Vaccines, Blood & Biologics

October 29, 2014 Approval Letter - Flublok

October 29, 2014

ACCELERATED SUPPLEMENT APPROVAL

Our STN: BL 125285/78

Protein Sciences Corporation
Attention: Penny Post, Ph.D.
1000 Research Parkway
Meriden, CT 06450-7159

Dear Dr. Post:

We have approved your request to supplement your biologics license application for Influenza Vaccine (Flublok) manufactured at your Meriden, CT facility to include use in persons 50 years of age and older according to the regulations for accelerated approval, 21 CFR 601.40-46.

The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT00395174, NCT00539864 and NCT01825200.

We are granting marketing approval of this product for use in persons 50 years of age and older under the accelerated approval of biological products regulations, 21 CFR 601.40-46.  Under these regulations we may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.  This approval requires you to study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome.

Approval of Flublok for use in persons 50 years of age and older under these regulations requires, among other things, that you conduct adequate and well-controlled studies to verify and describe clinical benefit attributable to this product.  Clinical benefit is evidenced by prevention of influenza disease. 

Accelerated Approval Required Study

We remind you of your postmarketing requirement specified in your submission of September 29, 2014 and as clarified in an October 9, 2014 teleconference.

  1. To conduct a confirmatory clinical efficacy and safety study (PSC12) in adults 50 years of age and older for active immunization for the prevention of disease caused by influenza virus subtypes A and types B contained in your investigational quadrivalent influenza vaccine manufactured according to the same process as Flublok

Final Protocol Submission: October 21, 2014

Study/Trial Completion: June 30, 2016

Final Report Submission: June 30, 2017

We expect you to complete design, initiation, accrual, completion, and reporting of this study within the framework described in your letter of September 29, 2014.

You must conduct the study with due diligence. If postmarketing studies fail to verify that clinical benefit in persons 50 years of age and older is conferred by Flublok, or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 601.43 (b), withdraw or modify approval for use in this age group if:

  • A postmarketing clinical study fails to verify clinical benefit
  • The applicant fails to perform the required postmarketing study with due diligence
  • Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product
  • The applicant fails to adhere to the postmarketing restrictions agreed upon
  • The promotional materials are false or misleading
  • Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.

Submit final study reports to this BLA as a supplemental application. For administrative purposes, all submissions relating to this postmarketing study requirement must be clearly designated as “Subpart E Postmarketing Study Requirements.”

Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels. In addition, please submit three original paper copies for carton and container final printed labeling. All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h.

In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.

Please note that the accelerated approval regulation concerning promotional materials (21 CFR 601.45) stipulates that all advertising and promotional labeling items that you wish to distribute in the first 120 days following approval, must have been received by FDA prior to the approval date.

After approval, promotional items intended for dissemination after the first 120 days following approval must be submitted to the FDA 30 days prior to the anticipated distribution date. Please submit draft materials with a cover letter noting that the items are for accelerated approval, and an accompanying Form FDA 2253 to the Advertising and Promotional Labeling Branch at the following address:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Ave.
WO71-G112
Silver Spring, MD 20993-0002

You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).

All promotional claims must be consistent with and not contrary to approved labeling. You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).

Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes these changes.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitment as described in your letter of September 29, 2014, and as clarified in an October 9, 2014, teleconference as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

  1. To conduct an observational postmarketing safety study (PSC13) in approximately 25,000 Flublok recipients 18 years of age and older to further characterize the safety profile of Flublok using recipients of U.S.-licensed, egg-based, trivalent or quadrivalent inactivated influenza virus vaccines as a comparator, with appropriate adjustment or matching for important covariates such as sex and age.

Final protocol submission date: April 30, 2015

Study/trial completion date: June 30, 2017

Final Report Submission date: June 30, 2018

We have concluded that you are released from conducting PMC #4 identified in the January 16, 2013 approval letter:

To conduct an observational postmarketing safety study in approximately 25,000 Flublok recipients aged 18 to 49 years to further characterize the safety profile of Flublok using recipients of egg-based, trivalent inactivated influenza virus vaccine as a comparator with appropriate adjustment or matching for important covariates such as sex and age.

We are administratively releasing you from that PMC because the study will be conducted under PMC #2 listed above.

Please submit clinical protocols to your IND 11951, with a cross-reference letter to this biologics license application (BLA), STN BL 125285/78. Submit all study final reports to your BLA STN BL 125285. If the information in the final study report supports a change in the labeling, the final study report should be submitted as a supplement. We may also request a supplement if we think labeling changes are needed. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Study Commitment Protocol
  • Postmarketing Study Correspondence
  • Postmarketing Study Commitment – Final Study Report
  • Supplement Contains Postmarketing Study Commitments – Final Study Report

For each postmarketing study subject to the reporting requirements of 21 CFR 601.70, you must describe the status in an annual report on postmarketing studies for this product. Label your annual report an “Annual Status Report of Postmarketing Study Commitments.” The status report for each study should include:

  • information to identify and describe the postmarketing commitment,
  • the original schedule for the commitment,
  • the status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted), and
  • an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).

As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our Web site (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm). Please refer to the February 2006 Guidance for Industry: Reports on the Status of Postmarketing Studies – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf) for further information.

We will include information contained in the above-referenced supplement in your biologics license application file.

Sincerely yours,

Wellington Sun, M.D.
Director
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research

Attachment: Approved Final Draft Labeling

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