
Information Request, November 12, 2014 - BEXSERO

 

 
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH 
 OFFICE OF VACCINES RESEARCH AND REVIEW
 DIVISION OF VACCINES AND RELATED PRODUCT APPLICATIONS

DATE: NOVEMBER 12, 2014     PAGES: 3

TO: NOVARTIS VACCINES AND DIAGNOSTICS, INC
 ATTENTION: PATRICIA STOEHR, PH.D.
 Senior Group Manager, Regulatory Affairs 

350 Massachusetts Avenue Cambridge, MA 02139 USA
 FAX: (617) 871-4711 TEL: (617) 871-8060

FROM: RAMACHANDRA S. NAIK, PH.D.
 Regulatory Project Manager
 FAX: (301) 595-1244 TEL: (301) 796-2640 

SUBJECT: STN: BL 125546/0 – Request For Information

MESSAGE:

Dear Dr. Stoehr: 

We have the following request for additional information regarding your submission of Biologics License Application STN 125546 (Meningococcal Group B Vaccine):

Please respond to the following comments by either providing the data requested or providing reasonable timelines for conduct of the work requested and submission of the data. 
1.The tests for the potency of the 936-741 antigens appear to be more variable than those for the other antigens. We believe this may be due in part to the (b)(4) conditions being used to assess the antibodies in the ----(b)(4)----. Please further optimize the assay used to quantitate the antibodies to 936-741. 

2.Please re-examine the dose response data in the immunogenicity test and provide additional data that verify that the optimum doses are being used to generate the dose response curve. Please provide data that verify that the dose levels and number of doses used are adequate to minimize the overall variability of the assay. 

3. Please re-evaluate the system suitability criteria for both the (b)(4) and potency estimation to further verify that the criteria are rejecting assays that are performing outside expected performance criteria. 
a. For the -(b)(4)-, please indicate the statistical basis for the system suitability criteria and the likelihood of rejecting assays due to chance alone. 
b.The system suitability criteria for the (b)(4) potency test were based on simulated data. Please update the criteria using data from the assays run to date. Please indicate the likelihood of rejecting assay due to chance alone. 

4.Please revalidate the (b)(4) in the laboratory in which the assays are performed for product release. Validation studies should mimic routine use. Accuracy and precision should be demonstrated using incurred and mock samples across the working range of the assay. The lower limit of quantitation (LLOQ) should be based on sample accuracy and precision at the reported LLOQ. 

5.We find the specification for the Upper Confidence Limit to be inadequate as it does not provide relevant information regarding the potency of the product. As communicated to you previously, Upper Confidence Limit is not a proper way of ensuring non-inferiority of a test lot, especially given the large variability of your potency assay. Although you showed in your responses submitted to Amendment 4 that with the additional criterion of the point estimate of RP being (b)(4), the chance of passing a subpotent lot is extremely low when the relative potencies of all four components are only (b)(4), the probability of falsely accepting a lot with RP slightly below (b)(4) or with low RP for only one or two of the four components can be high. Please discuss the use of a criterion based on the confidence limits to eliminate assay data from tests that are not precise enough to provide confidence in the point estimate of potency. 

6.Please propose drug product specifications based on the historical performance of the (b)(4) lots released since the introduction of the latest potency test. Please provide a comparison of the proposed specifications to the potency of lots shown to be immunogenic in clinical studies to demonstrate that the product as currently tested is similar to those clinical lots.

7.The ability of the potency test to detect degraded vaccine was determined by -----------------------------------------------(b)(4)-------------------------------------------------------. If the current potency specifications are applied to the results, the data are inconsistent with regard to the ability of the assay to detect changes in the component antigens. The only antigen consistently affected by ---(b)(4)------- was 287-953. Please provide additional data to demonstrate that the immunogenicity test can detect changes in product quality or concentration.

Please provide your responses to this information request in an Amendment to STN 125546 by December 1, 2014. 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 about this communication, please contact Ramachandra Naik, Ed Wolfgang or Kirk Prutzman at (301) 796-2640. 
