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U.S. Department of Health and Human Services

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June 21, 2011 Approval Letter - Laviv

Our STN:  BL 125348/0                                                                  

Fibrocell Technologies, Inc.
Attention: Jeanne M. Novak, Ph.D.
CBR International Corporation
2905 Wilderness Place, Suite 202
Boulder, CO  80301

Dear Dr. Novak:

We are issuing Department of Health and Human Services U.S. License No. 1818 to Fibrocell Technologies, Inc., Exton, PA, under the provisions of section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products.  The license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.

Under this license, you are authorized to manufacture the product azficel-T.  Azficel-T is indicated for the improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults.  The safety and efficacy of azficel-T for areas other than the nasolabial folds have not been established.  The efficacy of azficel-T beyond six months has not been established.

The review of this product was associated with the following National Clinical Trial (NCT) numbers: 00649428, 00655356, and 00654654.

Under this license, you are approved to manufacture azficel-T at your facility in Exton, PA.  You may label your product with the proprietary name LAVIV and market it in 2 milliliter cryovials.

The dating period for azficel-T shall be 24 hours from the date of manufacture when stored at 2-8°C. The date of manufacture shall be defined as the time of shipment.

You currently are not required to submit samples of future lots of azficel-T to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, under 21 CFR 610.2.  We will continue to monitor compliance with 21 CFR 610.1 requiring completion of tests for conformity with standards applicable to each product prior to release of each lot.

You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing, packaging or labeling of azficel-T, or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14.  You should promptly identify and investigate all manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution.  If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulation, you must submit a report on Form FDA-3486 to the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.

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
.

You may submit two draft copies of the proposed introductory advertising and promotional labeling with an FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. 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)).

ADVERSE EVENT REPORTING
You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports as described in 21 CFR 600.81.  You should submit postmarketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology HFM-210, Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448.  Prominently identify all adverse experience reports as described in 21 CFR 600.80.  Per 21 CFR 600.2(f), please refer to http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.

PEDIATRIC REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.

We are waiving the pediatric study requirement for this application because this product is not likely to be used in a substantial number of pediatric patients. The product is a human autologous cell therapy which has very limited applicability to pediatric patients for the improvement of nasolabial fold wrinkles because this condition occurs only in the adult population.

POSTMARKETING REQUIREMENTS UNDER 505(o)

Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)). 

We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of systemic hypersensitivity reactions and to identify an unexpected serious risk of skin cancer in the area of azficel-T administration because available data indicates the potential for such a risk.

Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.

Therefore, based on appropriate scientific data, we require that you conduct the following study:

1.  A post-marketing study, based on a registry design, to assess the risk of skin cancer in the area of azficel-T injections and the risk of immune-mediated hypersensitivity reactions in 2700 patients who receive azficel-T.

We acknowledge the timetable you submitted on May 6, 2011, which states that you will conduct this study according to the following schedule:

Final Protocol Submission: September 30, 2011

Study Completion Date: September 30, 2016

Final Report Submission: December 31, 2016

Interim reports must be submitted to the FDA every six months for the duration of the study. These reports must include the total number of patients treated thus far; the number of patients enrolled in the registry categorized by age, gender, and skin type; the proportion of subjects for whom you successfully obtained follow-up information; the proportion of subjects with reports of outcomes specified in the study protocol categorized by age, skin type, and length of time since injection; your assessment of this accumulating data; and your assessment of whether any difficulties in completing the registry study have been encountered.

Please submit the protocol to your IND -(b)(4)- with a cross-reference letter to this BLA.  Submit all final reports to this BLA and prominently identify them as appropriate: 

  • Required Postmarketing Protocol under 505(o)
  • Required Postmarketing Final Report under 505(o)
  • Required Postmarketing Correspondence under 505(o)

Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any  study or clinical trial required under this section.  This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue.  Section 506B of the FDCA, as well as, 21 CFR 601.70, requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.

We will consider the submission of your annual report under section 506B and 21 CFR 601.70 to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 601.70.  We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue.  Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your letter of May 27, 2011 as outlined below:

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.

2.         --------------------------------------------(b)(4)--------------------------------------------------          --------------------------------------

--------------------------------------------(b)(4)----------------------------------------------------        ------------------------------------------

--------------------------------------------(b)(4)-------------------------------------------------------   --------------------------------------------------------------

--------------------------------------------(b)(4)--------------------------------------------------------- ----------------------------------------------------------------------------------------------------------   -----------------------------

We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL 125348.

Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

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

For each postmarketing commitment not subject to the reporting requirements of 21 CFR 610.70, you may report the status to FDA as a “PMC Submission – Status Update.”  The status report for each commitment should include:

  • The original schedule for the commitment, and
  • The status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted).

When you have fulfilled your commitment, submit your final report as PMC Submission – Final Study Report or Supplement Contains Postmarketing Study Commitment – Final Study Report.

Sincerely yours,   

                                            

Mary A. Malarkey  
Director 
Office of Compliance and  Biologics Quality
Center for Biologics Evaluation and Research   

 

Celia M. Witten, Ph.D., M.D
Director 
Office of Cellular, Tissue and Gene Therapies
Center for Biologics Evaluation and Research