Date and Time:
July 20, 2012 1:00 PM – 2:30 PM
CBER Conf. WOC2-2330
ID Biomedical Corporation of Quebec (dba GlaxoSmithKline Biologicals)
Influenza A (H5N1) Virus Monovalent Vaccine
Carmen M. Collazo-Custodio
|Attended Committee Member||Review Assignment||Supervisor|
|Carmen Collazo-Custodio||Chair||Elizabeth Sutkowski|
|Jeremy Wally||Lead RPM||Elizabeth Sutkowski|
|Kirk Prutzman||Co-RPM||Elizabeth Sutkowski|
|Andrea James||Clinical||Lewis Schrager|
|Hana Golding||Product CMC||Jerry Weir|
|Surender Khurana||Product CMC||Hana Golding|
|Nabil Al-Humadi||Toxicology||David Green|
|Tsai-Lien Lin||Clinical/Assay Stats||Dale Horne|
|Tielin Qin||Assays Stats||Dale Horne|
|Maryann Gallagher||Advertising/Promotional Labeling||Lisa Stockbridge|
|Cheryl Hulme||Lot Release||Joseph Quander III|
|Yandong Qiang||Pharmacovigilance||Wei Hua|
|Hector Izurieta||Epidemiology (Effectiveness)||Richard Forshee|
|Anthony Hawkins||BIMO||Patricia Holobaugh|
|Randa Melhem||Facilities/DMPQ||Chiang Syin|
|Jei He||Facilities/DMPQ||Chiang Syin|
|Manju Joshi||Product Quality||William McCormick|
|Lokesh Bhattacharyya||Product Quality||William McCormick|
|Karen Campbel||Product Quality||William McCormick|
|David Schwab||Electronic Integrity Review||Laraine Henchal|
The objectives of this meeting were:
- To brief management on the status of reviews.
- To describe any issues identified with the file.
The proposed indication of BLA STN 125419 is for active immunization for the prevention of disease in persons 18 years of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine.Influenza A (H5N1) Virus Monovalent Vaccine is also denoted Q-Pan H5N1 in the context of this meeting summary.
MILESTONES AND MEETINGS
|Application Received||February 22, 2012|
|Committee Assignment||March 7, 2012 (FDA Tracked Milestone)|
|1st Committee Meeting||March 12, 2012|
|Filing Meeting||April 9, 2012|
|Filing Letter Issued||April 22, 2012|
|1st Draft Reviews||June 21, 2012|
|Mid-Cycle Review Meeting||July 20, 2012(FDA Tracked Milestone)|
|2nd Draft Reviews||August 30, 2012|
|Final Reviews (Signed/Uploaded)||October 14, 2012|
|Present to PeRC||October 20, 2012 (Target Date, Saturday)|
|Labeling Comments to Sponsor )||November 9, 2012 (FDA Tracked Milestone|
|Notify GSK of PMC/PMR||November 12, 2012|
|Labeling Complete||December 4, 2012|
|First Action Due||December 22, 2012 (Saturday)|
|First Committee Meeting||March 6, 2012|
|Filing Meeting||April 9, 2012|
|Monthly Team Meeting||April 30, 2012 (revised date - May Meeting)|
|Monthly Team Meeting||June 11, 2012|
|Monthly Team Meeting||July 9, 2012|
|Monthly Team Meeting||August 3, 2012 (revised date)|
|Monthly Team Meeting||August 31, 2012 (revised date – Sept. Meeting)|
|Monthly Team Meeting||October 5, 2012 (revised date)|
|Monthly Team Meeting||November 6, 2012 (revised date)|
|Monthly Team Meeting||December 10, 2012|
|Mid-Cycle Review Meeting||July 20, 2012|
|PeRC||September 26, 2012|
|VRBPAC||November 14, 2012|
|SWG||Not Yet Scheduled|
|Labeling Meetings||Not Yet Scheduled|
DISCUSSION TOPICS:REVIEW STATUS AND ISSUES
The Chair gave a short background of the BLA and updated management on the progress of the review.All reviewers reported that they had completed their first draft reviews.GSK submitted their responses on June 20, 2012, July 18, 2012, and July 19, 2012, to CBER’s Information Request provided on April 30, 2012.GSK submitted a pediatric plan on July 19, 2012.PeRC and VRBPAC meetings were scheduled (see above).
The Facilities/DMPQ reviewer reported that she drafted a memo recommending waiving the pre-license inspection for Influenza A (H5N1) Monovalent Vaccine at the Ste Foy Facility in Quebec, Canada. In addition, the manufacturing facilities of Adjuvant AS03 (Rixensart/Wavre, Belgium) will not be inspected because the site is US licensed with an acceptable compliance history.
Clinical Review Report
The Clinical reviewer discussed the preliminary evaluation of the safety and immunogenicity studies. Immunogenicity:Studies Q-Pan-001 and Q-Pan-002 met their immunogenicity endpoints.
Safety:The Clinical reviewer discussed that both studies Q-Pan-001 and Q-Pan-002 reported more Grade 1, 2, and 3 injection site pain reactions in the adjuvanted vaccine treatment groups when compared with unadjuvanted vaccine controls or placebo.Studies Q-Pan-001 and Q-Pan-002 reported more systemic symptoms (for example: fatigue, headache, muscle aches, joint aches, and shivering) in the adjuvanted vaccine groups vs. unadjuvanted vaccine.The ISS confirmed findings of studies Q-Pan-001 and Q-Pan-002 with respect to reactogenicity events.An increased relative risk (RR) of adverse events associated with Q-Pan H5N1 over control was observed for:
- solicited reactogenicity events – nausea, malaise, injection site pruritus, injection site reaction, injection site warmth, RR 2- 10 (1.1,38).
- cystitis RR – 7(1.1,277)
- dizziness RR- 2 (1,2.5)
- insomniaRR – 4 (1.3,21)
There were no differences in SAEs or deaths between the treatment groups and control.
Statistical Review Report
The Statistics reviewer discussed the preliminary review of the Van Buynder clinical study report, submitted to the application as a pivotal study to support the traditional approval of the Q-Pan H5N1 vaccine. The Van Buynder study was a case-control test negative retrospective, observational study.The reviewer identified multiple issues with the Van Buynder study, including:
- Small sample size:91 participants completed the study.There are wide confidence intervals in any analysis of the data.Additionally, all analyses of the data are sensitive to how missing data values are handled.
- Design methodology issues: Many sources of bias/confounders were discussed.For example, selection bias may have been introduced because ordering H1N1 tests was done at the decision of the patient’s physician and not as part of a pre-written protocol for testing patients.The study does not account for health care seeking behavior.There were no data collected for previous H1N1 infection.The number of days between sample collection and ILI onset were not considered.
- Missing data: 20/111 (18%) tested subjects should have been eligible but were not included in the study.
The Statistics reviewer was not able to draw any meaningful conclusions from the Van Buynder study.She expressed concern of using the information from this study in a label for the Q-Pan H5N1 vaccine, such as extrapolation of vaccine efficacy (100%) and the definition of a statistical criterion for vaccine effectiveness.
Epidemiology (Effectiveness Study)
A preliminary review of the ensemble of three published studies (Van Buynder et al. -Influenza Other Respi Viruses.2010;4(4):171-178; Mahmud et al.– Vaccine 29 (2011) 7975-7981; Skowronski et al. – BMJ 342 (2011) c7297) led to the conclusion that the monovalent H1N1 adjuvanted vaccine is effective against the pandemic H1N1 Influenza virus. The effectiveness of the adjuvanted H1N1 vaccine was higher for younger age groups.The Epidemiology reviewer also noted the limitations of the Van Buynder study as described by the Statistics and Clinical reviewers and concurred with their recommendation that the Van Buynder study alone should not be considered as a pivotal study for traditional approval of the Q-Pan H5N1 vaccine.
Conclusions and Recommendations
There was discussion among the review team and management about using the Van Buynder study and the path forward for approval.Both the review team and management agreed that the Van Buynder study was not sufficient to serve as a pivotal study for traditional approval of the Q-Pan H5N1 vaccine.There was also agreement that the preliminary reviews of the safety and immunogenicity data submitted in the BLA support licensure of the Q-Pan H5N1 vaccine in individuals ≥ 18 years of age via the accelerated approval regulations.Several scenarios were considered as possible confirmatory studies.
One path discussed was accelerated approval of the Q-Pan H5N1 vaccine using the results from the FluLaval efficacy study FLU Q-QIV-006 [A phase III, observer blind, randomized, non-influenza vaccine comparator-controlled, multi-country and multi-centre study of the efficacy of GSK Biologicals’ quadrivalent, inactivated, split virion, seasonal influenza vaccine candidate, GSK2282512A (FLU Q-QIV), administered intramuscularly in healthy children 3 to 8 years of age] as a confirmatory study.The other path was accelerated approval using the results of a post-marketing study conducted during an H5N1 outbreak used as a confirmatory study.
Post-Meeting Update:On August 7, 2012, Management informed the review committee that the VRBPAC would be solicited for advice regarding the licensure pathway for the Q-Pan H5N1 vaccine at the November 2012, meeting.
Information RequestsConclusions and Recommendations
|Request Date||CBER Rep(s)||Request||CBER Requester for Info||BLA Amendment Response||Review Pending?||Reviewed by and Date Reviewed|
|4/30/2012a||Carmen Collazo-Custodio||IR for Pediatric Plan, stability data, clinical assay validation, HA content by SRID validation, other assay validation, facilities information, pharmacovigilance||Andrea James, Hana Golding, Surender Khurana, Tsai-Lien Lin, Tielin Qin, Manju Joshi Lokesh Bhattacharyya, Yandong Qiang, Randa Melhem||125419.2||Yes|
|4/30/2012b||Carmen Collazo-Custodio||Revised 356h form, SRID testing reagents and results||Carmen Collazo, Karen Campbell||125419.1||Yes|
|6/21/2012||Carmen Collazo-Custodio||Adjuvant lots and SRID calculation spreadsheet||Karen Campbell||-||-|
|May 3, 2012 |
|Partial response to 4/30/2012b IR. Revised 356h form.|
|May 25, 2012 |
|Partial response to 4/30/2012b IR. Answers to Item 2.|
|June 20, 2012 |
|Partial response to 4/30/2012a IR. Answers to Items 24-34.|
|July 18, 2012 |
|Partial response to 4/30/2012a IR. Answers to Items 2-23 and 35-36.|
|July 19, 2012 |
|Partial response to 4/30/2012a IR. Answer to Item 1. All responses to IR now submitted.|