Submission Type: Original Application Submission ID: 125347/0 Office: OVRR
Product: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) “Hiberix”
Applicant: GlaxoSmithKline Biologicals
Telecon Date/Time: 26-MAY-2009 1:00 PM Initiated by FDA? Yes
Communication Category: Advice
Author: JASON HUMBERT
Discussion of clarification to questions pertaining to the pharmacovigilence plan
Jay Slater, M.D.
David Menschik, M.D., MPH
Robert Wise, MD, MPH
Jody Gould, Director, Vaccines, North American Regulatory Affairs
Elisa Harkins, Associate Director, Vaccines, North American Regulatory Affairs
This teleconference was scheduled to discuss questions still unanswered regarding the Pharmacovigilance Plan. Items were initially sent in the April 30, 2009 Deficiencies Identified letter, then GSK requested clarification on May 7, 2009, to which CBER provided further details on May 12, 2009. On May 18, 2009, GSK requested a telephone call with members of the review team to discuss the comments related to the Hiberix PVP, but also to gain a better understanding of what will be required in future submissions. A 12:30 call was scheduled for May 19, 2009 with Dr. Harry Seifert and Elisa Harkins of GSK and Drs. Jay Slater and David Menschik and Jason Humbert. On the morning of May 19, 2009, GSK called CBER and asked that a supervisor(s) within OBE be available for the call. Dr Slater and Jason Humbert of CBER asked that the sponsor provide a list of questions and/or discussion items in advance of the call, but cautioned that the 12:30 call would most likely be canceled. GSK provided a list of discussion items/questions in an e-mail on 11:28 AM on May 19, 2009. CBER attempted to contact Elisa Harkins of GSK to notify her that the requested members from CBER were available for the originally scheduled 12:30 call, but an e-mail and a voicemail were not returned. The call was rescheduled for 1:00 PM on May 26, 2009 to accommodate GSK.
The following are the discussion items submitted in the May 19, 2009 e-mail:
"Please specify your enhanced pharmacovigilance procedures for evaluating the three identified adverse events (deaths, leukocytoclastic vasculitis, and type III hypersensitivity reactions), as well as potential unanticipated safety signals."
- It is unclear what is being asked for by "specify [GSK's] enhanced pharmacovigilance procedures for evaluating" the three event terms listed. Is the reviewer asking how we will performed enhanced pharmacovigilance (e.g., by employing targeted follow-up questionnaires), how we will analyze the data, both, or something else?
- Similarly, it is unclear what the reviewer is asking for in his reference to "potential unanticipated safety signals"?
a. This is a very broad and general question - it would be helpful to understand what he wants to know (e.g., is there a specific event or type of signal of concern, what level of detail is expected for this very general question, etc).
b. Is this information expected to be included in all future PVPs, including those for other BLAs, or is it specific to this instance?
c. Would this information best be placed elsewhere in the CTA (Module 1) than in the PVP?
"We recommend that the following post-marketing adverse events should also be reported in an expedited fashion in addition to 21 CFR 600.80 requirements. This expanded adverse experience reporting should be provided as 15-day reports to the Vaccine Adverse Event Reporting System for one year following product licensure as follows:
All serious adverse events whether expected/labeled or unexpected/unlabeled, including but not limited to vaccine failure, seizures, shock, respiratory distress or difficulty breathing, angioedema, inspiratory stridor, and bilateral wheezing."
- We would like to understand the context of the request. Is there a specific safety concern underlying the requirement for expedite reporting of serious/expected events?
a. Would monthly periodic reporting of serious/expected events (with a data lock point of, for example, the 15th of the previous month) fulfill CBER's needs?
b. Will this be a requirement for all new BLAs?
- The specific events listed do not appear to be MedDRA terms. So that we understand exactly what terms CBER wants to be reported within 15 calendar days of receipt, we request that a list of MedDRA Preferred Terms be provided.
May 26, 2009 Discussion:
The sponsor asked if CBER wants to know how GSK will analyze the data or are we asking for how GSK will perform enhanced pharmacovigilence. GSK also asked whether CBER is asking for SOPs for identifying new signals or methods for evaluating signals. CBER stated that they are interested in how the sponsor will perform enhanced pharmacovigilence for the safety concerns identified as well as the sponsor’s methods for identifying new signals and evaluating identified signals.
GSK asked if the comments related to the PVP in this submission could be applied to future submission, or if they are specific to this BLA. CBER stated that they are unable to comment on future submissions as the thinking within CBER regarding these plans is actively evolving.
CBER commented on item 2.a., stating that the current description needs to distinguish safety signals from “noise” and account for factors such as false-positives. CBER agreed with the sponsors approach to include the requested information in eCTD format in Module 1. CBER requested if this information is not included in the PVP, a cross-reference link should be provided in the PVP. GSK stated that they will check feasibility with their publishing group.
For the second comment, CBER acknowledged that the list of conditions may be a source of confusion. It was agreed that GSK will provide serious/expected US adverse events on a monthly basis for the first year post licensure. GSK asked for clarification regarding the duration of the monthly reports. CBER stated that they will be required for the first year post licensure and CBER will have the option to renew if CBER deems it is warranted by safety concerns. The monthly reposts will supplement and not replace the standard quarterly reports.
No other issues discussed and the call concluded.