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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

Complete Response Letter - Flubok

 

Our STN: BL 125285/0
 
Protein Sciences Corporation
Attention: Drs Manon M. Cox
1000 Research Parkway
Meriden, CT 06450-7159
 
Dear Drs Cox:
 
This letter is in regard to your biologics license application (BLA) for Influenza Vaccine manufactured at your Meriden, CT location and submitted under section 351 of the Public Health Service Act (42 U.S.C. 262).
 
We have completed our review of all the submissions you have made relating to this BLA with the exception of the information in the amendment dated December 18, 2009, as noted below. After our complete review, we have concluded that we cannot grant final approval because of the deficiencies outlined below. Please note that the items listed in the CMC section were previously requested by CBER on August 29, 2008, July 30, 2009, October 1, 2009 and November 6, 2009 and an acceptable response has not been received.
 
CMC
 
1.     You have not demonstrated complete process validation:

 
a.      The Final 2009 H3 Process Validation Report (document R-09-036) received October 7, 2009 in response to our October 1, 2009, Information Request does not support consistent manufacture of HA from B/Brisbane/60/2008. We note that you have committed to providing additional information to support consistent manufacture of Influenza B rHA. The data you provide should demonstrate that your corrective action (i.e. –b(4)-------------------------) has resolved the inconsistency in yield and        -b(4)-------------. Please provide the validation protocol together with a report that includes process parameters and in-process results to demonstrate product yield and quality at all downstream steps for 3 consecutive lots of Influenza B rHA. The report must include –b(4)------------------------------------------------------------------------------------------------------------------. Please identify any additional quality control tests or parameters you have put in place to attain consistent manufacture.
 
b.     Data requested by CBER in its November 6, 2009, Information Request (item #1) and provided in your December 11, 2009, submission do not support validation of the        -b(4)--chromatography step for purification of the H1 hemagglutinin for the following reasons: (i) chromatograms provided show different elution profiles for validation lots ---b(4)----------------------------------, demonstrating performance of this step is not consistent; (ii) the investigation described in report 09-073 indicates a problem during the –b(4)- step - we do not agree that the root cause of this deviation was incorrect collection of the eluted fraction, as your data show that the performance of this step was not consistent with validation lots; and (iii) your investigation 09-075 concludes that the yield of lot –b(4)--- was not out of trend when compared to 2008 H1 yields; however, the investigation neglects to consider –b(4)---------------- was implemented prior to 2009 H1 production in order to increase yields and therefore yields obtained during 2009 validation runs, and not 2008 lots, are the appropriate comparator. The discrepancies in –b(4)------- performance should be investigated and resolved. Please provide your investigation reports together with changes you have implemented to obtain consistent column performance. Please provide process parameters, --b(4)---------------------------------------------------------------------------------------------------------- results for 3 consecutive H1 lots to demonstrate consistent step performance, product yield and product quality at the b(4) as well as other –b(4)----------- steps.
 
c.      Please provide the Drug Product Blend and Fill Validation report and data summaries for runs #2 and #3 as requested in our October 1, 2009, Information Request (item 11d). This report should include batch records for each lot, a summary report of deviations and corrective actions, summary tables of parameters, quality control and lot release results. In addition, please provide validation reports and data summaries for shipping and any hold times associated with the bulk drug substance.
 
2.     In response to CBER’s November 6, 2009, Information Request (item #5cii), you indicated in your December 11, 2009, submission that –b(4)------- was detected in the two trivalent vialed batches of FluBlok, drug product lot –b(4)---- and lot # --b(4)-------. Please submit these test results once the final report is available from –b(4)-------- as well as the results of your repeat b(4) assays once they are available for review. In addition, we would like to review and discuss your strategy for investigating the origin and nature of the –b(4)------- in your product, including plans for ----b(4)---- studies, prior to initiation, in order to facilitate resolution of this issue.
 
3.     In your April 28, 2009, response to our Complete Response letter dated August 29, 2008, regarding the b(4) assays for adventitious agent testing of the –b(4)------------- (item 5f) you stated that you were investigating the ---b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Please submit the results of your analysis. Additionally you indicated that efforts were underway to improve the sensitivity of the assays and that an assay for virus species belonging to the –b(4)---------------------------------------------- was still under development. Please provide a table of b(4)assays you have in place for adventitious agent testing of the –b(4)----------- with limit of detection for each assay.
 
4.     Please provide a synopsis of the study you performed to evaluate particle characteristics as described in your August 24, 2009, response to our July 30, 2009, Information Request
(item 4a). 

Please provide the data characterizing the nature of these aggregates and changes that occur with time. Please include information that defines the change in aggregation within monovalent bulk and drug product shelf-life and the impact of any change on potency.
 
5.     We acknowledge your December 11, 2009, response to our November 6, 2009 Information Request (Additional requests/comments item #1) regarding concerns about the sequence of B/Brisbane/60/2008 HA in your recombinant baculovirus. Please provide results of B/Brisbane rHA antigenic analysis that includes recombinant HA derived from a prior influenza B vaccine strain and/or B/Brisbane/60/2008 with the original reported amino acid sequence (Asn-197) as controls together with the corresponding whole influenza viruses.
 
6.     In your response to our October 1, 2009, Information Request (item 11fB) you acknowledge our request to repeat container closure integrity testing to include dynamic conditions (i.e., exposure to differential pressures to simulate anticipated product processing or distribution conditions), and to provide sensitivity data for your container closure test method. Please provide the requested information and data.
 
7.     Information regarding product purity is incomplete:
 
a.      As requested in our Complete Response letter dated August 29, 2008, [item #10a)iii.], please provide additional information to validate the accuracy of the assay for contaminants that are either smaller or larger than –b(4)-----.
 
b.     As requested in our July 30, 2009, Information Request [item 8c], please provide data to support –b(4)-----------------------------------------------------------------
 
c.      As requested in our October 1, 2009 Information Request [item 1aC)h)v.], please provide the validation report for Tween 20 quantitation.
 
d.     As requested in our October 1, 2009, Information Request [item #10c.C)], please provide results to complete the –b(4)-------------- DNA assay validation.
 
8.     Outstanding inspectional issues identified on the FDA Form 483 dated October 23, 2009, were issued at the conclusion of the pre-approval inspection of your Meriden, Connecticut location. You must satisfactorily resolve these issues. Comments regarding review of your November 13, 2009, response to the FDA Form 483 will be communicated in a separate letter.
 
We acknowledge receipt of your amendment dated December 18, 2009, and are aware that this amendment may address some of the outstanding items listed above. Please be aware that we have stopped the review clock with the issuance of this letter. We will reset and start the review clock when we receive your complete response. You may cross reference applicable sections of the amendment dated December 18, 2009, in your complete response to this letter and we will review those sections as a part of your complete response.
 
We acknowledge that you have included a Pharmacovigilance plan in your BLA; however, we reserve our comments on this proposal for later, when this application is found suitable for approval. Depending on subsequent CBER evaluation and final labeling, CBER may request additions to the Pharmacovigilance plan. 
 
Review and comment on the proposed final labeling will be completed when the application is otherwise acceptable. Extensive revision of the proposed final labeling may be required based on any additional information relating to the safety and effectiveness of this drug product.
 
The Pediatric Research Equity Act (PREA) requires that all NDAs, BLAs, or supplemental applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration contain a pediatric assessment unless a waiver or deferral has been obtained. Your proposed Pediatric Plan was presented to the Pediatric Review Committee (PeRC) on December 2, 2009. The Committee agreed with your proposal to defer studies in children and adolescents 6 months to less than 18 years of age and to waive studies in infants less than 6 months of age. However, the PeRC requests that you submit a more formal proposal and timeline to study FluBlok in children 6 to 35 months (similar to the proposals submitted for the age groups 3 to 8 years and 9 to 17 years). We realize that the specifics of this study will depend on results from the proposed studies in older children. Therefore, please submit as detailed a plan for this population as is feasible at this time, and similar in format to the proposals submitted for the age groups 3 to 8 years and 9 to 17 years.
 
We stopped the review clock with the issuance of this letter. We will reset and start the review clock when we receive your complete response.
 
Within 10 days after the date of this letter, you should take one of the following actions: (1) amend the application; (2) notify us of your intent to file an amendment; or (3) withdraw the application.
 
You may request a meeting or teleconference with us to discuss the steps necessary for approval. For PDUFA products please submit your meeting request as described in our “Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products,” dated February 2000. This document is available on the internet at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079744.pdf or may be requested from the Office of Communication, Outreach, and Development, at (301) 827-1800. For non-PDUFA products, please contact the regulatory project manager. For details, please also follow the instructions described in CBER’s SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants. This document also is available on the internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079448.htm, or may be requested from the Office of Communication, Outreach, and Development.
 
Please be advised that, as stated in 21 CFR 601.3(c), if we do not receive your complete response within one year of the date of this letter, we may consider your failure to resubmit to be a request to withdraw the application. 
Reasonable requests for an extension of time in which to resubmit will be granted. However, failure to resubmit the application within the extended time period may also be considered a request for withdrawal of the application.
 
 
If you have any questions regarding the above, please contact the Regulatory Project Managers, Katherine Matrakas or Timothy Fritz at (301) 827-3070.
 
Sincerely yours,
 
 
 /s/
 
Wellington Sun, M.D.

 

Director
Division of Vaccines and
  Related Product Applications
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research