RARE DISEASE AND ORPHAN DRUG DEVELOPMENT EFFICIENT TRIAL DESIGN TO - PowerPoint PPT Presentation

RARE DISEASE AND ORPHAN DRUG DEVELOPMENT EFFICIENT TRIAL DESIGN TO MINIMISE CASH BURN Douglas Cookson Senior Vice President, Commercial Development 14 September 2017 1

1. ORPHAN DRUGS : DEVELOPMENT PRINCIPLES 2

ORPHAN DRUG DEVELOPMENT PRINCIPLES Duties to Purpose Patients • Bringing the safe and effective therapeutic option in the shortest time to all patients and ensuring that the risks are identified and adequately mitigated Investors • De-risk drug development in the shortest time through the most professional and efficient work to ensure the financial risks are identified and adequately mitigated Regulators • Assurance to provide comprehensive, consistent and high quality data for appropriate review and opinion in the shortest time to ensure that the review risks are identified and adequately mitigated Payers • Assuring “market access” in the shortest time and proposing a creative price model based on the demonstrated clinical benefit to ensure that the commercial risks are identified and adequately mitigated 3

ROAD TO THE FINAL OBJECTIVE REDUCE BURDEN OF THE DISEASE IN TERMS OF QUALITY CASH BURN IS DIRECTLY OF LIFE AND IMPACT LINKED REDUCE THE ECONOMIC IMPACT TO TIME TO MARKET Pricing & REGULATORY CLINICAL AND Reimbursement SCIENTIFIC PATHWAYS + PRODUCT RESEARCH MAA = MA MARKET DEVELOPMENT ACCESS 4

2. ORPHAN DRUG : REGULATORY WORLD 5

UNIQUE ASPECTS OF ORPHAN DRUG DEVELOPMENT Many rare and orphan diseases affect paediatric Multiple Collective patients Endpoints • Different PK / PD • Efficacy markers selection Clinical condition • Dose modelling and simulation • Outcome assessment tools • Visit/hospitalisation • Serious and life-threatening (often lacking) • Ethical issues • High unmet medical need Small population • Lack of regulatory and • Limited opportunity for development precedent studies and replication in clinical trials • Few treating physicians • Few treatment centres 6

REGULATORY CONDITIONS & REVIEW EU VERSUS USA 7

FROM PHASE I TO APPROVAL Probability (%) or Likelihood of Approval (FDA 2006-2015) 30 25.9 25.3 25 20 15 11.9 9.6 10 8.4 5.1 5 0 FDA - LOA from Ph I to Approval General Oncology Non-Oncology Orphan With Selection Biomarker Without Selection Biomarker 8

REGULATORY CONDITIONS – CLINICAL DEVELOPMENT TIME US Development Time Standard vs. Orphan Drugs 80 69 70 60 51 50 40 30 22 20 17 16 9 10 0 Average Time (mo) in Clinical Probability (%) of NDA Approval Average Time in FDA Review Trials Standard Orphan 9

TRANSPARENCY IN THE REGULATORY PROCCESS POSITIVE EVOLUTION OF REGULATORY PATHWAYS IN THE EU AND THE US REGULAR INTERACTION BETWEEN FDA AND MORE DETAILED AND SPECIFIC EMA MORE OPPORTUNITES TO INTERACT WITH FDA AND EMA YOUR REGULATORY STRATEGY SHOULD INCLUDE FDA AND EMA APPROVAL ORPHAN DRUG DEVELOPMENT GIVES MARKET EARLY INTERACTION WITH THE AUTHORITIES= EXCLUSIVITY TO THE FIRST TO BE APPROVED INCREASED PROBABILITY OF SUCCESS 10

3. KEY CHALLENGES TO IMPROVE COST-EFFICIENCY IN CLINICAL DEVELOPMENT OF ORPHAN DRUGS 11

DRUG FAILURES On average ~ 37% of drugs in Phase I don’t move to Phase II Data from Clinical Development Success Rates 2006-2015 produced by BIO, Biomedtracker & AMPLION 12

CONSIDER THE LOCATION OF YOUR PHASE I STUDIES UK has the probably strictest In the USA safety regulations For FiH studies in the US you must have the IND written before you enter the clinic • in Phase I up to 6 months to prepare & submit • studies. The MHRA is respected by the In the UK FDA & UK data For FiH studies in the UK you need a CTA only before you enter the clinic • accepted by • 2 months to prepare & submit. them Keep a dialogue Without the initial need for expensive IND, in the UK you can have data coming back open with FDA & from the clinic before you’ve even started enrolling volunteers in the USA. MHRA If your data is positive, then apply for the IND REDUCED FINANCIAL RISK, REDUCED TIME, INCREASED SPEED TO PATIENTS. 13

TRANSLATIONAL EXERCISE 14

TRANSLATIONAL EXERCISE Accurate animal model (reproducible disease) • ✓ Dose selection • Outcome of reliable research (PK, PD) and toxicity data ✓ Safety: risk and minimisation • Dose modelling and simulation Comprehensive information of the natural history • ✓ Selection of efficacy endpoint Translation of markers non-clinical into clinical • ✓ Selection of primary and secondary • Development of meaningful markers: clinical, endpoints biological and imaging • Validation of selected markers ✓ Patient stratification upon “selection biomarkers” Development of accurate tools to evaluate • safety and response to the treatment ✓ Selection of meaningful disease • Useful drug product pharmaceutical form and route evaluation tools of administration • Identification of patient selection Markers, Biomarkers and / or Molecular markers 15

Reason of Efficacy Failure “… The time invested in consistent non - clinical and toxicity studies and … … the validation of assays… … reduce the risk of failure in the clinical development and increase the certainty of clinical pathway…” 16

CLINICAL STUDY DESIGN 17

CLINICAL DEVELOPMENT – BENEFIT VALUE “Clinical development must deliver payer value… … focusing on primary and secondary endpoints … … deliver value to the healthcare system … … deliver true benefit…” 18

THE IMPORTANCE OF MULTI-STAKEHOLDER COLLABORATION Multi-disciplinary research and development consortium • Academic researchers ROBUST DATA TO • Clinical experts SUPPORT THE CLINICAL BENEFITS OF • Patient associations THE DRUG IN THE SPECIFIC INDICATION • Statisticians • Drug developers • Government research (NIH) 19

MULTI -STAKEHOLDER COLLABORATION CLINICAL AND BIOLOGICAL MARKERS MUST BE VALIDATED IN EARLY RESEARCH AND ADAPTED TO CLINICAL APPLICATION TO ASSURE REGULATOR INPUT CONFIDENCE ON THE SAFETY AND EFFICACY OF DATA GENERATED IN RESEARCH AND DEVELOPMENT ROBUST DATA TO SUPPORT THE CLINICAL BENEFITS OF THE DRUG IN THE SPECIFIC INDICATION ACADEMIC RESEARCH SHOULD BE PERFORMED THROUGH EFFICIENT WORKING MODELS TO PATIENT INTEREST GROUPS CAN PROVIDE INPUT GENERATE MEANINGFUL DATA WHICH CAN BE ON THE EXPECTED BENEFITS ANALYSED AND TRANSLATED IN TO POWERFUL CLINICAL ENDPOINTS 20

STUDY DESIGN CONSIDERATIONS OUT -OF-THE FEASIBILITY & RCT’S BOX PATIENTS THINKING PRAGMATIC SOFT LOCK + GOLD STANDARD APPROACH FDA/EMA DISCUSSION ADAPTIVE DESIGN COMPETING STUDIES MODULAR DESIGN 2 ADEQUATE WELL PATIENT BURDEN CONTROLLED TRIALS – FOCUS ON THE = AFFIRM AND PRIMARY CONFIRM ENDPOINT INVOLVE PATIENT SUPPORT GROUPS EARLY REFERENCE CENTERS/PATIENT TRANSPORT AND TRAVEL 21

PROTOCOL DESIGN – SOME IDEAS Historical cohort as control group / Natural Observational or interventional non- history therapeutic protocol to enrol patients into a study - with a therapeutic roll-over protocol Patient Input Deviating from regulatory guidelines does not mean that we do not know the guidelines. It is because there is a strong rationale to do so. The more we deviate from guidelines the more we have to demonstrate to the regulator that we are fully aware of those guidelines. Ask for a meeting with regulatory bodies: FDA, EMA, MHRA 22

The clinical development plan should be creative enough to design the base endpoints to facilitate the regulatory review and approval processes, with follow-up post marketing surveillance to fill- in any ‘gaps’ and bring confidence of a smooth and successful market access. 23

SITE & COUNTRY SELECTION 24

SITE SELECTION AND MANAGEMENT ✓ Engage in a partnership with sites early ✓ Site specific approach, recruitment strategies and Site Management Plan ✓ Flexibility in SOPs and logistic processes “hand made” vs “mass produced” ✓ Involve reference centres ✓ Organising patients’ transport is a much lower cost than opening new countries and sites ✓ Quality and integrity of data critical in view of the low volume ✓ Secure the primary endpoint ✓ Limit academic approach to avoid unnecessary tests 25

PATIENT RECRUITMENT AND RETENTION 26

PATIENT CENTRICITY Early patient engagement leads to deeper insights into the high unmet need and the potential impact the asset would have on alleviating symptoms and improving quality of life Social Media Tools/Apps Scientific Publications / Experts / Patient Input to KOLs design PATIENT eLearning / Multimedia Interactive (Webinars, Web Podcast, etc) Patient Advocacy 27

APPROPRIATE PATIENTS Identifying the appropriate patient is defining and identifying those patients most likely to be responders. • Numbers needed to treat (NNT) • Disease progression • Proper diagnosis • Biological markers • Imaging markers 28