Vaccines, Blood & Biologics

July 16, 2014 Approval Letter - RUCONEST

Our STN: BL125495/0                                                                                     

Pharming Group NV
Attention:  Ms. Zohra Lomri
Salix Pharmaceuticals, Inc.
8510 Colonnade Center Drive
Raleigh, NC  27615

Dear Ms. Lomri:

We are issuing Department of Health and Human Services U.S. License No. 1857 to Pharming Group NV, (Leiden, the Netherlands), 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 C1 Esterase Inhibitor (Recombinant).  C1 Esterase Inhibitor (Recombinant) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adult and adolescent patients.

The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT01188564; NCT00262301; NCT00225147; NCT00851409; and NCT01397864.

Under this license, you are approved to manufacture C1 Esterase Inhibitor (Recombinant) drug substance at ----------------(b)(4)------------------.  The finished drug product will be manufactured at --------(b)(4)--------, the Netherlands, and labeled and packaged at -----------(b)(4)--------------------, the Netherlands.  You may label your product with the proprietary name RUCONEST and will market it in 2100 IU per vial fill size.

We did not refer your application to the Blood Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.

The dating period for C1 Esterase Inhibitor (Recombinant) shall be 48 months from the date of manufacture when stored at 2 °C to 25 °C.  The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product in accordance with 21 CFR 610.50.  Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency.  The dating period for your drug substance shall be -------------------(b)(4)-------------.

You currently are not required to submit samples of future lots of RUCONEST 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 C1 Esterase Inhibitor (Recombinant) , or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14.  You should identify and investigate all manufacturing deviations promptly, 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, 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

Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert.  We request that the text of information distributed to patients be printed in a minimum of 10-point font.

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 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)).

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 Office of Biostatistics and Epidemiology, 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

Prominently identify all adverse experience reports as described in 21 CFR 600.80. 

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.

Because the biological product for this indication has an orphan drug designation, you are exempt from this requirement.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your letters of June 30, 2014, July 3, 2014, and July 15, 2014 as outlined below:

Postmarketing Study subject to reporting requirements of 21 CFR 601.70.

  • Pharming commits to conduct a study consisting of establishment and maintenance of a registry of HAE patients 13 years of age and older who are prescribed RUCONEST without plasma-derived C1 esterase inhibitors to evaluate the incidence of adverse events and time to symptom relief, as well as to characterize hypersensitivity reactions, thrombotic events, and the safety profile in pregnant and nursing women in the treatment of acute attacks of HAE in adult and adolescent patients.  The study will continue until either a) three years have elapsed, or b) 100 patients have been enrolled, 35 of whom will be treated with RUCONEST for at least three attacks.

Final Protocol Submission Date:   January 16, 2015
Study Completion:   July 16, 2018
Final Study Report:   January 16, 2019

Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL125495.  Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL125495.  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. 

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

2.   Pharming commits to perform stability studies for DP batches -----------------------(b)(4)--------------- (which were produced from the DS manufactured at ----(b)(4)-----) up to -------(b)(4)----.  The stability study results will be submitted annually in a PMC Submission- Status Update until completion.

3.   Pharming commits to performing a long-term post-approval stability study for these three batches, -------------(b)(4)-----------------, which were produced from the DS manufactured   at ----(b)(4)----.  Stability data will be submitted annually in a PMC Submission-Status             Update.

4.   In addition, at least one production lot will be placed on stability annually after approval. The data will be submitted in a PMC Submission-Status Update.

5.   Pharming commits to submitting a quantitative procedure for the determination of the       impurities ---------------(b)(4)------------ along with validation data to replace the limits
test described in the initial submission. The quantitative procedure and validation data                  will be submitted to the BLA as a CBE-30 supplement no later than January 15, 2015. 

6.   During the pre-license inspection it was noted that ---------------(b)(4)------------------- is not assessed in the performance qualification for the ---(b)(4)---.

        Pharming agrees to the following PMC:

     A test method will be developed and implemented to demonstrate --------------------------------------------------(b)(4)------------------ by July 1, 2014.  The current qualification for ----(b)(4)--------------- will be amended by performing a prospective performance qualification study on
the -------------------(b)(4)------------------------- by December 15, 2014.  The qualification of the -------(b)(4)------ will be submitted as a PMC Submission-Final Study Report by January 31, 2015.

7.   During the pre-license inspection it was noted that the performance and validation of the container closure integrity test was not adequately performed.

        Pharming agrees to the following PMC:

 An appropriate container closure integrity test method will be developed and validated     and the actual final product container closure will be tested.  The method will be  validated and the vials tested by September 30, 2014.  The final report for the container closure integrity testing will be submitted as a PMC Submission-Final Study Report by October 31, 2014.  The report will include information such as a complete description of   test method and test parameters, test sensitivity, limit of detection, correlation of defect to microbial size, and a description of positive and negative control.

We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL125495.

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 601.70, 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.

PDUFA V APPLICANT INTERVIEW

FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing. The purpose of the interview is to better understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review.

ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments.

Sincerely yours,                                              

Mary A. Malarkey                                           Jay S. Epstein, MD                                        
Director                                                          Director                                                                      
Office of Compliance and                               Office of Blood Research and Review
Biologics Quality                                            Center for Biologics 
Center for Biologics                                          Evaluation and Research     
Evaluation and Research                                                                                           

Enclosure

 

Resources for You

Page Last Updated: 03/09/2015
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.