Report of Telephone Conversation
Submission Type: BLA         Submission ID: STN#125512/0       Office: OBRR
Title/Product: Antihemophilic Factor (Recombinant), Porcine Sequence [OBIZUR]
Applicant: Baxter Healcare Corp.
Telecon Date/Time: June 9, 2014, 1 p.m. – 2 p.m.   FDA Initiated: No
Communication Category/Subject:
OTHER - To discuss the plan of immediate actions of the ongoing review of the BLA and FDA
expectations for inspections-related information.
Telephone Number: 1-855-422-9837
FDA Participants:
Natalya Ananyeva, CBER/OBRR/DHRR/LH
Alexey Khrenov, CBER/OBRR/DHRR/LH
Qiao Bobo, CBER/OCBQ/DMPQ/BII
Jie He, CBER/OCBQ/DMPQ/BII
Sonday L. Kelly, CBER/OBRR/IOD/RPMS
Baxter Participants:
Susanne Schober-Bendixen, Vice President, Quality Compliance and Safety
Mehrshid Alai-Safar, Senior Director, Regulatory Affairs
William Bryan Silvey, Senior Director, Regulatory Affairs
Donna M Welch, Director, Quality
Lemieux, Linda, Associate Director, Regulatory Affairs
Iraj Daizadeh, Senior Manager, Regulatory Affairs
Mathias Ferencic, Senior Project Manager
Minna Rannikko, Project Manager, Process Engineering 
Kien S Du, Manager, Regulatory Affairs

Teleconference Discussion:
This teleconference was requested by Baxter in response to the Major Amendment Acknowledgement letter issued by FDA on May 28, 2014. FDA explained that the extension of the review timeframe was triggered by Baxter’s April 25, 2014 submission – the first amendment that qualified as Major under the PDUFA V program. FDA decision is also supported by Baxter’s subsequent amendments dated May 16, 2014 and May 22, 2014. Amendment dated May 16, 2014 projects completion of the relevant studies to address 483 items from the recent inspection of (b)(4) facility too close to the original Action Due Date (ADD). Amendment dated May 22, 2014 contains a substantial amount of new manufacturing information and data not previously submitted to or reviewed by the Agency. According to the PDUFA V Program, the new Action Due Date is October 25, 2014, as stated in the Acknowledgement letter.
FDA outlined its expectations and the following action items for Baxter for the near future:
1. FDA expects final responses to pending CMC questions from April 4, 2014 Information Request. 
FDA stated that most questions were addressed in April 25, 2014 amendment; however, some items required additional corrective actions or studies with the projected completion dates in the end of May 2014. Specifically, FDA expects the final response to Question 2 related to the implementation of controls over ---(b)(4)--- performance during routine production. The response may include updated SOP and/or relevant sections or pages of Batch Record and Training Program documents. For Question 4 (approach to validate the Intermediate Precision of the One-Stage Clotting Assay), Baxter should submit the amended Validation Report for this analytical procedure.
Baxter agreed to submit this information as soon as feasible.
2. FDA expects final responses to the 483 items from Pre-License Inspection of Baxter’s facility in ---(b)(4)----- reflecting implementation of corrective actions and including relevant documentation. 
FDA stated that Baxter’s resolution plan submitted in the March 28, 2014 amendment indicated projected completion dates for corrective actions in the end of May, 2014. Baxter asked how they should submit the inspection close-out information in the eCTD structure. FDA clarified that Baxter should submit the response to inspectional issues from Form FDA 483 as one amendment to the BLA file under Module 1 with the supporting documents as appendices. Baxter should submit the appropriate documentation to show that corrective actions have been implemented.
FDA emphasized that, wherever possible, Baxter should send the complete documents, and where not possible, submit summary reports and relevant pages of the revised SOPs or other relevant documents. This information should come as the final resolution report to all Form FDA 483 items to allow FDA to complete its review of inspectional items. FDA stated that submission of this information will not affect the Action Due Date but is needed for FDA in order to close out the inspectional items.
Baxter committed to submit the final resolution report from the (b)(4)-- inspection by June 30, 2014.
3. FDA expects final responses to the 483 items from -------(b)(4)------------ inspection reflecting implementation of corrective actions and including relevant documentation. 
FDA stated that Baxter should refer to their resolution plan in the May 16, 2014 amendment and projected completion dates for part of 483 items in the end of June and the end of July, 2014. FDA requested the final responses to all 483 items to come in eCTD format as one amendment to the BLA in Module 1, to ease FDA’s review of this information as a stand-alone amendment.
Addressing Baxter’s inquiry, FDA stated that for the items that Baxter cannot complete the resolution one month before the PDUFA ADD of October 25, 2014, Baxter must provide a substantive justification and indicate the target completion date(s).
Baxter will coordinate with (b)(4) the preparation of the inspectional resolution package and will get back to FDA on the timeline for submission of the final report to 483 items to FDA for review.
4. Baxter’s May 22, 2014 submission is currently under FDA review. 
FDA understands that some of the studies are on-going. For instance, with regard to Question 4, updated stability data, the next testing time points will be in June and July 2014. To ease FDA review, Baxter was requested to combine the results of all on-going activities and submit them as one amendment in August 2014, after all activities have been completed.
Baxter asked for these requests in writing. FDA replied that this is unnecessary because this teleconference is a follow up to a previous written correspondence (May 12, 2014). The message from this call is that FDA expects Baxter to submit the responses to the pending items together, once completed, on the projected dates as stated in the May 22, 2014 amendment.
5. Discussion on other review disciplines’ aspects 
Baxter asked if there are any further Information Requests (IR) forthcoming from the CMC or from Non-clinical disciplines.
FDA does not expect any additional IRs from the CMC discipline (product- or facility-related), unless Baxter’s responses are found incomplete. Thus far, the non-clinical data appear sufficient. There could potentially be a future IR for clinical information.
FDA is currently preparing the labeling comments (for Package Insert, vial and carton labels) and will send them to Baxter close to or immediately after the Late-Cycle Meeting scheduled for August 19, 2014. FDA explained that the labeling negotiations generally begin after the CMC issues and clinical items are resolved.
Baxter asked if FDA would be amenable to more frequent conversations between the lead reviewer (Chairperson), subject experts and Baxter to ensure that Baxter meets FDA expectations as best as they can.
FDA is open to regular discussions with Baxter through the Regulatory Project Manager.
6. Additional discussion on inspectional items 
Baxter noted that in some cases, they previously committed to submit a protocol as the resolution of a 483 item but on this call FDA has requested final reports. Baxter asked that if they did not meet FDA expectations, could FDA notify them.
FDA reiterated that to complete its review of inspection-related information, FDA requests validation reports, not protocols, unless the 483 observation cites a protocol error. In this case, FDA may request both the revised protocol and the completed validation report. This will depend on the observation and what Baxter decides is sufficient evidence to address the issue.
FDA requested that Baxter submit complete reports for the shipping validation. This item was planned to be addressed in the post-marketing phase, but extension of the review clock due to the major amendment has allowed for more time in this review cycle. FDA asked Baxter to provide via email the projected completion dates for the shipping validation and lyophilizer validation. Baxter said they intend to request a telecon to discuss the lyophilizer validation completion date once they decide on all of the information that needs to be composed.
Action items as summarized by Baxter:
* The CMC information is approaching a level of stability. Baxter will submit responses to pending items from April 25, 2014 amendment and to the Form FDA 483 items from the PLI/PAI of the two facilities.
* Final responses to 483 items from both -----(b)(4)---------- inspections will be submitted as individual and self-contained amendments with supporting information in Module 1 and appendices to Module 1.
* Baxter committed to submit final resolution responses to (b)(4)-- 483 items by June 30, 2014. Submission date for (b)(4) inspection responses will be determined.
* Any item that cannot be closed out one month before the PDUFA ADD (October 25, 2014), requires a substantive justification for FDA and indication of the target completion date.
* Baxter will submit the updated stability data for OBI-1 Drug Product in August 2014 as a follow-up to their May 22, 2014 amendment.
* FDA Labeling comments will be relayed to Baxter close to or immediately after the Late Cycle Meeting.
* Baxter will maintain increased communication with FDA to better meet FDA expectations.
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