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Vaccines, Blood & Biologics

Mid-Cycle Review Meeting Summary - Cervarix, June 17, 2009


Proprietary Name:CERVARIX™
Proper Name: Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant
BLA: STN 125259
Manufacturer:GlaxoSmithKline Biologicals
Meeting Date: June 17, 2009
Location: WOC-1
Time: 10:30am – 12:30pm
BLA Receipt:29-Mar-2007
Complete Response:14-Dec-2007
Resubmission Receipt:29-Mar-2009
Action Due:29-Sep-2009
BLA Review Team: 
 Robin LevisChair, Product, Facility, Pre-Clinical
Helen GemignaniRegulatory Project Manager
Laura MontaguePERC and VRBPAC RPM
Deanna ShoneElectronic Integrity
Nancy MillerClinical
Martha LeeStatistics
Lev SirotaAssay Validation Statistics
Marion GruberDevelopmental Toxicology
Liz SutkowskiAdjuvant Toxicity, CMC for MPL
Steve KunderPharmacological Toxicology
Rebecca OlinFacility CMC, Inspector
Gang Wang  Facility CMC, Inspector
Solomon YimamBioresearch Monitoring
Andrea SutherlandEpidemiology
Lisa StockbridgePromotional Labeling
Gennady RezapkinPotency assay

Meeting Attendees:

Helen Gemignani, Nancy Miller, Deanna Shone, Loris McVittie, Andrea Sutherland,

Jeff Roberts, Martha Lee, Elizabeth Sutkowski, Laura Montague, Robin Levis, Rakesh Pandey, Rose Tiernan, Wellington Sun, Maureen Hess, Lev Sirota, Ruby Lerner, Michael Nguyen, Marion Gruber, Rajesh Gupta, Lisa Stockbridge, Rebecca Olin

Resubmission Review Cycle Timetable: 
April MonthlyTeam MeetingApril 24
VRBPAC Planning Meeting  May 15
Internal PREA Decision  May 27
Mid-cycle Review MeetingJune 17
Draft Review Memos DueJune 28
Proprietary Name ReviewJuly 1
PeRC PresentationJuly 8
First Labeling MeetingJuly 17
VRBPAC Briefing Docs Due To CBER ManagementJuly 24
Final Reviews DueJuly 28
Determination of PMCs/PMRsAugust 11
Notify FDAAA SWG of PMRsAugust 11
RPM begin draft of Action LetterAugust 25
1st VRBPAC Run-ThroughAugust 25
Action Pkg to Management  September 1
2nd VRBPAC Run-ThroughSeptember 1
VRBPACSeptember 9
Action DueSeptember 29
 September 29
CBER Correspondence with GSK Since Resubmission: 
Clinical (PREA)April 1
EpidemiologyMay 4
eIntegrity IssuesMay 15, 22, 28
VRBPAC itemsMay 18, 20
Amendments Submitted to the BLA Since Resubmission: 
0048  Resubmission
0049eIntegrity - Replacement of Corrupt Datasets (Response to IR)
0050PREA revised (Response to IR)
0051Draft VRBPAC Briefing Document; Epidemiology (Response to IR)
0052eIntegrity (Response to IR)


Mid-Cycle Review Summary:

Ms. Gemignaniprovided some regulatory advice and reminders to the team as well as status updates:


Review Memos Notes: Please note some important information requested to be included in your Review Memo(s):

  • On the first page, please list:
    • the sections of the BLA reviewed
    • each Amendment number reviewed
  • Any Information Requests you asked for from GSK
    • which Amendment responded to your request, and 
    • whether their response was acceptable

The review team was reminded that their draft review memos are due by June 28, 2009, and their final review memos are due July 28, 2009.

VRBPAC planning is on track. Panel experts are being contacted and invited to join the September VRBPAC.

Cervarix is scheduled on the PERC committee agenda for July 8. Dr. Jeff Roberts will prepare the documentation for and present to the PERC.

Deanna Shoneprovided an update that corrupted files were identified in the BLA resubmission, by CBER, and they were replaced by GSK. BLA communications in EDR have been QCed for proper certification and will continue to be QCed until after Action Due.

Dr. Levis is working to complete her draft review by the end of the month. Bulk and final product specifications for CMC are acceptable. She has been working with Dr. Rezapkinon his potency testing and his summary memo indicates that ----b(4)------------------------- assay is coincident with GSK’s results. In addition, she and Rebecca Olin will be conducting an inspection of the MPL manufacturing site from June 22 - 26. She will complete her inspection report and follow up on any findings on the inspection upon returning. Both site inspection report documentation needs to be completed.  Dr. Levis does not have any additional issues related to the product review and will be able to finalize her review memo, including the inspection report by the end of July. The Chair SBRA Memo will be drafted for the Action Package by September 1 and finalized after VRBPAC prior to Action Due.

Dr. Miller is preparing VRBPAC slides and her presentation, her clinical review memo and labeling review.

Dr. Lee expressed concern in her review for imbalances in spontaneous abortions. NCI pooled data from studies HPV-008 and HPV-009 and it can not be excluded that there may be a relationship between spontaneous abortion and use of Cervarix. Dr. Gruber inquired as to the background rates of spontaneous abortion in other countries. Dr. Lee responded that it is very wide range and very difficult to determine discrepancies.

Dr. Sutherland provided an update on GSK’s Phase IV study that was scheduled to be conducted in Scotland. GSK has informed FDA that the Scotland study is no longer feasible to conduct and they can not pursue. GSK wants to do a study in the US and are in the planning and design stages now. They will submit a concept protocol to the BLA in July. International PSURs are not robust and there is very little safety data pre-licensure for this adjuvant. It was discussed whether this concept protocol would be a Major Amendment. Dr. Sutherland said that she can work with GSK until September 29, without designating the submission as a Major Amendment. Dr. Gruber questioned whether we should consider a Post Marketing Requirement (PMR) for the pregnancy registry. This will be discussed internally at a meeting to be set up as soon as possible.

The Testing Plan was discussed and it was agreed that a meeting should be set up with the Product Release Branch, DPQ, and Dr. Levis to review the lot release protocols.

Dr. Sirota had no issues with his review and none to share at this meeting.

Dr. Sutkowski has reviewed her CR response items and they are acceptable.

Dr. Gruber has completed her final review memo and will submit. One CR response item for reproductive toxicity was merged with clinical items, in the CR letter, and she has deferred response to that item to Dr. Miller for review.

Dr. Stockbridge will begin review of the Proprietary Name on July 1 in accordance with FDAAA timelines. She does not foresee any issues and will provide labeling comments for the July 17 labeling meeting. Her final evaluation will be forthcoming.

Laura Montague reported that an adjuvant expert is still needed for the VRBPAC. Discussion ensued of various adjuvant experts that the agency would like to engage.

Maureen Hess reminded Ms. Gemignani that she will need a copy of the draft label for press release preparation and to please cc her on labeling issues and meetings.

Meeting Concluded

Page Last Updated: 04/13/2015
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