Proposals for Class 2 Resubmission Memo - Cervarix, September 3, 2008

Memorandum


To
Helen Gemignani HFM-478
Robin Levis, Ph.D. HFM-451
Nancy Miller, M.D. HFM-485 

From
Martha Lee, Ph.D. HFM-217
CBER/OBE/DB/VEB 

Through
A. Dale Horne, Dr. P.H.
Chief
Vaccines Evaluation Branch 

Subject
BLA (STN 125259/0.39) Cervarix (Human Papillomavirus Vaccine, AS04 Adjuvant Adsorbed) - Request for comment on proposals for Class 2 resubmission 

cc:
Chron file
HFM-217/A. Dale Horne
HFM-215/Hsu, Henry
HFM-210/Steven Anderson 

Executive Summary

This amendment contains the applicant’s request for comment on proposals for Class 2 resubmission . The submitted proposals describe the format and contents of the HPV-008 report and the supplemental safety information for CBER’s review.

The proposed HPV-008 study report will consist of two parts: the Main report (Part 1) and an Addendum report (Part 2). Details of the proposal are described in the Statistical Review section.

 Recommendation: We need the review team’s concurrence on the submission time of the addendum report.

Statistical Review:

HPV-008 Study Report Proposal

The report will consist of two parts: the main report (Part 1) and a short addendum (Part 2). The main part will contain all primary and secondary objectives, and selected exploratory analyses. Part 2 will contain the remaining exploratory analyses.

The main report will be submitted at the time the review clock for BLA 159259 is re-started. The findings will be included in a revised package insert. The report addendum will be available between 12 to 16 weeks later. The applicant proposes to provide the addendum as a post-licensure commitment.

Reviewer’s comments: Any negative findings, even for the exploratory endpoints, need to be included in the label. Therefore, the addendum should not be considered as a post-licensure commitment. It should be submitted prior to CBER’s decision on the label.

The main report contains results of analyses of all primary and secondary efficacy endpoints on the According-to-protocol (ATP) cohort as well as on the Total Vaccinated cohort (TVC-1). Efficacy endpoints, analysis populations, and statistical methods will be reported in correspondence to what have been defined in the protocol. Safety, immunogenicity, and selected exploratory endpoints will also be included in the main report.

Addendum report includes the following remaining exploratory efficacy endpoints:
•Histopathologically confirmed VIN1+ or VAIN1+ (combined endpoint) associated with the following oncogenic HPV types detected within the lesional component of the tissue specimen (by PCR): HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68.
•Histopathologically confirmed VIN1+ or VAIN1+ (combined endpoint), irrespective of HPV DNA results found in the lesional component of the tissue specimen.
•Incident infection with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA).
•Incident infection with the following oncogenic HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 (by PCR).
•Histopathologically confirmed CIN2+ associated with HPV-16 or HPV-18 detected in the preceding cytological specimen (by PCR), overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA). Preceding cytological specimen is defined as the last cervical cytology specimen collected before the histopathology specimen was obtained.
•Histopathologically confirmed CIN1+ or CIN2+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the tissue specimen (by PCR) in women infected prior to vaccination with the corresponding HPV type, i.e. positive for HPV DNA (by PCR) at Month 0, and with a normal or low-grade cytology (negative or ASC-US or LSIL) at Month 0, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA.
•Histopathologically confirmed CIN2+ associated with cervical infection by HPV-16 only, HPV-18 only or HPV-16 and HPV-18 only (by PCR) within the lesional component of the tissue specimen, overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA).
•Any cytological abnormality associated with HPV-16/18 or with the following oncogenic HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 (by PCR).
•Histopathologically-confirmed CIN2+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) in women with a normal or low-grade cytology (negative or ASC-US or LSIL) at Month 0, irrespective of their baseline HPV DNA status.
•Clearance of HPV-16 or HPV-18 cervical infection (by PCR) in women infected prior to vaccination with the corresponding HPV type, i.e., positive for HPV DNA (by PCR) at Month 0, and with a normal or low-grade cytology (negative or ASC-US or LSIL) at Month 0, overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA).

Clearance is defined as the first negative sample for HPV DNA (by PCR) for the corresponding HPV type after Month 0, after which no positive samples occur. Subjects that are double HPV DNA positive are cleared if they have a negative sample for either HPV-16 or HPV-18.
•Persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) in women with a history of infection with the other vaccine type (HPV DNA positive and/or seropositive) prior to vaccination.
•Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR) in women who received only two doses of the study vaccine, overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA).
•Incident infection with HPV-16 or HPV-18 (by PCR) in women who received only two doses of the study vaccine, overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA).
•Administration of local cervical therapy (LEEP, CONE, KNIFE or LASER), irrespective of baseline HPV DNA status.

Reviewer’s comments: As mentioned above, the addendum report should not be considered as a post-licensure commitment. I recommend that it be submitted prior to CBER’s decision on the label.

Comments and Questions to CBER:
•We request the applicant to submit the addendum report prior to CBER’s decision on the label. If the review team concurs on this request, please make it as a comment to the applicant.

Comments and Questions to Applicant: Please refer to the comments to CBER.
•CBER requests that you submit the addendum report prior to finalizing the label.
