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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

Filing Review, November 2, 2008 - Menveo

Novartis Vaccines and Diagnostics, Inc.

Attention:  Chris Webster, Ph. D.
350 Massachusetts Ave
Cambridge, MA, 02139

Dear Dr. Webster:

This letter is in regard to your biologics license application (BLA) submitted under section 351 of the Public Health Service Act and to our filing letter dated October 21, 2008  While conducting our filing review we identified the following potential review issues:

Assay validation for the pertussis ELISAs in support of clinical serology:

  1. At this time, the validation reports for the pertussis ELISAsconducted at --b(4)----------------------------------------------------------------------------- are missing critical information such that the validity and soundness of the data generated using these assays cannot be adequately evaluated.  A considerable amount of addition information and data are needed to demonstrate that the assays are appropriately validated.

Examples of critical information and data that are missing from the reports are provided below:

    1. A detailed description of the methods for each of the three pertussis assays including system suitability and acceptance criteria,
    2. A description of the methods used to calculate ELISA units/ml of test samples and representative sample calculations,
    3. A description of the critical reagents used in the assay and a summary of the data generated to qualify the batches used,
    4. For each coating antigen the source and a summary of the testing done to ensure purity,
    5. A definition of the working range of the assay and data demonstrating that the assay has acceptable precision and accuracy over the entire working range,
    6. Data supporting the precision and accuracy of the assay for samples at or near the lower limit of quantitation,
    7. Data demonstrating that critical assay parameters did not change from the time of assay validation to the time the clinical assays reported in this submission were conducted,
    8. Data demonstrating acceptable performance of the assay over the time period that the clinical samples were analyzed.
  1. The validation reports did not indicate pre-defined acceptance criteria.  Please comment.

In regards to the --b(4)------- assays:

  1. ------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

 In regards to the assays performed by the --b(4)---------------------------------------:

  1. Please provide a detailed description of the dilutional linearity study described including a description of the samples and diluent used.  Please include a more detailed description of the labels for the x- and y-axes (currently noted as “concentration” and “reading”, respectively).
  2. Please provide more detail regarding how the lower limit of quantification for each assay was determined.  You indicate limits of quantification for each of the --b(4)--- assays, however the units are expressed only as “concentration”.  Please specifically define the units of these limits of quantification.
  3. You indicate that prior to September 2007, the lower limits of quantification for -b(4)-------------------------------------------------, respectively.  These limits were based on the -b(4)--------------------------------------- with a Coefficient of Variation --b(4)---------------------.  Please provide a rationale for changing these limits of quantification.
  4. The test for specificity of the assays is inadequate.  The ----b(4)-------------------------------------------------- used in this study yield very -b(4)-- suggesting that they are not optimal reagents to use for this purpose.  The --b(4)------------ did not react at all in the --b(4)----------- and therefore is not an appropriate reagent to use for this purpose.  Also, the -b(4)---------------- reacted to -b(4)--.  No further investigation was conducted to determine whether this result was due to cross-reactivity as suggested or rather it was due to lack of specificity of the assay.  

    In regards to Clinical Trial V59P1:
  1. Please specify what value was assigned to samples with titers below the assay limit of quantification for purposes of calculating GMC and percent responders.

 Assay validation for the diphtheria and tetanus -b(4)------ in support of clinical serology:

In regards to Clinical Trial V59P18

  1. The diphtheria and tetanus immunogenicity data generated in this trial and submitted in this application were obtained from -b(4)---------- performed and analyzed at --b(4)----------------------.  After preliminary review of these validation reports, there is considered to be insufficient information to allow adequate assessment of the validity of each -b(4)--- and the data generated from these assays.  Specific comments with regard to the --b(4)----------- diphtheria and tetanus -b(4)--- validation reports are as follows:

While not inclusive, please provide the following types of information and data in the validation reports:

  1. The source of the diphtheria and tetanus toxoids used in the assays,
  2. A detailed description of how critical reagents were qualified with accompanying data,
  3. More detailed information on the methods used to calculate the IU/ml of clinical samples with a sample calculation included,
  4. The concentrations of the control low, medium and high positive human serum samples routinely used in the diphtheria and tetanus -b(4)--
  5. The specific IU/ml of the diphtheria and tetanus serum samples used to determine precision.
  1. For the determination of --b(4)------- in the tetanus -b(4)-, the absence of --b(4)------- is considered to occur when ----b(4)---------------------------------------------------------------------------------------------------------------------------.  Please provide the acceptance range. 
  2. For the evaluation of specificity for the diphtheria and tetanus -b(4)----- an unrelated antigen appears to be included as a control and is the --b(4)---------.  Please clarify.
  3. Please explain why in neither the diphtheria nor tetanus -b(4)- validation reports has pre-determined acceptance criteria been provided for linearity, precision and accuracy. 
  4. The assay drift data provided in both the diphtheria and tetanus validation reports were obtained between 1997 and 1998.  Please provide more recent data to indicate that the assays still perform in a stable manner.
  5. For both the diphtheria and tetanus -b(4)----- two dates are indicated for when the validation experimentation was performed: July 1994 – July 1998 and December 2003 – June 2004.  Please confirm that the data presented in these reports is from the more recent validation testing.

Performance qualification comments:

  1. Please provide Performance Qualification (PQ) data and summaries for all major equipment and pertinent utilities PQ studies.  We could only locate references to PQ studies with such general statements that everything passed and all deviations were investigated and corrective actions implemented.  Please include a summary of all deviations, investigations, and corrective actions associated with these PQ studies.
  2. Please provide container closure integrity PQ/validation data for the Container Closure System.  This data was not included in section 3.2.P.7 of your BLA submission. Please also include summary data of any extractables/leachables studies. 

Product stability comments:

  1. Please provide full stability data on ALL ----b(4)-------------------; including, but not limited, to stability data at -b(4)- such as --b(4)---------------------------------------.   
  2. Please provide correct document for the “Stability” in Section 2.3.S. -b(4)- – Novartis Vaccines and Diagnosis S.r.l.
  3. Please provide correct document for the “Stability” in Section 2.3.S. --b(4)-------------------------- – Novartis Vaccines and Diagnosis S.r.l.
  4. Please provide detailed SOPs for all the analytical methods involved in the preparation, characterization and quality control of the in-process intermediates.

Statistical comments regarding Clinical Trial V59P13:

  1. On Page 64 of the Clinical Study Report, you summarized the changes in the study design. The second amendment for study V59P13 was submitted to the Agency on April 30, 2008. It appears that this submission took place after you performed statistical analyses on the study data. In the revised version of the protocol, the power to demonstrate noninferiority of MenACWY with respect to Menactra was modified, and the sample sizes of subsets for all four serogroups were increased. 
    Please note that such late protocol modifications are problematic because they might be influenced by the known study results. Please comment.
  2. On page 70 of the Clinical Study Report, you indicated that the evaluating investigators/study staff of two study sites have been unblinded to vaccine group assignment. To assure that these incidents did not impact the study integrity, please perform a statistical analysis showing that these two sites did not have significant influence on the primary endpoints results.
  3. The sero-responses to MenACWY and Menactra were measured using the hSBA assays and serum bactericidal activity geometric mean titer responses (hSBA GMTs). Results of the primary endpoints depend heavily on the quality of the hSBA assays. In your data set ‘LABDATA’ you included dates of the laboratory analyses, but you did not supply information (e.g., assay identification number) that would enable analysis of the influence of assay variability on the estimation of the primary endpoints.   We have the following comments, please respond:
    1. Please re-submit ‘LABDATA’ with additional information that indicates which assay was used for each subject to test for immunogenicity.
    2. Please perform a statistical analysis to evaluate the influence of the ‘Assay’ factor on the estimation of the primary endpoints.
    3. Please submit a SAS statistical program that you plan to use for the above mentioned analysis.
    4. Please explain why the laboratory analysis was done in July 2006 for 80 cases, when the first sample draw date was March 1st, 2007.  
  1. On pages 68 – 71 of the Clinical Study Report, you summarized incidents of protocol deviations. We have the following comments, please respond:
  1. Please present this summary in a tabular form showing numbers of the most frequent deviations (without listing individual patients) stratified by age.
  2. Please submit a statistical program that you will use to generate the summary.

We are providing the above comments to give you preliminary notice of potential review issues.  Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our complete review.  Issues may be added, deleted, expanded upon, or modified as we review the application.  If you respond to these issues during this review cycle, we may not consider your response before we take an action on your application.  Following a review of the application, we shall advise you in writing of any action we have taken and request additional information if needed.

In your reply to this letter, we recommend that you restate each item and follow it with your explanation or clarification.  Use of this format helps organize the relevant information and provides a self-contained document that facilitates future reference.

If you have any questions, please contact the primary reviewer, Cara Fiore, Ph. D., at
(301) 827-3070.

Sincerely yours,

--signature--

Wellington Sun, MD
Director
Division of Vaccines and
Related Products Applications
Office of Vaccines
Research and Review
Center for Biologics
  Evaluation and Research