Vaccines, Blood & Biologics

April 17, 2014 Approval Letter - RAGWITEK

Our STN:BL 125478/0

Merck Sharp & Dohme Corp.

Attention: Scott Greenfeder, Ph.D.

Associate Director, Worldwide Regulatory Affairs

126 E. Lincoln Avenue

Rahway, NJ 07065

Dear Dr. Greenfeder:

We have approved your biologics license application for Short Ragweed Pollen Allergen Extract effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Short Ragweed Pollen Allergen Extract under your existing Department of Health and Human Services U.S. License No. 0002.Short Ragweed Pollen Allergen Extract is indicated as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen. RAGWITEK is approved for use in adults 18 through 65 years of age.

The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT01469182, NCT00978029, NCT00770315, and NCT00783198.

Under this license, you are approved to manufacture Short Ragweed Pollen Allergen Extract drug substance at ALK-Abello A/S in Horsholm, Denmark. The final formulated product will be manufactured, filled, labeled, and packaged at Catalent Pharma Solutions Limited in Wiltshire, United Kingdom. You may label your product with the proprietary name RAGWITEK and will market it as a tablet for sublingual use with a potency of 12 Amb a 1-Unit of short ragweed (Ambrosia artemisiifolia) pollen allergen extract and supplied in 10-tablet all aluminum blister packages.

The dating period for Short Ragweed Pollen Allergen Extract Tablet for Sublingual Use shall be 36 months from the date of manufacture when stored at 20°C-25°C.The date of manufacture shall be defined as the date when the drug substance is added to the excipient solution.

You must submit 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 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 Short Ragweed Pollen 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. RAGWITEK 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 April 16, 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 BLAat 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 .

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.

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 Short Ragweed pollen is too small.

We are deferring submission of your pediatric studies for ages 5 to 17 years for this application because this product is ready for approval for use in adults and the pediatric studies have not been completed.

Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and Cosmetic act are required postmarketing studies. The status of these postmarketing studies must be reported annually according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.

These required studies are listed below:

1. Deferred pediatric study, protocol #P008, under PREA to evaluate both safety and efficacy of RAGWITEK as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen in pediatric subjects aged 5 to 17 years.

Final Protocol Submission: December 31, 2014

Study Completion Date: December 31, 2018

Final Report Submission: September 30, 2019

2. Deferred pediatric study, protocol #P009, under PREA to evaluate safety of RAGWITEK as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen in pediatric subjects aged 5 to 17 years.

Final Protocol Submission: June 30, 2016

Study Completion Date: September 30, 2017

Final Report Submission: September 30, 2019

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

AGREED UPON POSTMARKETING COMMITMENTS

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

We acknowledge your written commitments as described in your letter of April 9, 2014, to conduct the studies outlined below:

3. A postmarket claims-based study to further describe the safety profile of RAGWITEK in marketed use in the United States. The study will enroll all new users of RAGWITEK identified through claims data from a large U.S. health insurance database for a period of at least three years from launch of RAGWITEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both postmarketing studies. Outcomes of interest identified through claims data will be verified using medical record review.

Final protocol submission date: January 31, 2015

Study completion date: June 30, 2017 (projected)

Final Report Submission date: June 30, 2018 (or one year after study completion date, whichever is later).

4. A postmarket electronic medical record study to further describe the safety profile of RAGWITEK in marketed use in the United States. The study will enroll all new users of RAGWITEK identified through electronic medical records in a large U.S. integrated health system for a period of at least three years from launch of RAGWITEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both postmarketing studies. This study will include early exposures to RAGWITEK, including administration through starter packs provided in physician offices as well as all subsequent exposures.

Final protocol submission date: November 30, 2015

Study completion date: June 30, 2017 (projected)

Final Report Submission date: June 30, 2018 (or one year after study completion date, whichever is later).

For postmarketing studies subject to reporting requirements of 21 CFR 601.70, please submit clinical protocols to your IND 12970, with a cross-reference letter to this BLA, STN BL 125478. Submit all study final reports to your BLA, STN BL 125478. 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.)

Sincerely yours,

Marion F. Gruber, Ph.D.

Director

Office of Vaccines

Research and Review

Center for Biologics

Evaluation and Research

Attachment: Approved Final Draft Labeling

Our STN:BL 125478/0

Merck Sharp & Dohme Corp.

Attention: Scott Greenfeder, Ph.D.

Associate Director, Worldwide Regulatory Affairs

126 E. Lincoln Avenue

Rahway, NJ 07065

Dear Dr. Greenfeder:

We have approved your biologics license application for Short Ragweed Pollen Allergen Extract effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Short Ragweed Pollen Allergen Extract under your existing Department of Health and Human Services U.S. License No. 0002.Short Ragweed Pollen Allergen Extract is indicated as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen. RAGWITEK is approved for use in adults 18 through 65 years of age.

The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT01469182, NCT00978029, NCT00770315, and NCT00783198.

Under this license, you are approved to manufacture Short Ragweed Pollen Allergen Extract drug substance at ALK-Abello A/S in Horsholm, Denmark. The final formulated product will be manufactured, filled, labeled, and packaged at Catalent Pharma Solutions Limited in Wiltshire, United Kingdom. You may label your product with the proprietary name RAGWITEK and will market it as a tablet for sublingual use with a potency of 12 Amb a 1-Unit of short ragweed (Ambrosia artemisiifolia) pollen allergen extract and supplied in 10-tablet all aluminum blister packages.

The dating period for Short Ragweed Pollen Allergen Extract Tablet for Sublingual Use shall be 36 months from the date of manufacture when stored at 20°C-25°C.The date of manufacture shall be defined as the date when the drug substance is added to the excipient solution.

You must submit 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 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 Short Ragweed Pollen 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. RAGWITEK 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 April 16, 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 BLAat 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, 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 Short Ragweed pollen is too small.

We are deferring submission of your pediatric studies for ages 5 to 17 years for this application because this product is ready for approval for use in adults and the pediatric studies have not been completed.

Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and Cosmetic act are required postmarketing studies. The status of these postmarketing studies must be reported annually according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.

These required studies are listed below:

1. Deferred pediatric study, protocol #P008, under PREA to evaluate both safety and efficacy of RAGWITEK as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen in pediatric subjects aged 5 to 17 years.

Final Protocol Submission: December 31, 2014

Study Completion Date: December 31, 2018

Final Report Submission: September 30, 2019

2. Deferred pediatric study, protocol #P009, under PREA to evaluate safety of RAGWITEK as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen in pediatric subjects aged 5 to 17 years.

Final Protocol Submission: June 30, 2016

Study Completion Date: September 30, 2017

Final Report Submission: September 30, 2019

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

AGREED UPON POSTMARKETING COMMITMENTS

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

We acknowledge your written commitments as described in your letter of April 9, 2014, to conduct the studies outlined below:

3. A postmarket claims-based study to further describe the safety profile of RAGWITEK in marketed use in the United States. The study will enroll all new users of RAGWITEK identified through claims data from a large U.S. health insurance database for a period of at least three years from launch of RAGWITEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both postmarketing studies. Outcomes of interest identified through claims data will be verified using medical record review.

Final protocol submission date: January 31, 2015

Study completion date: June 30, 2017 (projected)

Final Report Submission date: June 30, 2018 (or one year after study completion date, whichever is later).

4. A postmarket electronic medical record study to further describe the safety profile of RAGWITEK in marketed use in the United States. The study will enroll all new users of RAGWITEK identified through electronic medical records in a large U.S. integrated health system for a period of at least three years from launch of RAGWITEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both postmarketing studies. This study will include early exposures to RAGWITEK, including administration through starter packs provided in physician offices as well as all subsequent exposures.

Final protocol submission date: November 30, 2015

Study completion date: June 30, 2017 (projected)

Final Report Submission date: June 30, 2018 (or one year after study completion date, whichever is later).

For postmarketing studies subject to reporting requirements of 21 CFR 601.70, please submit clinical protocols to your IND 12970, with a cross-reference letter to this BLA, STN BL 125478. Submit all study final reports to your BLA, STN BL 125478. 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.)

Sincerely yours,

Marion F. Gruber, Ph.D.

Director

Office of Vaccines

Research and Review

Center for Biologics

Evaluation and Research

Attachment: Approved Final Draft Labeling

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