Vaccines, Blood & Biologics
Submission Type: BLA Submission ID: 125285/0 Office: OVRR
Protein Sciences Corporation
Telecon Date/Time: 08-Aug-2012 09:30 AM Initiated by FDA? Yes
Telephone Number: 605-475-5950
Author: TIMOTHY FRITZ
Rationale for limiting licensure to persons 18-49 years old.
FDA Participants: Marion Gruber, Wellington Sun, Jerry Weir, Cynthia Nolletti, Andrea James, Douglas Pratt, Barbara Krasnicka, Jane Woo, Timothy Nelle, Timothy Fritz
PSC: Manon Cox, Dan Adams, Lisa Dunkle, Sam Simons, Peter Patriarca, Penny Post
BARDA: Tanima Sinha, Frank Arnold, Suzanne Sensabaugh
University of Rochester: John Treanor
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
CBER informed Protein Sciences in an August 1, 2012 telecon that, if approved, the Flublok age indication would be for persons 18-49 years old. PSC responded later in the day via e-mail with a request for a telecon to discuss our reasons for limiting approval to persons 18-49 years old.
CBER informed PSC that the reasons for not granting licensure for persons 50 and older were 1) the small size of the safety database in this population, 2) the failure of the non-inferiority and immunogenicity studies in this population, and 3) the failure of Study PSC04 to meet its primary endpoint. For these reasons, we felt we could not bridge approval to persons 50 years and older who are at higher risk for influenza infection.
PSC asked why the safety data in persons 18-49 could not be extrapolated to the older age groups since hypersensitivity rates may be higher in persons 18-49 compared to older age groups. We reiterated that the current safety database for persons 50 years and older is small and additional safety data was needed for all age groups. Additionally, we noted that older individuals are at increased risk for adverse events because of co-morbid conditions and concomitant medications, and that Dr. Eickhoff expressed a concern about hypersensitivity in elderly populations at the 2009 VRBPAC.
PSC asked why additional safety data was being required now when CBER and PSC had previously reached an agreement regarding the size of the safety database. We explained that the previous agreement was based on consideration for accelerated approval. PSC explained that some additional safety data may be available from DMID studies of approximately 400 subjects 65 years and older studies and asked whether we would consider this data to grant accelerated approval for persons 50 years and older. PSC noted that FluBlok had failed in only 1 of 12 immunogenicity comparisons with Fluzone (the B strain) and had performed better than Fluzone in 7 of 12 immunogenicity comparisons. We explained that even though accelerated approval for persons 50 years and older is still an option, additional CBER internal discussion is needed and we could not provide details on the requirements to extend the age indication to persons 50 years and older at this meeting. We also clarified that the additional safety information for persons 50 years and older would be needed prior to licensure, and that a post approval efficacy study would be required in the case of accelerated approval.
PSC asked why we had not requested the additional safety information in our 2010 CR letter and whether we could tell them the size of the additional safety information needed. PSC also asked if we had specific safety concerns. We acknowledged PSC’s concerns and noted that the FluBlok BLA does support approval for persons 18-49 years old. We reminded PSC of the concerns regarding the safety database size for persons over 50 years old expressed at the 2009 VRBPAC. We also explained that, at the time the CR letter was issued in 2010, there were major concerns regarding FluBlok’s manufacturing and that the product might not be ready for clinical testing at that time.
PSC noted that Flulaval had been granted accelerated approval despite failing immunogenicity criteria for the B strain. We acknowledged this but noted that our decision regarding FluBlok was not based on the B strain failure alone but was due to consideration of the totality of the data. We noted that other influenza vaccines had shown good immunogenicity but failed to demonstrate clinical efficacy and that the efficacy data for FluBlok was relatively weak. We have required a second season clinical endpoint study for full approval of products that have failed the first season study, and some of these vaccine efficacy studies have been conducted in elderly or pediatric populations at higher risk for complications of influenza.
PSC indicated a very large study, not just an additional 1000 subjects, would be needed to identify safety signals in the older age groups and that they were prepared to begin their proposed Phase 4, open-label safety study with 150,000 doses of FluBlok. PSC said that it was willing to work with CBER on the design of an efficacy study and collecting additional safety data in the event that accelerated approval was granted for persons 50 years and older. PSC asked if we would grant accelerated approval for persons 50 years and older using the data in the current submission. We repeated that we would need additional safety data prior to granting accelerated approval and also indicated that additional immunogenicity data may be required but that we would defer discussion of these issues following additional internal discussions.
PSC asked whether they should submit a revised package insert based on the 18-49 age indication even though this would result in a reduction in the size of the safety database. We responded that they should submit a package insert based on this age indication. PSC also asked how best to have the discussions between PSC and FDA as soon as possible regarding approval of FluBlok for persons 18 and above granted for the 2013-2014 season. We suggested that PSC submit a meeting request.