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May 4, 2007 Approval Letter - Aralast NP

May 4, 2007

Our STN: BL 125039/263

Baxter Healthcare Corporation
Attention: Ms. Tracy Dianis
One Baxter Way
Westlake Village , California 91362

Dear Ms. Dianis:

We have approved your request to supplement your biologics license application for Alpha-1-Proteinase Inhibitor (Human) to use ---------------------------------------------------------------------------------, from your ------------------------------------------- locations, for further manufacture into Alpha-1-Proteinase Inhibitor (A1PI), at your -------------------- location.

We acknowledge your written commitments as described in your submission of May 2, 2007, as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

  1. You affirm your commitment made at approval of STN 125039/69, to conduct further clinical investigations. These investigations will be performed using Aralast NP as the study material. As stated in the approval letter to STN 125039/69, you will conduct:

     

    1. 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. 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 FDA 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 six months of the date of this letter.
      • The trial should be initiated within six 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 FDA 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, you commit 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 the 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 the BLA.

    Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125039/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL 125039/0. If the information in the final study report supports a change in the labeling, the final study report should be submitted as a supplement. We may also request a supplement if we think labeling changes are needed. P lease use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

    • Postmarketing Study Protocol
    • Postmarketing Study Final Report
    • Postmarketing Study Correspondence
    • Annual Report on Postmarketing Studies

    For each postmarketing study subject to the reporting requirements of 21 CFR 601.70, you must describe the status in an annual report on postmarketing studies for this product. The status report for each study should include:

    • information to identify and describe the postmarketing commitment,
    • the original schedule for the commitment,
    • the status of the commitment (i.e. pending, ongoing, delayed, terminated, or submitted), and
    • an explanation of the status including, for clinical studies, the patient accrual rate (i.e. number enrolled to date and the total planned enrollment).

    As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our Internet site (http://www.fda.gov/cder/pmc/default.htm). For further information, please refer to the April 2001 Draft Guidance for Industry: Reports on the Status of Postmarketing Studies – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/cber/gdlns/post040401.htm).

    Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.

    ------------------------------------------------------------------------------------------------ ----------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- ----------------------------------

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We have considered your proposed proprietary name for Alpha-1-Proteinase Inhibitor (Human) in consultation with the Center for Biologics Evaluation and Research's Advertising and Promotional Labeling Branch, and conclude that the proposed proprietary name "Aralast NP" is acceptable under 21 CFR Part 201.

Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h. Please provide an MS-WORD and PDF-format electronic copy as well as original paper copies (ten for circulars and five for other labels).

All promotional claims must be consistent with and not contrary to approved labeling. You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence to support that claim.

We will include information contained in the above-referenced supplement in your biologics license application file.

Sincerely yours,

/s/

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