate efficacy in terms of clinically meaningful endpoints directly relating to emphysema.

Prolastin:  Epidemiology study completed
Zemaira:  Placebo-control RCT approved
Aralast:  RCT requested, final protocol pending

- Prolastin:  Epidemiology study completed
- Zemaira:  Placebo-control RCT approved
- Aralast:  RCT requested, final protocol pending

## Prolastin Postmarketing Study	

- Completed “NIH Registry [Epidemiology] Study”
- At the time, a RCT thought unfeasible
- Non-Randomized Design incapable of validating PK surrogate
- No testing of A1PI blood levels
- Large numerical imbalances
- Am. J. Respir Crit Care Med 1998;158:49-59

## NHLBI Registry Study Outcomes

- Decreased mortality among those who received A1-PI (Prolastin, RR 0.64, 95% CI 0.43-0.94 (p = 0.02)
- No difference in rate of FEV1 decline, except in post-hoc moderate subgroup

## Several experts have recommended RCTs to establish efficacy of A1PI augmentation 

- “Definitive conclusion will require a randomized controlled trial.” – NHLBI Registry Study Group                                                    Am. J. Respir Crit Care Med 1998;158:49-59
- The Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000;161:796-801.
- “Urgent need” M. Luisetti. Eur Respir Rev 2002;12:309
- “Augmentation therapy ...costly and inconvenient...” J.K. Stoller. Eur Respir Rev 2002;12:86/87:311-315

## One RCT Evaluating French A1PI Effects on Lung Function and CT Density Completed

- Dirksen et al.  Am J Respir Crit Care Med 1999;160:1468
- N = 56; NS trend A1PI worse than Placebo by FEV1 (p =0.20); A1PI better than Placebo by CT (p 0.07)
- Retrospective power suggests n = 130 needed for CT endpoint RCT

## Postmarketing Studies of Newer Intravenous A1PI Products

- 2-Stage Investigations of 1 or more Clinically meaningful efficacy endpoints:
- Serial Lung Density Changes by CT
- Pulmonary Exacerbations of COPD
- Serial Pulmonary Function Testing
- (Mortality)

## Postmarketing Studies of Newer Intravenous A1PI Products

- Stage I PMC RCT Objective:
- Estimate magnitude treatment effect
- Assist sample size determination for adequately-powered Stage 2 f/u study
- Stage 2 PMC RCT Objective:
- Substantial evidence of efficacy?
- Additional longer-term safety data.

## Stage I Postmarketing Studies of Newer IV A1PI Products

- Randomized, controlled, parallel, masked design.
- Minimum 60 subjects (30 per group)
- Control:
- Dose-controlled (i.e.,  120 mg/kg/week or 240 mg/kg/2 weeks  vs. labeled 60 mg/kg/week) or
- Placebo-controlled.
- Minimum 1-year duration to avoid seasonal bias in pulmonary exacerbations.
- Baseline & steady state antigenic and functional 1PI blood levels.
- +/- longer post-trial follow-up.

## Stage 2 Postmarketing Studies of Newer IV A1PI Products

- Conduct of Adequately Powered Stage 2 Study may be contingent on:
- Outcome of Stage I Study
- Strongly positive outcome in Stage I study may obviate need for Stage 2 study.
- Amount of Product(s) available
- Availability of Subjects
- Number of Subject-Years of f/u needed
- Participation of other A1PI manufacturer(s) (possible factorial design)

## Baxter Postmarketing Studies

- Stage I Efficacy RCT
-  – investigational version A1PI
- Stage II Efficacy RCT
- – investigational version A1PI
- Repeat BAL RCT
- investigational version A1PI
- Uncontrolled Safety Study
- - current version A1PI in 60 subjects x 2 years for anti-A1PI antibodies, hepatic and renal function, AEs, and quality of life measures.

## ZLB Behring Postmarketing Studies

- 2 year, 100 subject Placebo-controlled multinational, parallel group Stage I RCT
- Primary objective:  Effect of Zemaira on progression of emphysema, assessed by decline in lung density, measured by CT (detect trend with P _<_ 0.20)
- Secondary objectives:
- Assess effect of treatment of A1-I on the number and duration of pulmonary exacerbations
- FEV1, DLCO, A1PI levels, exercise capacity, mortality, BMI, safety, QOL, anti- A1PI antibodies

## Postmarketing Studies

- Conclusion
- Definitive efficacy data lacking for A1PI products
- Newer data suggest Efficacy studies now feasible
- Sponsors of all newer intravenous A1PI products are asked to  conduct 2-stage postmarketing investigations of 1 or more clinically meaningful endpoints.
- Longer term (2 year) safety data are being collected for Aralast and Zemaira in 50-60 subjects to include anti- A1PI antibodies.

## QUESTIONS FOR THE COMMITTEE:
Based on the differences in primary structure of A1PI..., does the Committee have comments/ recommendations re:

Adequacy of requested/planned post-marketing commitment studies to evaluate the longer-term safety & efficacy of A1PI  products, as measured by specified clinically meaningful endpoints?
Adequacy of proposed safety monitoring programs?

- Based on the differences in primary structure of A1PI..., does the Committee have comments/ recommendations re:
- Adequacy of requested/planned post-marketing commitment studies to evaluate the longer-term safety & efficacy of A1PI  products, as measured by specified clinically meaningful endpoints?
- Adequacy of proposed safety monitoring programs?

## Need and Feasibility of RCTs in Evaluating A1PI Effects on Lung

- “In the context that i.v. augmentation therapy remains costly and inconvenient but that definitive, supportive data from a randomized, controlled clinical trial remain unavailable, definitive studies to resolve this ongoing controversy are clearly desirable.”
- - J.K. Stoller. Eur Respir Rev 2002;12:86/87:311-315.

## NIH (NHLBI) Registry Study

- “...Finding that recipients of augmentation therapy have better survival...and the rate in decline in FEV1 values of 35 to 49% predicted suggest clinical efficacy..., although these differences may have been due to factors for which we could not control.”
- “A definitive conclusion will require a randomized controlled trial.”

## Need and Feasibility of RCTs in Evaluating A1PI Effects on Lung

- “Unambiguous evidence of [augmentation therapy with A1PI]...efficacy on progression of emphysema is still lacking.”
- “There is urgent need of clinical trials to optimise the medical management of inherited 1-antitrypsin deficiency.”
- -M. Luisetti. Eur Respir Rev 2002;12:309

## Need and Feasibility of RCTs in Evaluating A1PI Effects on Lung

- “Although significant obstacles to conducting a placebo-controlled clinical trial still exist, like others, we recommend a randomized, placebo-controlled clinical trial as the best method to definitively evaluate the efficacy of IV augmentation therapy...”
- The Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000;161:796-801.

## Need and Feasibility of RCTs in Evaluating A1PI Effects on Lung

- The Alpha 1-Antitrypsin Deficiency Registry Study Group:
- “...Our calculation of required sample sizes for a placebo-controlled [RCT]...using estimates derived from the large NHLBI-sponsored Registry suggests that fewer subjects would be needed than were originally projected...”