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Vaccines, Blood & Biologics

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Midcycle Meeting_Minutes, July 20 2012 - Q-Pan


Date and Time:          July 20, 2012 1:00 PM – 2:30 PM
Location:                    CBER Conf. WOC2-2330
STN #:                        125419/0
Applicant:                   ID Biomedical Corporation of Quebec (dba GlaxoSmithKline Biologicals)
Product:                                 Influenza A (H5N1) Virus Monovalent Vaccine        
Meeting Chair:          Carmen M. Collazo-Custodio
Meeting Recorder:    Kirk Prutzman
CBER/FDA Invitees
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 Campbell                  Product Quality                                  William McCormick      
                  David Schwab                      Electronic Integrity Review               Laraine Henchal
Marion Gruber            Elizabeth Sutkowski   Wellington Sun          Douglas Pratt
Theresa Finn                           Herb Smith                 Annisa Cheung           Dale Horne
Philip Krause                          Erik Henchal               Robert Ball                 Richard Forshee
Maureen Hess                         Jerry Weir                   Brenda Baldwin          Chiang Syin
Estelle Russek-Cohen
1.0            PURPOSE
The objectives of this meeting were:
·       To brief management on the status of reviews.
·       To describe any issues identified with the file.
2.0            BACKGROUND
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.
3.0            DISCUSSION TOPICS
3.1            Milestones and Meetings
Milestone                                          Projected Date
 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)
Meetings                                            Scheduled Date
 First Committee Meeting                   March 6, 2012
 Filing Meeting                                                April 9, 2012
 Monthly Team Meetings                    April 30, 2012 (revised date - May Meeting)
                        June 11, 2012
                        July 9, 2012
                        August 3, 2012 (revised date)
                        August 31, 2012 (revised date – Sept. Meeting)
                        October 5, 2012 (revised date)
                        November 6, 2012 (revised date)
                        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
3.3.1       Introduction – Chair Report
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). 
3.3.2       Facilities/DMPQReview Report
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.
3.3.3       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.
3.3.4       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.
3.3.5       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.
3.3.6       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.
4.0       Information Requests
Request Date
CBER Rep(s)
CBER Requester for Info
BLA Amendment Response
Review Pending?
Reviewed by and Date Reviewed
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
Carmen Collazo-Custodio
Revised 356h form, SRID testing reagents and results
Carmen Collazo, Karen Campbell
Carmen Collazo-Custodio
Adjuvant lots and SRID calculation spreadsheet
Karen Campbell
5.0       Amendments

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.