Ultomiris (ravulizumab-cwvz) injection (Corrected Supplement Approval)

by Tanya Morgan Wroblewski

BLA 761108/S-021

CORRECTED SUPPLEMENT APPROVAL

Alexion Pharmaceuticals, Inc.
Attention: Leyla Toksoy
Director, Global Regulatory Affairs CMC
121 Seaport Boulevard
Boston, MA 02210

Dear Ms. Toksoy:

Please refer to your supplemental biologics license application (sBLA), dated and received September 23, 2021, and your amendments submitted under section 351(a) of the Public Health Service Act for Ultomiris (ravulizumab-cwvz) injection. We also refer to our approval letter dated July 22, 2022, which contained the following error: the REMS document was inadvertently omitted from the letter.

This corrected action letter incorporates the correction of the error. The effective action date will remain July 22, 2022, the date of the original letter.

This Prior Approval supplemental biologics license application provides for adding a new route of administration for Ultomiris via subcutaneous injection for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), and a new dosage form and strength, the Ultomiris 70mg/mL, 3.5 mL on-body delivery system. This supplement also provides for modifications to the approved Ultomiris risk evaluation and mitigation strategy (REMS).

APPROVAL & LABELING

We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling.

MANUFACTURING LOCATIONS

The final formulated 70mg/mL, 3.5 mL single-dose prefilled cartridge will be manufactured and filled at   and tested for release at   and at Alexion Pharma International Operations Unlimited Company, Alexion Dublin manufacturing Facility (ADMF), Dublin, Ireland.

The single-use on body injector will be manufactured and tested at     and at    

The Ultomiris on body delivery system combination product will be manufactured at Alexion Pharma International Operations Unlimited Company, Alexion Dublin manufacturing Facility (ADMF), Dublin, Ireland, and will be tested for release at       and at ADMF, Dublin, Ireland.

DATING PERIOD

The dating period for the 3.5 mL single-dose prefilled cartridge shall be 24 months from the date of manufacture when stored at 2 °C - 8 °C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product.

The dating period for the Ultomiris on body delivery system combination product shall be 24 months from the date of manufacture when stored at 2°C - 8 °C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product in the single-dose prefilled cartridge.

CONTENT OF LABELING

As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA automated drug registration and listing system (eLIST), the content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format, as described at FDA.gov,^[1] that is identical to the enclosed labeling (text for the Prescribing Information, Instructions for Use, and Medication Guide) and include the labeling changes proposed in any pending “Changes Being Effected” (CBE) supplements.

Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As.^[2]

The SPL will be accessible via publicly available labeling repositories.

Also within 14 days, amend all pending supplemental applications that include labeling changes for this BLA, including pending “Changes Being Effected” (CBE) supplements, for which FDA has not yet issued an action letter, with the content of labeling [21 CFR 601.12(f)] in Microsoft Word format that includes the changes approved in this supplemental application, as well as annual reportable changes. To facilitate review of your submission(s), provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should provide appropriate annotations, including supplement number(s) and annual report date(s).

We request that the labeling approved today be available on your website within 10 days of receipt of this letter.

CARTON AND CONTAINER LABELING

Submit final printed carton and container labeling that are identical to the enclosed carton and container labeling, as soon as they are available, but no more than 30 days after they are printed. Please submit these labeling electronically according to the guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. For administrative purposes, designate this submission “Final Printed Carton and Container Labeling for approved BLA 761108/S-021.” Approval of this submission by FDA is not required before the labeling is used.

We have completed our review of this supplemental application, as amended. It is approved effective on the date of this letter.

RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS

The REMS for Ultomiris (ravulizumab-cwvz) was originally approved on December 21, 2018, and the most recent REMS modification was approved on April 27, 2022. The REMS consists of a elements to assure safe use and a timetable for submission of assessments of the REMS.

Your proposed modifications to the REMS consists of changes to the REMS document to align with labeling and updated REMS materials to incorporate the revised logo capturing both intravenous and subcutaneous routes of administration.

Your proposed modified REMS, submitted on September 23, 2021, amended and appended to this letter, is approved.

The timetable for submission of assessments of the REMS remains the same as that approved on December 21, 2018.

There are no changes to the REMS assessment plan described in our December 2, 2021, letter.

We remind you that in addition to the REMS assessments submitted according to the timetable in the approved REMS, you must include an adequate rationale to support a proposed REMS modification for the addition, modification, or removal of any goal or element of the REMS, as described in section 505-1(g)(4) of the FDCA.

We also remind you that you must submit a REMS assessment when you submit a supplemental application for a new indication for use, as described in section 5051(g)(2)(A) of the FDCA. This assessment should include:

a)		An evaluation of how the benefit-risk profile will or will not change with the new indication;
b)		A determination of the implications of a change in the benefit-risk profile for the current REMS;
c)		If the new indication for use introduces unexpected risks: A description of those risks and an evaluation of whether those risks can be appropriately managed with the currently approved REMS.
d)		If a REMS assessment was submitted in the 18 months prior to submission of the supplemental application for a new indication for use: A statement about whether the REMS was meeting its goals at the time of that last assessment and if any modifications of the REMS have been proposed since that assessment.
e)		If a REMS assessment has not been submitted in the 18 months prior to submission of the supplemental application for a new indication for use: Provision of as many of the currently listed assessment plan items as is feasible.
f)		If you propose a REMS modification based on a change in the benefit-risk profile or because of the new indication of use, submit an adequate rationale to support the modification, including: Provision of the reason(s) why the proposed REMS modification is necessary, the potential effect on the serious risk(s) for which the REMS was required, on patient access to the drug, and/or on the burden on the health care delivery system; and other appropriate evidence or data to support the proposed change. Additionally, include any changes to the assessment plan necessary to assess the proposed modified REMS. If you are not proposing REMS modifications, provide a rationale for why the REMS does not need to be modified.

If the assessment instruments and methodology for your REMS assessments are not included in the REMS supporting document, or if you propose changes to the submitted assessment instruments or methodology, you should update the REMS supporting document to include specific assessment instrument and methodology information at least 90 days before the assessments will be conducted. Updates to the REMS supporting document may be included in a new document that references previous REMS supporting document submission(s) for unchanged portions. Alternatively, updates may be made by modifying the complete previous REMS supporting document, with all changes marked and highlighted. Prominently identify the submission containing the assessment instruments and methodology with the following wording in bold capital letters at the top of the first page of the submission:

BLA 761108 REMS ASSESSMENT METHODOLOGY
(insert concise description of content in bold capital letters, e.g.,
ASSESSMENT METHODOLOGY, PROTOCOL, SURVEY METHODOLOGIES,
AUDIT PLAN, DRUG USE STUDY)

Prominently identify any submission containing the REMS assessments or proposed modifications of the REMS with the following wording in bold capital letters at the top of the first page of the submission as appropriate:

BLA 761108 REMS ASSESSMENT

or

NEW SUPPLEMENT FOR BLA 761108/ S-000
CHANGES BEING EFFECTED IN 30 DAYS
PROPOSED MINOR REMS MODIFICATION

or

NEW SUPPLEMENT FOR BLA 761108/ S-000
PRIOR APPROVAL SUPPLEMENT
PROPOSED MAJOR REMS MODIFICATION

or

NEW SUPPLEMENT FOR BLA 761108/ S-000
PRIOR APPROVAL SUPPLEMENT

PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
CHANGES SUBMITTED IN SUPPLEMENT XXX

or

NEW SUPPLEMENT (NEW INDICATION FOR USE)
FORBLA 761108/ S-000

REMS ASSESSMENT
PROPOSED REMS MODIFICATION (if included)

Should you choose to submit a REMS revision, prominently identify the submission containing the REMS revisions with the following wording in bold capital letters at the top of the first page of the submission:

REMS REVISIONS FOR BLA 761108

To facilitate review of your submission, we request that you submit your proposed modified REMS and other REMS-related materials in Microsoft Word format. If certain documents, such as enrollment forms, or website screenshots are only in PDF format, they may be submitted as such, but Word format is preferred.

SUBMISSION OF REMS DOCUMENT IN SPL FORMAT

FDA can accept the REMS document in Structured Product Labeling (SPL) format. If you intend to submit the REMS document in SPL format, as soon as possible, but no later than 14 days from the date of this letter, submit the REMS document in SPL format using the FDA automated drug registration and listing system (eLIST).

For more information on submitting REMS in SPL format, please email FDAREMSwebsite@fda.hhs.gov.

PROMOTIONAL MATERIALS

You may request advisory comments on proposed introductory advertising and promotional labeling. For information about submitting promotional materials, see the final guidance for industry Providing Regulatory Submissions in Electronic and Non-Electronic Format—Promotional Labeling and Advertising Materials for Human Prescription Drugs.^[3]

As required under 21 CFR 601.12(f)(4), you must submit final promotional materials, and the Prescribing Information, at the time of initial dissemination or publication, accompanied by a Form FDA 2253. Form FDA 2253 is available at FDA.gov.^[4] Information and Instructions for completing the form can be found at FDA.gov.^[5]

REPORTING REQUIREMENTS

We remind you that you must comply with reporting requirements for an approved BLA (in 21 CFR 600.80 and in 21 CFR 600.81).

If you have any questions, contact Caden Brennen, Regulatory Project Manager, at 301-796-6591 or at Caden.Brennen@fda.hhs.gov.

Sincerely, {See appended electronic signature page}

Tanya Wroblewski, MD Associate Director of Therapeutic Review Division of Nonmalignant Hematology Office of Cardiology, Hematology, Endocrinology, and Nephrology Center for Drug Evaluation and Research

ENCLOSURES:
• Content of Labeling
o Prescribing Information
o Medication Guide
o Instructions for Use
• Carton and Container Labeling
• REMS

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1. http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
2. We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
3. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/media/128163/download.
4. http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
5. http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf

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This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

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TANYA M WROBLEWSKI
07/26/2022 03:29:43 PM