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Julia C. Tierney, J.D.Senior Policy Advisor for Strategic Planning & Legislation
Office of the Center Director
Center for Biologics Evaluation and Research
Food and Drug Administration
September 27, 2018
Emerging BiopharmaceuticalTherapies
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• Blood Products
• Vaccines (preventative and therapeutic)
• Allergenics
• Live Biotherapeutic Products
• Devices Related to Biologics
• Human Tissues and Cellular Products
• Xenotransplantation Products
• Gene Therapies
www.fda.gov
Products Regulated by CBER
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Regenerative Medicine Products
www.fda.gov
Bioengineered skin Bioengineered blood vessel
Bioengineered bladder Chimeric antigen receptor-T cell
Red-colored cell is a Tcell
Yellow-colored cell is acancer cell
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Comprehensive Regenerative MedicinePolicy Framework - November 2017
• Clarify existing regulations to make it simpler forsponsors to determine if they need to obtainpremarket authorization for their products
• Expedite the development and approval of safeand effective innovative regenerative medicinetherapies and associated devices
www.fda.gov
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1. Same Surgical Procedure Exception under 21 CFR 1271.15(b):Questions and Answers Regarding the Scope of the Exception (Final)
2. Regulatory Considerations for HCT/Ps: Minimal Manipulation andHomologous Use (Final)
3. Evaluation of Devices Used with Regenerative Medicine AdvancedTherapies (Draft)
4. Expedited Programs for Regenerative Medicine Therapies for SeriousConditions (Draft)
www.fda.gov
Comprehensive Regenerative MedicinePolicy Framework – November 2017
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Regulation of Human Cells, Tissues &Cellular and Tissue-Based Products (HCT/Ps)
• Section 351 of the Public Health Service Act– License needed to distribute in interstate commerce– Product must be safe, pure, potent– Suspension/revocation power, recall authority
• Section 361 of the Public Health Service Act– Authorizes FDA to issue and enforce regulations necessary
to prevent introduction, transmission, or spread ofcommunicable diseases from foreign countries into theUS, or interstate
www.fda.gov
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Two Regulatory Tiers for HCT/Ps
1. Drugs, devices, biological products (351 HCT/Ps)– Regulated under authority of section 361 and section
351 of Public Health Service Act and/or the Federal
Food, Drug, and Cosmetic Act
2. 361 HCT/P (meet criteria to be kicked down)– Regulated solely under authority of section 361
– Subject to “Tissue Regulations” (21 CFR Part 1271)
– Premarket review and approval not required
www.fda.gov
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Section 361 HCT/Ps
To be regulated solely under section 361 of the PHS Act, HCT/Psmust meet the following criteria (21 CFR Part 1271.10(a)):
1. Minimally manipulated (MM)*;
2. Intended for homologous use (HU)** only;
3. Not combined with another article (with some exceptions); AND
4. Either:i. Does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its
primary function; or
ii. Has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function,and is for autologous, 1st or 2nd degree blood relative, or reproductive use
www.fda.gov
* Defined in § 1271.3(f)
** Defined in § 1271.3(c)
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Regenerative Medicine AdvancedTherapy (RMAT) Designation
• Established by the 21st Century Cures Act to help expedite development andreview of regenerative medicine advanced therapies (RMATs)
• RMAT designation provides
– all breakthrough therapy features, including early interactions to discuss anypotential surrogate or intermediate endpoints
– possible priority review and accelerated approval (if eligible)
– statutory flexibility with regard to accelerated approval and post-approvalrequirements
www.fda.gov
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Regenerative Medicine AdvancedTherapy (RMAT) Designation
• A drug is eligible for designation if:
– It is a regenerative medicine therapy
• Includes cell therapies, genetically modified cells, gene therapies producingdurable effects, therapeutic tissue engineering products, human cell andtissue products, or any combination product using such therapies or products
– It is intended to treat, modify, reverse, or cure a serious or life-threateningdisease or condition, and
– Preliminary clinical evidence indicates that the drug has the potential to addressunmet medical needs for such disease or condition
www.fda.gov
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Regenerative Medicine AdvancedTherapy (RMAT) Designation
www.fda.gov
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40
8 3
Granted Denied
Pending Withdrawn
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Requests
• Of 26 RMAT designationsgranted:
• 17 have OrphanProduct designation
• 10 have Fast Trackdesignation
• Most are cellular therapyproducts or gene therapyproducts (including cellulargene therapies)
Data as of Sept. 21, 2018
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Innovative Development Program
for Regenerative Medicine Therapies
www.fda.gov
NEJM 2018; 378: 954-959
13www.fda.gov
Gene Therapies
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Gene Therapies Approved by FDA in 2017
Chimeric Antigen Receptor T cells (CAR-T cells) (ex vivo):• Tisagenlecleucel (KYMRIAH): for treatment of patients up to 25 years
of age with B-cell precursor acute lymphoblastic leukemia (ALL)refractory or in second or later relapse
• Axicabtagene ciloleucel (YESCARTA): for the treatment of adultpatients with relapsed or refractory large B-cell lymphoma after twoor more lines of systemic therapy
Directly Administered (in vivo) gene therapy:• etigene neparvovec-rzyl (LUXTURNA): for the treatment of patients
with confirmed biallelic RPE65 mutation-associated retinal dystrophyin patients with viable retinal cells as determined by the attendingphysician(s).– Novel endpoint used for approval developed by sponsor with input from FDA
www.fda.gov
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All Investigational New Drug Applicationsfor Gene Therapy Products, CY 2002-2017
Yearly submissions to the Center for Biologics Evaluation and Researchwww.fda.gov
16www.fda.gov
Suite of Gene TherapyDraft Guidance Documents – July 2018
1. Chemistry, Manufacturing, and Control (CMC) Information forHuman Gene Therapy Investigational New Drug Applications(INDs)
2. Testing of Retroviral Vector-Based Gene Therapy Products forReplication Competent Retrovirus (RCR) during ProductManufacture and Patient Follow-up
3. Long Term Follow-up After Administration of Human GeneTherapy Products
4. Human Gene Therapy for Hemophilia, on gene therapyproducts intended for treatment of hemophilia
5. Human Gene Therapy for Retinal Disorders
6. Human Gene Therapy for Rare Diseaseshttps://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/default.htm
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• Gene therapy protocol sponsors interact with both theRecombinant DNA Advisory Committee (RAC) at NIHand the FDA for approval and reporting of adverseevents
• Given recent advances in gene therapy, FDA and NIHreviewed the utility of the existing framework
• FDA and NIH have proposed eliminating the need forsponsors to submit proposals for RAC review and toreport adverse events to NIH
www.fda.gov
Simplifying Agency Interactions forGene Therapy Products
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• CBER is working with NIH and National Institute ofStandards and Technology (NIST) and others tofacilitate the development of standards for genetherapies and similar products
• Plans for CBER laboratory research programs andcollaborations with academic and public privatepartners to advance field– Improved cell lines for vector production
• Advanced Manufacturing for Complex Biologicsgrants awarded
www.fda.gov
Improving the Manufacture ofGene Therapies
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Resources for Product Developers:INTERACT Meetings
• We encourage sponsors to contact CBER’s Office of Tissues andAdvanced Therapies early
• INTERACT Meetings replaces pre-pre-IND meetings across CBER
• INTERACT Meetings Program wascreated for potential sponsors toengage with CBER staff and obtainadvice on a specific topic or issuethat is critical to early productdevelopment
• Contact via email [email protected]
www.fda.govhttps://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm
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Resources for Product Developers
• CBER’s Product Jurisdiction Officer ([email protected])Questions about how a product is classified (e.g., a biologic, drug, device, combination,361 HCT/P or other), who regulates it (which center or which office within CBER), or whichregulatory path/requirements apply. Informal assignment questions can be submitteddirectly to CBER’s jurisdiction officer.
• Tissue Reference Group ([email protected])Provides recommendations on product specific questions concerning jurisdiction andapplicable regulation of HCT/Ps, including application of criteria in 21 CFR 1271.10(a),whether 1271.15 (Same Surgical Procedure Exemption) applies, and which regulationsapply when criteria in 1271.10(a) are not met
• Manufacturers Assistance Branch ([email protected])
• Office of Combination Products ([email protected])Requests for Designation/pre-Requests for Designation
www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry
www.fda.gov
