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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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March 22, 2013 Approval Letter - BAT

DEPARTMENT OF HEALTH & HUMAN SERVICES                                                     Public Health Service
 


                                                                                                                            Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448

 

 

Our STN: BL 125462/0
 
Cangene Corporation
Attention: Mr. Terry Kraynyk
155 Innovation Drive
Winnipeg, Manitoba R3T 5Y3
Canada
 
Dear Mr. Kraynyk:
 
We have approved your biologics license application for Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) effective this date.   You are hereby authorized to introduce or deliver for introduction into interstate commerce, Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) under your existing Department of Health and Human Services U.S. License No. 1201. Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) is indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients.
 
Under this authorization, you are approved to manufacture Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) at your facility in Winnipeg, Manitoba, Canada. You may label your product with the proprietary name BAT and will market it as 20 and 50 mL vials containing no less than 4,500 Units (U) for serotype A antitoxin, 3,300 U for serotype B antitoxin, 3,000 U for serotype C antitoxin, 600 U for serotype D antitoxin, 5,100 U for serotype E antitoxin, 3,000 U for serotype F antitoxin, and 600 U for serotype G antitoxin regardless of fill volume.  
 
The dating period for Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine), stored at
-20 oC + 5 oC is defined on a lot-by-lot basis, and shall be as indicated in Table 1.


 

Table 1. Dating period for BAT
lot
Dating period when stored at
-20 ±5 °C
(months)
2060401
114
10703057
78
10804879
66
10804882
66
10804883
66
10906017
66
10805011
54
10805253
54
10805254
54
10805294
54
10805299
54
10906018
54
10906136
54
10906149
54
10906166
54
10906167
54
 
Lots manufactured subsequent to those listed in the above table should be stored for a maximum of 48 months if stored at -20 ±5 °C. Once thawed, Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) may be stored for a maximum of 36 months at 2-8 oC or until 48 months from the date of manufacture, whichever comes first.  Do not refreeze.
 
Lot 2060401 that is currently stored at 2-8 oC will expire November 22, 2013.  
 
The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency. 
 
You currently are not required to submit samples of future lots of Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) 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 Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine), 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, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.
 
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 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. 
 
In addition, you must submit adverse event reports for any infectious disease transmission within 15 days after learning of the event. Infectious disease transmission refers to an adverse event that involves suspected or confirmed transmission of an infectious agent, whether the recipient develops the infectious disease or only has serologic or other evidence. If an infectious disease transmission event is serious and unexpected, you must submit a 15-day “alert report,” as required under 21 CFR 600.80 (c)(1)(i). Infectious disease transmission events that do not meet criteria for expedited submission require periodic reports and must be submitted as individual case reports within 15 days, as authorized under 21 CFR 600.80(c)(2)(i). You should submit reports for all other non-expedited adverse events under the periodic reporting requirements specified in 21 CFR 600.80(c)(2).
 
You must submit as 15-day expedited report (i) all serious reports (labeled and unlabeled), and (ii) non-serious reports related to hypersensitivity/allergic reactions including serum sickness; febrile reactions; and hemodynamic instability and bradycardia.
 
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.
 
SUBPART H APPROVAL REQUIREMENTS
 
Approvals under 21 CFR Part 601, Subpart H (Approval of Biological Product When Human Efficacy Studies Are Not Ethical or Feasible) are subject to three requirements: 
  1. Approval with restrictions to ensure safe use.  
 
This subsection permits the Agency to require postmarketing restrictions as are needed to ensure safe use of the drug product, commensurate with the specific safety concerns presented by the drug product.  We have concluded that Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) can be safely used without restrictions on distribution or use.
 
  1. Information to be provided to patient recipients.
 
This subsection requires applicants to prepare labeling to be provided to patient recipients for drug products approved under this subpart.  We have concluded that the FDA-Approved Patient Labeling for Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) meets the requirements of this subsection.  We remind you that the Patient Labeling must be available with the product to be provided, when possible, prior to administration or dispensing of the drug product for the use approved under this subpart.
 
  1. Postmarketing Studies.
 
This subsection requires you to conduct postmarketing studies, such as field studies, to verify and describe the biological product's clinical benefit and to assess its safety when used as indicated when such studies are feasible and ethical.
  
1.   We refer to your letter dated March 18, 2013, stating that you agree to re-initiate the BAT patient registry in the event of a mass botulism exposure scenario.  The registry will evaluate the safety and clinical benefit of Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) used to treat adult, pediatric and infant patients with a confirmed or suspected exposure to botulism.  We acknowledge the timetable you submitted on March 18, 2013 which states that you will conduct this study according to the following schedule:
 
                        Final Study Protocol Submission:     May 2014
 
                        Final Study Completion Date:           12 months after date of mass exposure
                       
                        Final Study Report Submission:        18 months after date of mass exposure
 
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 identify an unexpected serious risk of hemodynamic instability and/or bradycardia when the available data indicate the potential for a serious 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.
 
Clinical study to further assess these risks is needed as the completed studies are considered too small to reliably identify the unexpected serious risk. Therefore, based on appropriate scientific data, we have determined that you are required to conduct the following studies:
 
2. Three-year Patient Registry
 
Cangene commits to conducting a patient registry study for 3 years to evaluate safety following BAT administration in adult, pediatric and infant patients with a confirmed or suspected exposure to botulism.
 
We acknowledge the timetable you submitted on March 18, 2013, which states that you will conduct this study according to the following schedule:
 
Final Study Protocol Submission:                 October 2013
 
Final Study Completion Date:                       June 2017
 
Final Study Report Submission:                    December 2017
 
Please submit the protocols to your IND 12052, with a cross-reference letter to BLA 125462/0. 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 letters of March 18, 2013 and March 21, 2013 as outlined below:
 
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
 
3.   Pediatric PK Study
 
Cangene commits to conducting a pharmacokinetic (PK) study in pediatric patients to verify the pediatric dosing recommendations for BAT. A study protocol and final study report will be submitted as PMR Submissions according to the following timelines:
 
Final Study Protocol Submission:                 October 2013
 
Final Study Completion Date:                       June 2017
 
Final Study Report Submission:                    December 2017
 
Please submit clinical protocols to IND 12052, with a cross-reference letter to BLA 125462/0. Submit protocols and all study final reports to your BLA STN BL 125462/0. 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.  
 
4.   Cangene commits to -------------------------------------(b)(4)-------------------------------------------------------------, and submitting a concurrent validation for --------------(b)(4)------------------. A modified SOP and/or batch record limiting -----(b)(4)----- will be submitted as a CBE30 within 60 days of approval.
 
5.   Cangene commits to re-validating the maximum hold time for the --------(b)(4)------         -------------------------------------------------------------------------------------------------------       --------------------------------------------------------------------------------------------------------      -------------------------------------------------------, within 1 year of approval. The validation will be performed with at least 3 lots of each solution held at the maximum time requested. The validation study report will be submitted as a PMC-Final Study Report within 60 days of completion.
 
6.     Cangene commits to re-validating the hold time for ------------------(b)(4)------------------------------------------------------------------------------------------------------------. The validation will be performed with the next ------------------------(b)(4)------------------------------ lots, which will be held at the maximum time requested. The validation study report will be submitted as a PMC-Final Study Report within 60 days of completion.
 
7.     Cangene commits to perform a process validation study prior to the manufacture of any new lots of BAT bulk drug substance.  The process validation will include at least two lots, one of which may be a simulated batch manufactured with normal or low anti-botulinum titer equine plasma.  If normal equine plasma is used, a feasible biological endpoint such as tetanus, rabies, or West Nile Virus antibody measures can be used in lieu of botulinum neurotoxin neutralization levels for the purpose of monitoring biological activity in the simulated bulk drug substance.  The process validation protocol (including equipment requalification) will be submitted as a Postmarketing Study Correspondence at least 60 days prior to execution of the process validation, and the final validation report will be submitted within 60 days of completion as a Prior Approval Supplement.
 
8.     Cangene commits to developing a qualified ----(b)(4)--- test for detection and quantification of canine hepacivirus and GBV-like viruses in equine plasma.  This test will be used to quantitate canine hepacivirus and GBV-like viruses in retention samples from plasma used to manufacture lots of BAT currently maintained in the Strategic National Stockpile.  The results of this testing will be used to develop a risk assessment based on the qualified BAT manufacturing viral clearance process and to establish an upper limit for screened plasma units and manufacturing pools for canine hepacivirus and GBV-like viruses.  The ----(b)(4)---- test validation, retention sample results, and risk assessment will be submitted as a Prior Approval Supplement by 22 September 2013. 
 
9.     Cangene commits to add additional Serotype A potency testing to stability protocols according to the following time points (0, 36, 48, -----(b)(4)----- months) for lots of BAT drug product currently on reduced stability testing.  Results will be reported in a PMC- annual report.  The final results of stability profiles for these lots will be reported 6 months after the final lot reaches the -(b)(4)- month time point, as a PMC-final study report.
 
10. Cangene commits to perform a container closure integrity test that utilizes the -(b)(4)- ------------------------------------------------------------------------------------------------- ------------------------------------------------------------------- area that utilizes appropriate positive controls that approximate a critical or worst case leak and that challenges the vials under extremes of pressure.  The results of the container closure integrity study will be submitted by the end of September 2013.  The data will be submitted as a PMC submission - Final Study Report by September 30, 2013.
 
11. Cangene commits to performing a concurrent stability study for BAT lot 2060401, stored at 2ºto 8º C.  The stability protocol will be submitted to the BLA as a CBE-30, within 1 month of licensure.
 
We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL 125462.
 
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.
 
 
Sincerely yours,
 
 
 
Jay S. Epstein, MD
Director
Office of Blood Research and Review
Center for Biologics
 Evaluation and Research