Kite Pharma, Inc.
Dear Ms. Siu:
Please refer to your Biologics License Application (BLA) submitted and received December 11, 2019, under section 351(a) of the Public Health Service Act (PHS Act) for brexucabtagene autoleucel.
Effective this date, we have approved your BLA for brexucabtagene autoleucel, according to the regulations for accelerated approval, 21 CFR 601.41. You are hereby authorized to introduce or deliver for introduction into interstate commerce, brexucabtagene autoleucel under your existing Department of Health and Human Services U.S. License No. 2064. Brexucabtagene autoleucel is indicated for the treatment of adult patients with relapsed/refractory mantle cell lymphoma (MCL).
This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT02601313, NCT02614066, NCT02625480, NCT03624036.
ACCELERATED APPROVAL REQUIREMENTS
Under accelerated approval regulations we may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on an intermediate clinical endpoint other than survival or irreversible morbidity. This approval requires you to study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome.
Approval under these regulations requires, among other things, that you conduct adequate and well-controlled clinical trials/studies to verify and describe clinical benefit attributable to this product. Clinical benefit is evidenced by effects such as favorable objective response rate, complete response rate, and durability of response after a minimum follow-up of 18 months from the time of first objective response.
Accelerated Approval Required Studies
We remind you of your postmarketing requirements specified in your submission of July15, 2020.
1. Complete additional follow-up of all 68 subjects treated with brexucabtageneautoleucel in ZUMA-2 Cohort 1 to a minimum of 18 months from the time of firstresponse. Data will continue to be collected according to the ZUMA-2 protocol’sestablished schedule of assessments.
Final Protocol Submission: Submitted November 13, 2018
Study/Trial Completion: December 31, 2020
Final Report Submission: July 31, 2021
2. Conduct a study of brexucabtagene autoleucel treatment of subjects withrelapsed or refractory mantle cell lymphoma who have not been exposed to aBruton tyrosine kinase (BTK) inhibitor. A cohort of subjects naïve to BTKinhibitor therapy will be added to the ongoing ZUMA-2 study to fulfill thisrequirement. Eighty-six subjects will be enrolled. The primary efficacy endpointwill be objective response rate with a supportive efficacy endpoint of duration ofresponse based on a minimum follow-up of 18 months after first objectivedisease response.
Final Protocol Submission: January 15, 2021
Study/Trial Completion: April 30, 2025
Final Report Submission: October 31, 2025
We expect you to complete design, initiation, accrual, completion, and reporting of thesestudies within the framework described in your letter of July 15, 2020.You must conduct these studies with due diligence. If postmarketing studies fail toverify that clinical benefit is conferred by brexucabtagene autoleucel, or are notconducted with due diligence, we may, following a hearing in accordance with 21 CFR601.43 (b), withdraw or modify approval ----
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MANUFACTURING LOCATIONS (page 3)
Under this license, you are approved to manufacture brexucabtagene autoleucel at your facility located at ___
( ) will be manufactured at ____
You may label your product with the proprietary name TECARTUS ----
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DATING PERIOD (page 3)
The dating period for brexucabtagene autoleucel shall be 12 months from the date of manufacture when stored at not greater than -150 °C. The date of manufacture shall be defined as the date of cryopreservation of the formulated drug product.
The dating period for the vector shall be when stored at We have approved the stability protocols in your license application for the purpose of extending the expiration dating period of your vector and drug product under 21 CFR 601.12.
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FDA LOT RELEASE (page 4)
You are not currently required to submit samples or protocols of future lots of brexucabtagene autoleucel to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, under 21 CFR 610.2(a). 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.
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PEDIATRIC REQUIREMENTS (page 7)
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.
POSTMARKETING REQUIREMENTS UNDER SECTION 505(o)Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA torequire holders of approved drug and biological product applications to conductpostmarketing studies and clinical trials for certain purposes, if FDA makes certainfindings 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 eventsreported under section 505(k)(1) of the FDCA will not be sufficient to identify a seriousrisk of secondary malignancies associated with use of brexucabtagene autoleucel.
Furthermore, the pharmacovigilance system that FDA is required to maintain undersection 505(k)(3) of the FDCA is not sufficient to assess this serious risk.
Therefore, based on appropriate scientific data, we have determined that you arerequired to conduct the following study:
3. A post-marketing, prospective, multi-center, observational study to assess thelong-term safetyof brexucabtagene autoleucel and the risk of secondarymalignancies occurring after treatment with brexucabtagene autoleucel. Thestudy will include at least 500 adult patients with relapsed or refractory mantlecell lymphoma after two or more lines of systemic therapy; the enrolled patientswill be followed for 15 years after the product administration.
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RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS (page 9)
Section 505-1 of the FDCA authorizes FDA to require the submission of a riskevaluation and mitigation strategy (REMS), if FDA determines that such a strategy isnecessary to ensure that the benefits of the drug outweigh the risks [section 505-1(a)].
In accordance with section 505-1 of the FDCA, we have determined that a REMS isnecessary for TECARTUS to ensure that the benefits of the drug outweigh the risks ofcytokine release syndrome (CRS) and neurological toxicities.
Your proposed REMS must include the following:
Elements to Assure Safe Use: Pursuant to 505-1(f)(1), we have determined thatTECARTUS can be approved only if elements necessary to assure safe use arerequired as part of the REMS to mitigate the risks of CRS and neurological toxicities.
Your REMS includes the following elements to mitigate these risks:
• Health care settings that dispense YESCARTA or TECARTUS are speciallycertified
• YESCARTA or TECARTUS is dispensed to patients only in certain health caresettings
Implementation System: The REMS must include an implementation system tomonitor, evaluate, and work to improve the implementation of the elements to assuresafe use which require healthcare settings that dispense the drug be specially certifiedand that the drug be dispensed to patients only in certain healthcare settings,specifically, certified hospitals and their associated clinics with appropriate access totocilizumab.
Due to the similar serious risks of CRS and neurological toxicities of YESCARTA(approved on October 18, 2017), and in order to minimize burden on the healthcaredelivery system [section 505-1(f)(2)(D)], your REMS for YESCARTA (BLA 125643) andyour REMS for TECARTUS (125703) have been merged into a single “YESCARTA andTECARTUS REMS” program and, consequently, subject to the same REMSassessment plan and subsequent REMS assessments.
Your YESCARTA andTECARTUS REMS must be fully operational before you introduce TECARTUS intointerstate commerce.Your proposed YESCARTA and TECARTUS REMS, submitted on July 23, 2020, andappended to this letter, is approved. The REMS consists of elements to assure safe use, an implementation system and a timetable for submission of assessments of the REMS.
POST-APPROVAL FEEDBACK MEETING
New biological products qualify for a post-approval feedback meeting. Such meetingsare used to discuss the quality of the application and to evaluate the communicationprocess during drug development and marketing application review. The purpose is tolearn from successful aspects of the review process and to identify areas that couldbenefit from improvement. If you would like to have such a meeting with us, pleasecontact the Regulatory Project Manager for this application.
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END OF EXCERPTS OF LETTER----
Now that you're done reading, ask yourselves:
1. Is anything mandated upon the company, by the FDA, something MSB had not foreseen, and is not prepared for?
- think of all the pre-planning that's been happening by SI, lonza, manufacturing
- insurance companies getting prepared for remestemcel-l
- hiring of an A-list exec team in the US for scaling and marketing
2. Has anyone come up with anything to outright refute anything but a positive outcome between Thursday's voting and September 30th by the FDA?
- with provisions like post approval trials,
- labelling restrictions etc
- SI and his team have said they are extensively prepared for this meeting
Is this not what we've been waiting for?---
Approval letter from FDA Source - https://www.fda.gov/media/140415/download 
(20min delay)