US FDA Expedited Programs and Expanded Access Ke Liu, MD, PhD - PowerPoint PPT Presentation

US FDA Expedited Programs and Expanded Access Ke Liu, MD, PhD Chief, Oncology Branch Division of Clinical Evalua;on, Pharmacology and Toxicology Office of Tissues and Advanced Therapies Center for Biologics Evalua;on and Research Op;mising the development of ATMPs to meet pa;ent needs London, United Kingdom December 16, 2016 1

Disclosures I have no financial rela;onships to disclose. I will not discuss off-label use of products. 2

Outline • US FDA Expedited Programs – Priority Review Designa;on: 1992 – Accelerated Approval: 1992 – Fast Track Designa;on (FTD): 1997 – Breakthrough Therapy Designa;on (BTD): 2012 • US FDA Expanded Access 3

FDA Expedited Programs: Goals v For drugs that address an unmet medical need in the treatment of a serious or life-threatening condi;on v Intended to help ensure that drugs for these condi;ons are approved & available to pa;ents as soon as it can be concluded that the therapies’ benefits jus;fy their risks v Allow for earlier a]en;on to drugs that have promise in trea;ng such condi;ons § Early consulta;on with FDA 4

FDA Expedited Programs Guidance v Guidance for Industry: Expedited Programs for Serious Condi;ons – Drugs and Biologics (2014) § Single resource for informa;on on FDA’s policies & procedures for four expedited programs § Describes threshold criteria applicable to concluding that a drug is a candidate for an expedited development and review program 5

FDA Expedited Programs Breakthrough Priority Accelerated Fast Track Therapy Review Approval Early Phase 3 NDA/BLA Non- APPROVAL Clinical Trial(s) Submission Clinical IND FDA Submission Review 6

Breakthrough Therapy Designa;on (BTD) v Qualifying criteria v Features v Breakthrough vs. Fast Track 7

BTD: Qualifying Criteria v A drug that § Is intended to treat a serious condition AND § Preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints 8

BTD: Qualifying Criteria v Serious Condition “ condition” : A disease or illness § Including life-threatening conditions § A clinical judgment, based on the condition’s § impact on factors, such as: o Survival o Day-to-day function, OR o The likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one 9

BTD: Qualifying Criteria v Intended to have an effect on a serious condition or a serious aspect of a condition § A direct effect on a serious manifestation or symptom of a condition § Other intended effects, such as o A product intended to improve or prevent a serious treatment-related side effect o A product intended to prevent a serious condition or reduce the likelihood that the condition will progress to a more serious condition or a more advanced stage of disease 10

BTD Qualifying Criteria v Preliminary clinical evidence of substan;al improvement over available therapy on one or more clinically significant endpoints Is approved or licensed in the United States § for the same indica;on, AND Is relevant to current US standard of care § (SOC) for the indica;on 11

BTD Qualifying Criteria v Preliminary clinical evidence Not sufficient (quality and/or quan;ty) to establish safety and § effec;veness for purposes of approval Generally derived from Phase 1 or 2 trials § Should involve a sufficient number of subjects to be considered § credible Ideally derived from a study comparing the drug to an available § therapy (or placebo, if no available therapy), or from a study comparing the drug + SOC to the SOC alone Single-arm studies comparing the study subjects’ clinical course § with well-documented historical experience, if the magnitude of difference is large 12

BTD Qualifying Criteria v Substan;al improvement A ma]er of judgment § Depends on: § The magnitude of the drug’s effect on a clinically o significant endpoint (including dura;on of the effect) AND The importance of the observed effect to the o treatment of the serious condi;on or serious aspect of the condi;on 13

BTD Qualifying Criteria v Approaches to demonstrate substan;al improvement Direct comparison of the drug to available therapy shows a much § greater response If there is no available therapy, the drug shows a clinically meaningful § effect on an important outcome when compared to placebo The drug plus available therapy result in a much greater response § compared to available therapy alone The drug reverses or inhibits disease progression, in contrast to § available therapy that provides only symptoma;c improvement The drug has an important safety advantage compared with available § therapy, and has similar efficacy 14

BTD Qualifying Criteria v Clinically significant endpoint An endpoint that measures an effect on irreversible § morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. An endpoint that suggests an effect on IMM or serious § symptoms, including: An effect on an established surrogate endpoint that typically would o be used to support tradi;onal approval An effect on a surrogate endpoint or intermediate clinical endpoint o considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard) A significantly improved safety profile compared with available o therapy (e.g., less dose-limi;ng toxicity for an oncology agent), with evidence of similar efficacy 15

Benefits / Features of Granted BTD v All benefits of Fast Track designation § FDA takes actions to expedite development and review § Eligible for rolling review of NDA or BLA (submission and review of portions of an application before submission of the complete application) v Intensive guidance on efficient drug development during IND, beginning as early as Phase 1 v Organizational commitment involving FDA senior managers 16

FTD vs BTD: Similari;es v Nature of programs: Designa;on v Timeline for FDA response: Within 60 calendar days v Intend to treat serious condi;on v Benefits: FDA’s Ac;ons to expedite development and review § Frequent interac;ons with the review team § May be eligible for priority review if supported by clinical data at the ;me of BLA / NDA submission § May qualify for rolling review v Designa;on may be rescinded if no longer mee;ng the qualifying criteria 17

FTD vs BTD: Differences BTD FTD Source Non-clinical or clinical data Preliminary clinical evidence of Data Substantial improvement on a Requirements Strength The potential to address clinically significant endpoint(s) for Designa>on of Evidence over available therapy unmet medical need Specify how this potential will Development be evaluated in the drug Not required Plan development program (e.g., a description of the Phase 3 trials) • All benefits of FTD FDA takes actions to • Intensive guidance on an Benefits expedite development and efficient drug development review program • Involvement of FDA senior managers 18

Breakthrough Designa>on Experience in CBER OTAT 19

BT Requests in OCTGT (12/2012 – 06/2016) v Total Requests: 54 47 products § 7 Repeated requests § 2 15 Requests Denied Requests Granted 37 Requests withdrawn 20

BTDs by Product Types Requested Granted Products BTDs BTDs Gene 26 12 Cellular 16 1 Tumor Vaccine 4 1 Oncolytic Virus 1 1 21

BTDs by Indica;ons Requests Granted Indications Oncology 33 9 21 6 Non-oncology Hematology 4 3 Ophthalmology 3 1 Cardiology 3 1 Neurology 4 1 Transplantation 2 0 Nephrology, Peripheral Vascular, 1 in each 0 Burn, Hepatology specialty 22

Common Reasons for BTD Denial v Evidence is too preliminary (quan;ty and/or quality) to be considered reliable § Small sample size § Lack of appropriate control § Post-hoc analyses of failed studies that iden;fy a subset that may benefit v Improvement over available therapy does not appear to be “substan;al” v Modifica;on of product 23

What OTAT Has Learned v BTD decisions are complex. § There is no one-size-fits-all characteriza;on of a BT product. v The reliability and persuasiveness of clinical evidence is cri;cal to making the BTD decision. § There is not a defini;ve threshold for substan;al improvement. 24

Expanded Access to Inves>ga>onal Drugs 25

What is Expanded Access? • Use of an inves;ga;onal drug to treat a pa;ent with a serious disease who has no other sa;sfactory op;ons • Intent is TREATMENT; also called “Compassionate Use” • Contrast with using an inves;ga;onal drug in a clinical trial, where the primary intent is RESEARCH 26

Types of Expanded Access Programs (EAPs) There are three types of EAPs defined in the code of federal regula;ons: Individual Intermediate Treatment 27

Requirements for all EAPs 21 CFR 312.305 • Serious or immediately life-threatening illness or condi;on • No comparable or sa;sfactory alterna;ve therapy • Poten;al benefit jus;fies the poten;al risks of the treatment (risks are not unreasonable in the context of the disease / condi;on being treated) • Providing drug will not compromise product development 28