1. Revolutionising the Lifecycle of Pharmaceuticals Eyeforpharma RWD conference June 5, 2013 1

2. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 2

3. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 3

4. 4 = Centre for the Advancement of Sustainable Medical Innovation = www.casmi.org.uk

5. The Innovation Gap time progress Bioscience – understanding human biology and disease = potential patient benefit Actual patient benefit The Innovation Gap

6. The danger of doing nothing progress Bioscience – understanding human biology and disease = potential patient benefit Actual patient benefit time - First ever industry reduction in R&D spend - $4bn drop in overall US spending in 2011

7. What’s distinctive about CASMI? Centre for the Advancement of Sustainable Medical Innovation  Providing independent thought leadership, convening power - and so acting as a catalyst for change  Embedded in UCL and Oxford, but networked with other European and international centres  Interdisciplinary – Medical, Bioscience, Law, Ethics, Business, Economics, Statistics etc  Convening all stakeholders: academia, industry, patient groups, regulators, policymakers, investors

8. A Global Solution requires a Global Network EFPIA IMI Other European centres

9. Basic bioscience Translation to clinical candidates Innovations in clinical trials Regulatory & reimbursement approval Approved products Uptake by health systems Innovations used by patients Patient Benefit 9 Gap 2: Failure to gain approval after costly development Gap 3: Failure to achieve widespread use and patient adherence to treatment Three core “gaps in translation” persist across the value chain Gap 1: Failure to turn early stage research into potential products

10. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Speculations about where we are headed 10

11. Current development path IIIIIIaReviewHTA IIIbIV PoCPh III entry Regul. Subm. & approval Launch Key characteristics of current model Inflexible processes and method Expensive and increasing data demands Lack of early alignment between key parties: Segmented input & decision making Access needs not designed in Patient perspective not fully addressed FIMP&R Access PV & RM External activities Sponsor activities

12. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 12

13. Forces shaping the future of biopharma Future of Biopharma Emergence of regulatory science and new technology Stratified medicine -> molecular definition of disease More flexible regulatory processes for better targeted drugs Pressure to make drugs more affordable Demand for real world (comparative) effectiveness evidence Emergence of tools to collect clinical and patient-reported outcomes Aspiration to collect and analyse Big Data 13

14. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 14

15. Potential New Flexible Blueprint Regulatory Review Access Reviews Patient Use PhV & B/R Preclinical Phase IPhase 2Phase 3 Phase IV Reference: Athenaeum Group Exploratory R&DConfirmatory trials Basic division between exploratory and confirmatory trials, rather than Phases I-IV

16. Potential New Flexible Blueprint Regulatory Review Exploratory R&DConfirmatory trials Collaborative design step before the most expensive confirmatory trials are commissioned Review & design Access Reviews Patient Use PhV & B/R

17. Potential New Flexible Blueprint Exploratory R&DConfirmatory trials Ability/need to customise the model for different benefit/risk/uncertainty profiles Review & design Access Reviews Patient Use Regulatory Review PhV & B/R Submit & Confirm approval Initial access

18. Potential New Flexible Blueprint Exploratory R&DConfirmatory trials Review & design Access Reviews Patient Use PhV & B/R Ability to allow early, controlled patient access, if justified by interim findings in confirmatory trials Submit & Confirm approval Initial access Early access on condition of data collection

19. Potential New Flexible Blueprint Exploratory R&DConfirmatory trials Review & design PhV & B/R Submit & Confirm approval Initial access Early access on condition of data collection Subject to requirements for pharmacovigilance and pharmaceconomic analyses before full ‘green light’ for wide access and longer term reimbursement policy Effectiveness/comparative studies

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22. Key elements of the concept Adaptive Licensing = MAPPs* Conditional Approval (or approval on conditions) Managed Market Entry Real world effectiveness tracking Co-design of confirmatory trials Stakeholders: -Sponsor -Regulator -HTA -Patient org EMA, based on rapporteur evaluation of submission Patients treated; sponsor reimbursed Outcome, safety data collection via reliable network * MAPPs = Medicines Adaptive Pathways for Patients

24. Do you have a potential pilot? - draft pilot selection criteria 1.A robust case for accelerated process – including unmet clinical need. 2.Strong efficacy signal from initial trials; positive benefit/risk profile likely 3.Sufficient numbers of patients that can be recruited. 4.Appropriate data collection mechanisms: robust trial networks in the specific disease area with clinicians that are interested in participating in research 5.Existing patient support mechanisms 6.Could be either a new NCE/NBE or one approved in another indication

25. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 25

26. RCTs  May be unnecessary, inappropriate, inadequate, or impractical  Efficacy versus effectiveness  Population: may not be available for sub-populations and vulnerable populations  Interventions: may not be able to assign high-risk interventions randomly  Comparators: may not represent standard care  Outcomes: may report intermediate outcomes rather than main health outcomes of interest  Timing: may be too short in duration  Setting: may not represent typical practice  Expense and bureaucracy

27. Hierarchies of evidence should be replaced by accepting—indeed embracing—a diversity of approaches. This is not a plea to abandon RCTs and replace them with observational studies. Nor is it a claim that the bayesian approaches to the design and analysis of experimental and non-experimental data should supplant all other statistical methods. Rather, it is a plea to investigators to continue to develop and improve their methods; to decision makers to avoid adopting entrenched positions about the nature of evidence; and for both to accept that the interpretation of evidence requires judgment.

28. Efficacy v effectiveness  Efficacy  patient benefit and harm in experimental and closely monitored research studies, normally RCTs.  major advantages in minimising bias  generalisability questionable  restricted entry criteria  unrepresentative settings  Effectiveness  patient benefit and harm when the technology is actually applied in everyday practice.  pragmatic clinical trials  adverse event reporting  clinical audit

30. 30 Groundbreaking RWD Study Launched in Salford The Salford Lung Study is a unique collaboration between GSK, North West e-Health (NWeH), The University of Manchester, Salford Royal NHS Foundation Trust, NHS Salford, local GPs and local community pharmacists. Around 4,000 patients with COPD and 5,000 patients with asthma from Salford, Greater Manchester, will be enrolled in the year- long study. It is the first time a large, ‘real-world’ study has been performed on a pre-licence medicine, across a large population within one geographical setting. It will utilise Salford’s e-Health records infrastructure – a clinical information system providing a single, integrated electronic patient record across both primary and secondary care.

31. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 31

32. Consequences of these developments ….? Industry is in the data business, not just the product business Big Data insights on routine use of drugs Real world data to confirm/refine B/R and value Adaptive approaches to pre-approval trials 32 Increasing pressure on budgets and prices CPRD and related e-health develop- ments Increasing focus on outcomes Sharper definition of patient populations

33. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 33

34. Topics  Introduction to CASMI  Current lifecycle and its issues  Forces shaping the future  Adaptive licensing and its consequences  Real world data and its role  Speculations about where we are headed  Lessons for today 34

35. Lessons for today  Ensure you’re well networked into industry bodies (like ABPI)  Have a medical information lead on board in your company  Ensure cross-functional dialogue  Consider AL/MAPPs for early stage projects (Phase 1 onwards)  Monitor RWD developments (like GSK’s Salford project and IMI’s GetReal) and their findings  Find one or more centres (HERCs?) focused on relevant therapeutic areas  Consider creating a collaborative project to monitor and evaluate your product’s outcomes 35