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U.S. Department of Health and Human Services

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April 1, 2014 Approval Letter - ORALAIR

Our STN:  BL 125471/0

Stallergenes S.A.
Attention:  Thomas Lang, Ph.D.
6, rue Alexis de Tocqueville
92183 Antony Cedex, France

Dear Dr. Lang:

We are issuing Department of Health and Human Services U.S. License No. 1893 to Stallergenes S.A., Antony Cedex, France, 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 Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract.   Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract is indicated as immunotherapy for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for any of the five grass species contained in the product.  Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract is approved for use in persons 10 through 65 years of age. 

The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT00955825, NCT00619827, NCT00409409, NCT00367640, and NCT00418379.

Under this license, you are authorized to manufacture Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract. Commercial manufacturing will be distributed among the following facilities:  Stallergenes S.A., located in Antony Cedex, France; and two contract facilities, --------------------------------------------------------------(b)(4)-------------------------------------------------------------. The manufacture of Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract will take place at the Antony Cedex facility. Final Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract formulation, filling, labeling and packaging will occur at --------------------(b)(4)-----------------------. You may label your product with the proprietary name ORALAIR® and you may market it in 100 IR and 300 IR tablets for sublingual use.

The dating period for Sweet Vernal, Orchard, Perennial Rye Timothy, and Kentucky Blue Grass, Mixed Pollens Allergen Extract shall be 36 months from the date of manufacture when stored at 20 - 25°C, for -----------(b)(4)----------------.  The dating period for Sweet Vernal, Orchard, Perennial Rye Timothy, and Kentucky Blue Grass, Mixed Pollens Allergen Extract shall be 24 months from the date of manufacture when stored at 20 - 25°C, for ---------------------------(b)(4)----------------------. The date of manufacture shall be defined as the date of weighing of the first ingredient when the drug product manufacturing process is initiated.

Please submit samples of the final blister package drug product together with protocols showing results of all applicable tests.  You may not distribute any lots of product until you receive a notification of release from the Director, Center for Biologics Evaluation and Research (CBER).

You must submit information to your Biologics License Application (BLA) 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 Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract, 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 Part 208, we have determined that this product poses a serious and significant public health concern requiring the distribution of a Medication Guide.  Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract is a product for which patient labeling could help prevent serious adverse effects and inform the patient of serious risks relative to benefit that could affect their decisions to use, or continue to use, the product.  Therefore, a Medication Guide is necessary for safe and effective use of this product and FDA hereby approves the draft Medication Guide you submitted March 27, 2014.  Please note that:

  • Under 21 CFR 201.57 (c)(18) this Medication Guide must be reprinted at the end of the package insert;
  • Under 21 CFR 208 you are responsible for ensuring that this Medication Guide is available for distribution to every patient who is dispensed a prescription for this product;
  • The final printed Medication Guide distributed to patients must conform to all conditions described in 21 CFR 208.20, including a minimum of 10 point text; and
  • You are responsible for ensuring that the label of each container or package includes a prominent and conspicuous instruction to authorized dispensers to provide a Medication Guide to each patient to whom the drug is dispensed, and states how the Medication Guide is provided.

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 and FDA Form 2567 as appropriate.

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, Food and Drug Administration, 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.
 
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 children less than 5 years because necessary studies are impossible or highly impracticable. This is because the number of children younger than 5 years of age with allergic rhinitis who have been diagnostically confirmed with sensitivity to one or more of the allergens in Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract is too small.       

We are deferring submission of your pediatric study for ages 5 to <10 years for this application because this product is ready for approval for use in adult and pediatric patients 10 years of age and older and the pediatric study in ages 5 to <10 years has not been completed.

Your deferred pediatric study required under 505B(a) of the Federal Food, Drug, and Cosmetic Act is a required postmarketing study.  The status of this postmarketing study must be reported annually according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.  This required study is listed below:
 

1. Deferred pediatric study (Study 140224) under PREA for immunotherapy for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for any of the five grass species contained in the product. 

Final Protocol Submission: June 30, 2014

Study Completion Date: June 30, 2016

Final Report Submission: December 31, 2016

Please submit the final study reports to this BLA.  For administrative purposes, all submissions related to this required pediatric postmarketing study must be clearly designated “Required Pediatric Assessment(s).”

We note that you have fulfilled the pediatric study requirement for ages 10 to 17 years of age.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your submission of March 14, 2014, as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

2. To conduct an observational postmarketing study (Study 140225) to further describe the safety profile in approximately 6,000 patients 10 to 65 years of age receiving Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract  approximately 4 months before the expected onset of the grass pollen season and throughout the grass pollen season.

Final Protocol Submission: July 31, 2014

Study Completion Date: December 31, 2017

Final Report Submission: June 30, 2018

For postmarketing studies subject to reporting requirements of 21 CFR 601.70, please submit clinical protocols to your IND 13776, with a cross-reference letter to this BLA, STN BL 125471. Submit all study final reports to your BLA, STN BL 125471.  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 requirements or commitments as appropriate:

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

In addition, for the deferred pediatric study, Study 140224, we request that you also use the following designation on all submissions:

  • “Required Pediatric Assessment”

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.  Please label your annual report as “Annual Status Report of Postmarketing Study Requirements/Commitments.”  The status report for each study should include:

  • information to identify and describe the postmarketing requirement or commitment,
  • the original schedule for  the requirement or commitment,
  • the status of the requirement or 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. 

Sincerely yours,

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

Marion F. Gruber, Ph.D
Director
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research