Postmarketing Clinical Postmarketing Clinical Studies of AStudies of A11PI ProductsPI Products

L. Ross Pierce, M.D. L. Ross Pierce, M.D.

Medical Officer, Clinical Review Medical Officer, Clinical Review Branch, Div. of Hematology, FDABranch, 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?

Pre-marketing Clinical Studies of Pre-marketing Clinical Studies of Intravenous AIntravenous A11PI ProductsPI 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 Postmarketing StudyProlastin 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 OutcomesNHLBI 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 Several experts have recommended RCTs

to establish efficacy of Ato establish efficacy of A11PI augmentationPI 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 AOne RCT Evaluating French A11PI Effects on PI Effects on

Lung Function and CT Density CompletedLung 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 Postmarketing Studies of Newer Intravenous AIntravenous A11PI ProductsPI 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 Postmarketing Studies of Newer Intravenous AIntravenous A11PI ProductsPI 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 Stage I Postmarketing Studies of Newer IV ANewer IV A11PI ProductsPI 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 Stage 2 Postmarketing Studies of Newer IV ANewer IV A11PI ProductsPI 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 StudiesBaxter 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 StudiesZLB 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 StudiesPostmarketing 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?

Need and Feasibility of RCTs in Need and Feasibility of RCTs in Evaluating AEvaluating A11PI Effects on LungPI 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 StudyNIH (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 Need and Feasibility of RCTs in Evaluating AEvaluating A11PI Effects on LungPI 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 Need and Feasibility of RCTs in Evaluating AEvaluating A11PI Effects on LungPI 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 Need and Feasibility of RCTs in Evaluating AEvaluating A11PI Effects on LungPI 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…”