5/20/2008 Review Memo - Pentacel

MEMORANDUM

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research

Date: May 20, 2008

From: Sandra Menzies, M.S., LMDQC, DBPAP, OVRR
Drusilla Burns, Ph.D., LRSP, DBPAP, OVRR

Subject: BLA STN: 125145 (PentacelTM, Sanofi Pasteur Limited, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine)

To: Theresa Finn, Ph.D., DVRPA, OVRR, Chair, BLA Review Committee

Through: Milan Blake, Ph.D., Director, DBPAP, OVRR

Reference: STN: 125145

Product and Indication: PentacelTM, Sanofi Pasteur Limited, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined. Indicated for active immunization of infants and toddlers with a four-dose series at 2, 4, 6, and 15-18 months of age.

Scope of Review: This review focuses on the methodology and validation of the PT ----- performed in the laboratory of Sanofi Pasteur, U.S. which was used to evaluate the pertussis toxin (PT) antibody responses elicited by Pentacel to support a claim of non-inferiority relative to DAPTACEL. The methodology and validation of the assay used to measure the antibody responses to the other pertussis components of the vaccine (filamentous hemagglutinin (FHA), pertactin, and fimbriae) were performed in the Sanofi Pasteur laboratory in Canada and have been evaluated by Bruce Meade in his review of the original submission and the sponsor's response to CBER's Information Request of May 26, 2006.

Overall conclusions: The PT ------, as conducted in the --- Laboratory in the U.S, is a well-controlled assay that is adequate for the purposes for which it was used in this application.

Correspondence relevant to this review:
•CR letter dated April 23, 2007
•125145.041 Sanofi Pasteur response of May 2, 2007, to CR letter
•Meeting held May 18, 2007
•CR letter dated June 8, 2007
•125145.045 Sanofi Pasteur response of July 4, 2007 to CR letter
•Telecons held September 12, 14, and 17, 2007
•125145.049 Sanofi Pasteur response of October 2, 2007 to requests made during telecons of September 12, 14, and 17, 2007
•Web telecon held November 14, 2007
•125145.054 Sanofi Pasteur response of November 22, 2007 to requests made during telecon held November 14, 2007
•Telecon held March 24, 2008
•125145.062 Sanofi Pasteur response of March 27, 2008 to request made during telecon held March 24, 2008

Review

As indicated in the CR letter issued by CBER on April 23, 2007, information that had been recently generated by Sanofi Pasteur and submitted to the Adacel license file (STN 125111) indicated that the PT ----- conducted in the Sanofi Pasteur Canadian laboratory generated higher ------ values as compared to those obtained in Sanofi Pasteur's U.S. Serology Laboratory known as -----------------------------------------------------------------. The PT serology assays used in pivotal Pentacel studies were conducted in the Canadian laboratory. Therefore, CBER requested information from Sanofi Pasteur's investigation into the root cause of the differences observed in the two assays.

Following receipt of the CR letter, Sanofi Pasteur requested a Type A meeting on May 2, 2007 and submitted a Briefing Package. The meeting was held May 18, 2007. The information provided in the Briefing Package indicated that the PT -------------- that had been used in the Canadian laboratory exhibited some contamination with fimbriae whereas the --- assay used a more highly purified PT -----------------. Sanofi Pasteur provided study data in that submission that suggested that the contaminated PT -------------- that had been used in the Canadian assay may have lead to erroneously high PT ----- values. This information raised concerns about the PT ----- assays conducted at the Canadian laboratory that were used to generate pivotal data to support licensure of Pentacel. Subsequent to the performance of those serology studies, the Canadian Laboratory ------ and the PT ----- was re-validated at ---. Upon considering the new information that was now available concerning the purity of the PT ---------------------- used in the Canadian PT ----- assay, CBER determined that Sanofi Pasteur should re-evaluate critical sera using the ------------------- assay to support a claim of non-inferiority of Pentacel relative to DAPTACEL.

Before re-evaluation of the sera took place, CBER reviewed the ------------------- to ensure its acceptability for this purpose. Much of the data from the ---------------------- validation was reviewed under a separate IND (IND ----) which is cross-referenced in this BLA. Outstanding issues regarding the validation of the --- assay were also reviewed in the context of the Pentacel BLA submission. Of particular importance were outstanding questions regarding purity of the PT ------------- used in the --- assay and whether fimbriae contamination of the PT ---------- ---------------- in the Canadian assay was the only factor which contributed to the increase in PT antibody levels observed in the Canadian assay as compared to the --- assay. On June 8, 2007, CBER issued a CR letter which elaborated these concerns.

Sanofi Pasteur submitted a partial response to the June 8, 2007 CR letter on July 4, 2007. In this response, Sanofi Pasteur addressed the issues of purity of the PT ----------------- used in the --- assay, whether fimbriae contamination of the PT ------------------- in the Canadian assay was the only factor which contributed to the increase in PT antibody levels, and issues regarding the refinement of acceptance criteria for new lots of ---------------. Sanofi Pasteur noted that ----- uses a PT ----------------- that is highly pure and provided specific data supporting the purity of the ------------------. Supporting data from the evaluation of the new lot of PT ------------------ included --------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------. In addition, ----------------------- --------------- data demonstrated the lack of contamination of the PT ---------------------- with other antigens present in the vaccine (FHA and pertactin). These data support the purity of the ------ ------. Sanofi Pasteur also provided results from ----------------------- in which ---------------------- from both the Canadian laboratory and from ---- were used and in which the sample diluent either did or did not contain fimbriae. Results from those studies support the conclusion that fimbriae contamination of the PT antigen was the cause of the increase in PT antibody levels observed when the Canadian assay was used. In addition, as requested by CBER, Sanofi Pasteur appropriately amended their acceptance criteria for new lots of -------------------.

Details concerning the calculation methods used for the PT ----- were also submitted in response to the June 8, 2007 CR letter. After reviewing these calculation methods, we had some concerns and requested additional information in the telecons of September 12, 14, and 17, 2007. In particular, we were concerned because Sanofi Pasteur indicated that they use a parallel line analysis for data reduction, however they did not limit their analysis to data points that are on the linear portion of the dose response curve. In this submission and during a Web telecon held between CBER and Sanofi Pasteur on November 14, 2007, Sanofi Pasteur responded to our concerns about their calculation methodology. During the discussion of November 14, 2007, it became apparent to us that, while their calculation methodology may not be optimal, Sanofi Pasteur's rational for using this calculation method was to maintain consistency with methodology employed in the Canadian assay that has been used for years. We understand their desire to maintain consistency since they had hoped to retain the ability to bridge current study data back to historical results. Given the difficulties in directly extrapolating data values from one lab to another, we do not recommend direct comparisons between results obtained in the two different laboratories; however we understand the goal of trying to maintain as much consistency as possible between the two assays as they began the assay transfer process.

In our opinion, the major issues with the calculation methodology are 1) when plotted, the data points show definite curvature, yet --- fits the data with a line and 2) a number of data points utilized in the calculation are at or very near background levels for the assay. Despite these issues, we believe that the calculation methodology that they use does yield meaningful values because the shape of the curve generated by the reference data points is very similar to the shape of the curve generated by the test points and the data points for both reference and test curves span approximately the same absorbance range. The assay is well behaved and reproducible. Moreover, --- has instituted stringent validity/acceptance criteria which we believe insure that the assay results are meaningful and accurately represent anti-PT antibody content of the samples tested using the assay. While --- should be encouraged to explore other, more modern, calculation methods, we believe that the calculation method currently used by --- is adequate for the purposes for which it was used in the studies submitted in this BLA.

During the telecons of September 12, 14, and 17, we requested data that demonstrated that the U.S. PT ----- performs in a stable manner over time. In their submission of October 2, 2007, Sanofi Pasteur provided trending charts supporting the stability of the assay over time.

In summary, we believe that Sanofi Pasteur has provided information and data that demonstrate that the PT ----- performed at --- is a well controlled assay that is adequate for the purpose for which it was used in the context of this BLA submission
