• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

  • Print
  • Share
  • E-mail

Section Contents Menu

Vaccines

Memo - Comments on the assay validation of Diphtheria and Tetanus concomitant vaccines, January 15 2009 - Menveo

Date:   January 15 2009 
To:  Christopher Webster, Ph. D.
Novartis Vaccines and Diagnostics, Inc.
350 Massachusetts Ave
Cambridge, MA  02139
From: Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Point of Contact: Cara Fiore, Ph. D.
 Subject: BLA 125300_.0, 0.3
Comments on the assay validation of Diphtheria and Tetanus concomitant vaccines.

 Study V59P18 Diphtheria and Tetanus -b(4)- Validation

  1. In neither Attachment Q1-12 (Section 5.6 “Qualifying a new lot of in-house controls” SOP b(4)003-07 “Qualification of New Reagents and Managing Change for Other Significant Components for -b(4)-- and Other Assays”) nor in Attachment Q9-2 “Reference values and acceptance range for currently used references slopes and controls for diphtheria and tetanus -b(4)-” are the specific concentrations (IU/ml) of the low, medium and high controls given.  Please provide the concentrations of the low, medium and high control samples currently used in the diphtheria and tetanus -b(4)---.
  2. In Attachment Q1-7 (SOP b(4)006-08 “Data Acquisition and Analysis”) there is no indication as to the linear range of the --b(4)----------------- used in the diphtheria and tetanus -b(4)-.  Please comment.  Additionally in Appendix 3 and 4 of SOP b(4)006-08 (Dip and Tet SBLCalc Settings) the minimum and maximum b(4) values for the calculation of titers are indicated as --b(4)------- however, in Section 15 “Calculation of Titers” in both the diphtheria and tetanus -b(4)- validation reports the minimum and maximumb(4)values used for titer calculation are --b(4)----  Please comment.
  3. In response to CBER’s question as to the use of pre-determined acceptance criteria (Question #12 in the DI letter), Novartis responded that at the time the -b(4)--were established and validated at -b(4)------------ (1994-1998) it was not common practice to establish pre-set acceptance criteria.  However, Novartis did indicate that a CV of 20% was generally applied to evaluate validation parameters and that --b(4)---------- targeted the 20% CV acceptance criteria for all --b(4)-. Later in their response Novartis stated that “in May 2001, FDA issued a “Guidance for Industry/Bioanalytical Method Validation” that defined acceptance criteria for precision, stating that the coefficient of variation should not exceed 15%, except for the lower limit of quantitation (LLOQ) where a CV of 20% is deemed acceptable and for accuracy, saying that the mean value should be within 15% of the actual value except for the LLOQ where a deviation of 20% is acceptable.  Neither FDA nor ICH guidelines specify a general acceptance criterion for linearity but a coefficient of correlation of R2 = 0.99 is generally accepted as indicating a good linearity.”  In the recent re-qualification of the tetanus -b(4)- by --b(4)---------- (Attachment Q1-13, “Qualification of --b(4)--------------------------------------------------------------- for Performance of Tetanus & Pertussis Antibody -b(4)-” dated June 27, 2006) the pre-specified acceptance criteria for precision was indicated as -b(4)-  Please confirm and justify the acceptance criteria for precision currently used by --b(4)----- for the tetanus -b(4)--
  4. In the original validation report no pre-set acceptance criteria was given for accuracy in the tetanus -b(4)-- however, in the 2006 re-qualification report (Attachment Q1-13) an acceptance criteria of -b(4)-------difference between the measured and nominal concentration was specified for accuracy.  As indicated above, Novartis also noted that “in May 2001, FDA issued a “Guidance for Industry/Bioanalytical Method Validation” that defined acceptance criteria for precision, stating that the coefficient of variation should not exceed 15%, except for the lower limit of quantitation (LLOQ) where a CV of 20% is deemed acceptable and for accuracy, saying that the mean value should be within 15% of the actual value except for the LLOQ where a deviation of 20% is acceptable.”  Please comment and justify the use of a -b(4)------difference as the acceptance criteria for accuracy in the tetanus -b(4)-.  Have any data on the accuracy of high and medium titer serum samples become available since the 2006 re-qualification of the tetanus -b(4)--?  Please comment.

V59P18 Clinical Serology Results

  1. For the Diphtheria immunogenicity results there appears to be a discrepancy between the GMTs recorded for Groups I and III at Day 31 and Group II at Day 61 (Table 14.2.1.31) and the GMT data presented in Table 14.2.1.18 and Table 14.2.1.25.  Please comment.

Study V59P11 Diphtheria and Tetanus -b(4)- Validation

  1. Please provide details on how the IU/ml of clinical sera samples was calculated and include a sample calculation.
  2. Please provide information on the qualification of new reagents used in the diphtheria and tetanus --b(4)--
  3. To confirm that the diphtheria and tetanus -b(4)-- performed in a stable manner over time please provide chart records for each -b(4)-that includes the time over which the clinical trial was run (April 2006 to May 2007).

Please submit your responses, prefaced with these questions, to the BLA