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Vaccines, Blood & Biologics

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September 22, 2005 (Corrected Approval Letter)

September 22, 2005

Our STN: BL 125039 / 69

Baxter Healthcare Corporation
Attention: Mr. Jesse K. Seidman, M.S.
Sr. Manager, Global Regulatory Affairs
One Baxter Way
Westlake Village, California 91362

Dear Mr. Seidman:

This letter corrects our approval letter of September 9, 2005, regarding your submission to supplement your Biologics License Application dated August 26, 2004, for Alpha1-Proteinase Inhibitor (Human) [ARALAST] to allow an approval of --------- Fr.IV1+4 paste as an alternate starting material for the manufacture of ARALAST.

Please note that Page 3, paragraph 1, line 5-6 of the original letter has been corrected to read Baxter Healthcare Corporation.

Your submission to supplement your Biologics License Application dated August 26, 2004, for Alpha1-Proteinase Inhibitor (Human) [ARALAST] to allow an approval of --------- Fr.IV1+4 paste as an alternate starting material for the manufacture of ARALAST, as amended, has been approved.

We note the post-approval commitments by Baxter Healthcare Corporation, described in your amendment dated September 1, 2005, to perform the following:

  • Baxter will submit to the IND for this product a protocol for the amended Coram Healthcare Patient Outcomes study within 30 days of the approval date of this Supplement (/69).

  • A minimum of 60 subjects will be enrolled in the enhanced study and undergo repeated anti-α1-PI antibody testing.

  • A final protocol acceptable to FDA will be submitted to the IND within 30 days of the date that FDA sends comments on the initial protocol.

  • The study will be initiated within 60 days of submission of the final protocol.

  • Baxter will inform FDA in writing within 30 days of when enrollment in the amended study is complete.

  • Baxter will submit a final study report within 6 months of completion of the study by the last participating subject.

The PMC letter also summarized the other outstanding clinical PMC studies which you have committed to conduct:

  1. You have agreed to conduct a phase IV clinical study to further verify treatment-emergent changes in levels of α1-PI, anti-neutrophil elastase capacity, neutrophil elastase (NE), α1-PI:NE complexes, neutrophils, and related pertinent analytes in epithelial lining fluid.

  2. You have agreed to conduct a clinical investigation, which shall be comprised of two stages as described below. The conduct of the second stage will be contingent on the outcome and results of the first stage.

    Stage 1

    You have agreed to conduct and report to us the results of a pilot trial to determine the effect of regular administration of the product on one or more clinically meaningful endpoint(s). Examples of acceptable endpoints include pulmonary exacerbations, serial pulmonary functions, and serial quantitative computerized axial tomographic (CT) lung scans.

    Details include:

    • A randomized, controlled, parallel, masked design.

    • A minimum enrollment of 60 subjects (30 subjects per treatment group) in the pilot study.

    • The control group may be a different dose of the test product (i.e., higher, such as 120 mg/kg/week or 240 mg/kg/2 weeks) in comparison to the labeled dosing regimen of the test product or placebo.

    • The trial will be a minimum of one-year's duration to avoid seasonal bias in pulmonary exacerbations.

    • The trial design will include measurement of baseline and steady state antigenic and functional alpha1-proteinase inhibitor blood levels.

    • The trial may include a post-trial follow-up assessment.

    • A final protocol should be filed to the IND and BLA within 6-12 months of the date of this letter.

    • The trial should be initiated within 6-12 months after protocol acceptance by the FDA.

    • Alternate study designs and features may be discussed with the Agency following feedback from experts.

    • The final study report should be submitted in a timely fashion to the IND and BLA.

    Stage 2

    Contingent on the outcome of the pilot trial described above, you have agreed to conduct and report to us the results of an adequately-powered study of clinically meaningful endpoints(s).

    • Based on the results of the aforementioned pilot study and the available scientific data at the time that this study is being designed, you have agreed to work with entities maintaining registries of alpha1-proteinase inhibitor deficient patients and with the National Institutes of Health (NIH) to design and conduct an adequately-powered study of a clinically meaningful endpoint(s). The study design could involve a single product or could potentially involve a cooperative simultaneous study of multiple products in parallel arms, using a factorial design. In the event that the study involves more than one product, Baxter Healthcare Corporation commits to provide sufficient product to administer to an equal proportion of subjects as are being provided any of the other products. The design/conduct of the study may be contingent upon:

      • The amount of product available.

      • The number of available subjects.

      • The number of subject-years necessary to attain an adequately powered study based on the results of the previous study and current scientific data.

      • The participation of other manufacturer(s) of this product class.
    • The results of the pilot study will be taken into account in the design of the follow-up study. A strong positive outcome in the pilot study may obviate the need for a follow-up study.

    • The trial may include one or more post-trial follow-up assessment(s).

    • The final protocol for this study should be filed to the IND and BLA within one year of the filing of the final report of the pilot study.

    • The final study report should be submitted in a timely fashion to the IND and BLA.

    We understand that the clinical investigations listed under A and B above will be conducted using the version of the product to be manufactured in your ------ facility using your Fraction IV1 paste. For each clinical PMC study please submit:

    1. The actual or anticipated original submission date of the study protocol to FDA;

    2. The actual or anticipated original date of completion of patient accrual into the study;

    3. The actual or anticipated original date of completion of the study; and

    4. The actual or anticipated original date of submission of the final study report to FDA.

In addition, please respond to the following comments made by the clinical reviewer by including responses in the IND submission of the amended Coram Healthcare Patient Outcomes study:

  1. Your proposal to amend the Coram Healthcare Patient Outcomes Study as described in your amendment submitted August 02, 2005 appears to be generally acceptable provided that a minimum of 60 subjects are enrolled in the enhanced study and undergo repeated anti-α1-PI antibody testing. If this enrollment target is not reached by May 2006, the enrollment period should be extended. CBER reserves the right to comment further once the full protocol is submitted to the IND.

  2. Regarding your submitted interim report for the above study, please clarify whether the baseline data ("All Cause 6 Months Prior to Initial Assessment") were collected prospectively or retrospectively. Any comparisons of retrospectively-collected baseline to prospectively-collected on-study data would probably not be valid due to differences in the data collection methodologies. Please comment.

  3. Regarding the subject from the above study who reported blurry vision 5 minutes post infusion of Aralast, please provide all available clinical details.

This information has been placed in your product license file. It is recommended that a copy of this letter be available for review at the time of FDA inspections.

Sincerely yours,

--- signature ---

Basil Golding, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research