Postgraduate Course in Pharmaceutical Medicine Session 1

1. Postgraduate Course in Pharmaceutical MedicineSession 1 Helicopter view: Drug development planning through to late stage challenges Madhu Davies January 2018

2. Madhu Davies January 2018

3. Forbes 4th Jan 2016: 2015 New Drug Approvals Hit 66-Year High! • “2015 has been a remarkable year for pharmaceutical innovation. What would have been a dream (or perhaps a delusion) a few years ago has happened. Last year’s new drug approvals reached 51, besting every year since 1950. This tally includes 45 drugs approved by FDA’s Center for Drug Evaluation and Research (CDER), and 6 recombinant therapies approved by the Center for Biologics Evaluation and Research (CBER). The latter include four drugs to treat blood coagulation disorders (e.g., hemophilia), a therapeutic vaccine for melanoma, and a preventive vaccine for meningococcal meningitis type B” Madhu Davies January 2018

4. By contrast.... Madhu Davies January 2018

5. And then 2017- back up again... (Source Forbes) Madhu Davies January 2018

6. What are we here for? • "It is not enough to be busy; so are the ants. The question is: What are we busy about?" Henry David Thoreau Madhu Davies January 2018

7. Industry overview and R&D structures Development planning theme Madhu Davies January 2018

8. What turns C33H34FN2O5 into a blockbuster? C33H34FN2O5 Madhu Davies January 2018

9. Strategy Madhu Davies January 2018

10. PGCPM: scope provides a firm foundation R&D structure-pressures and drivers Med education, information and promotion; KOL development Programme planning; IP/ legal; Statistics and data management; Drug safety/pharmacovigilance; HEOR; Logistics/operations Madhu Davies January 2018

11. R&D driving forces Madhu Davies January 2018

12. R&D driving forces • Pharma productivity stable • Attrition rates up • Cash: R&D costs up by c16% vs increased sales c12% by 20201 • Company size and therapy area split • Investor sentiment • Global economy • Skills/knowledge based economy 1.EvaluatePharma2014 / 17 Reports Madhu Davies January 2018

13. Therapy area split- 2013 vs 2020 Madhu Davies January 2018

14. Funding and sources of ideas Old world “DIY” New world “Collaboration” 1 Open Innovation Sponsored Research Consortium Alliance Partnership Joint Venture Co-promotion and Marketing Licensing Equity Input 1.Collaboration models: B.Hughes, Nature Reviews Drug Discovery, 7, 631-2, 2008 • Our discovery lab • Our scientists • Our compound library • Our cash (private or shareholders) Madhu Davies January 2018

15. Context • ‘Blockbusters’ up vs ‘patent cliff’ receding • Stocks up, VC investment/IPO up • Licensing down, Pharma investment lower (because prices relatively high…) • Collaborations trendy • Deals very complex/risk averse • Patent life • Opportunity cost/ time based competition Madhu Davies January 2018

16. Patent Lifetime Issues • Patent life set at 20 years from filing date (US) • EU provides 8+2+1 years of exclusivity • FDA will add time to this to recompense time under NDA review (Hatch Waxman act) • Phase II and III trials can be long – end points, patient recruitment etc • Regulatory burden increasing • Countries not aligned to World Patent &Trademark Exchange • Generic challenges before patent expiry • Later filings – competitive risk • WTP negotiations • Line extension • New business models that share risk Sales of a branded drug typically fall by >50% in the year following patent expiry (Bernstein and Co) Madhu Davies January 2018

17. Time based competition Peak sales Patent expiry PROFIT Trials Generic competition Launch Discovery TIME COST Pressure to speed up Madhu Davies January 2018

18. Discovery and early stage development planning Refer particularly to Introductory, Non-clinical and Clinical Pharmacology Sessions Madhu Davies January 2018

19. The internal organisation of R&D • Different companies have different structures- no right answer… • Usually create a multidisciplinary project team • Marketing and R&D and Manufacturing also represented • One team with different leadership at different times in the cycle? • Separate teams by function (discovery team hand on to development team hand onto commercial team)? • Someone has to be in charge! • Outsourcing • This is normal regardless of company size • Occurs at all levels in the process Madhu Davies January 2018

20. What does it take to develop a drug? Madhu Davies January 2018

21. Integrated drug development & commercialization capabilities Portfolio Management – Managing governance and delivery performance management Programme Strategy– to support clinical development and commercialization Regulatory Affairs Safety Management Strategy / Analytics Medical Affairs Clinical Operations Commercial Operations • Medical Evidence Generation (RWE / HEOR) • Market Access & Pricing • Compliance / Safety reporting • MSLs • Patient supportprogrammes • Regulatory Strategy & Submissions • Protocol design • Medical Writing • Operational Delivery • Biometrics & Data Management • Start-up & TMF • Market Research • Clinical (TPP) Strategy • QuantitativeMarket Forecast • Evidence Analysis • Brand Strategy • AE reporting • Pharmacovigilance • Salesforce • KAMs • Field reimbursement managers • Adherence solutions • Field force support systems • Advertising & PR Process, Therapeutic units, Advisory, Quality Assurance, Finance, HR, Legal, Contracting Based on an INC BD slide- with thanks

22. Outsourcing: What does a CRO do? • Exactly the same (R&D) processes as a pharma company- GXP • Project management • Discovery • Toxicology • Clinical Trials • Clinical Labs • Medical Consulting • Medical Marketing • Regulatory Affairs • Drug safety/PV/ QA/ audit • Pharmaceutical development of their own…. • Contract Manufacturing (“CMO”) • Etc., etc. Delegation NOT abdication! Madhu Davies January 2018

23. Managing investment and risk: Portfolio Management Cardiovascular Portfolio CNS Portfolio Probability of Success Size of shape represents resources required (FTE, $) for delivery Project decisions taken based on available resources and potential return – has to fit with company strategy Value G.E.Blau, J.F.Pekny, V.A.Varma, P.R.Bunch, J. Prod. Innov.Manag., 21, 227-245, 2004 Madhu Davies January 2018

24. Portfolio management- hierarchy Madhu Davies January 2018

25. Portfolio Management • Product effects • Assessment of future worth • Probability of success • Valuation of product revenue • Estimation of project costs – resources and time • Typically through a decision tree approach allowing the portfolio to be reassessed at key milestones. • Real Option valuations can also be used • a complex mathematical structure to estimate true project worth • Variation in estimates is very high, • making constant re-evaluation critical • Group effects • Conformance to strategic direction • Numbers of options in development Madhu Davies January 2018

26. What might we develop? MoA? e.g. agonists, antagonists, enzyme inhibitors, functional (genomics and proteomics) • Small molecules • Biologicals • Vaccines • Devices • Drug/device combinations • Medicinal gases • Cosmeceuticals (not a regulatory distinction) • Life style drugs • Foods and supplements • Other? Madhu Davies January 2018

27. Development planning Medical Rationale Scientific Rationale Expected MOA ‘Nomination’ Lead Identification Lead Optimisation Target Identification Development Discovery Madhu Davies January 2018

28. The goal? • United States Prescribing Information • Why? • How? Madhu Davies January 2018

29. DiscoveryRefer to Prof Gumbleton’s lecture • Target identification • Knowing what you are looking for • e.g. a more selective LTB4 inhibitor • Lead identification • Combinational chemistry • Substance Libraries • High through-put screening • Natural product screening • Rational development Madhu Davies January 2018

30. DiscoveryRefer to Prof Gumbleton’s lecture • Lead optimisation • The best of a series • balancing issues such as: • Synthetic route and simplicity / scalability • Oral activity • Duration of effect • Receptor specificity • Initial safety in animals Madhu Davies January 2018

31. Nomination: Candidate Drug Profile (Builds to Target Product Profile) Madhu Davies January 2018

32. Nomination: Candidate Drug Profile cont’d Development Madhu Davies January 2018

33. Phases of clinical development • Phase 0: Used to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. No data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. • Phase I: ~20-100 healthy volunteers/ patients with the disease; duration: ~months; Purpose: safety [dose]. ~70% of drugs move on to • Phase II: Several hundred patients with disease; several months – 2 years; Purpose- efficacy and adverse effects. ~33% move on to • Phase III: ~300-3000 patients with disease; 1-4 years; efficacy and monitoring of adverse effects. ~25% move on to the next phase • Licensure • Phase IV: Several thousand patients with disease; safety and efficacy; Madhu Davies January 2018

34. Development planning Madhu Davies January 2018

35. Safety ToxicologyCross refer to Non clinical and Clinical Pharmacology Sessions • Receptor binding information • Impact on • Respiratory • rates and volumes • Cardiovascular • in vitro and in vivo QT interval tests • Central nervous system • behaviour, sensory / motor responses, body temp • Gastrointestinal • Bowel transit times • Drug specific • E.g. bone density for a cytokine Madhu Davies January 2018

36. Endpoints- examples Madhu Davies January 2018

37. End of ED assessment • Posology • E.g., once daily oral administration • ADME / PK • FIM • Repeated Admin • Proportionality • Metabolite PK and activity • Increased bioavailability vs competition? • Interactions • With drugs of concern or commonly used in target population • Polymorphisms • P450 • CYP2D6 • Enzyme induction Madhu Davies January 2018

38. End of ED assessment cont’d • Proof of Concept • Human pharmacology (pain models, biomarkers) • PD – dose predictions • Range of doses that produce an effect and shape of curve • Cmax and AUC at NOAEL in most sensitive species, not protein bound • Animal toxicology- nature and severity • Species comparative disposition • Range of human doses expected to be needed Madhu Davies January 2018

39. End of ED assessment cont’d • Other drug specific features (must haves and must not haves) • Not affected by food • Not sedative • Signal generation • Evidence of developing side effect profile • Commercial assessment • Minimum acceptable profile compared to actual profile and viability assessed Madhu Davies January 2018

40. Dose ranging • The commonest error in development planning is the dose decision • The move from phase II to III is the greatest cost increment in the lifecycle • Running phase III studies at the wrong dose is a disaster in terms of direct and lost opportunity costs • Phase II studies must not be timid... • ...the trend is to undertake larger definitive studies, sooner Madhu Davies January 2018

41. Discovery planning-summary Madhu Davies January 2018

42. Madhu Davies January 2018

43. Late stage (full) development Refer particularly to Clinical Trials, Regulatory, Pharmacovigilance, Statistics, Ethics/Legal/Health economics Sessions. Madhu Davies January 2018

44. Discovery planning-summary Madhu Davies January 2018

45. Phase III design list - pivotal to authorisation • Objectives of study • Is it safe? • Is it effective? • Allocation to therapies • Statistical considerations • Medically significant difference, power calculation • Method of control of bias • Choice of therapies • Duration of therapies • Patient population • How are you going to reduce the variance? • How are you going to ensure the study is close to real life? Madhu Davies January 2018

46. Programme/project/product information • R&D/ Senior Management Committees -internal [and external] • Investigator Brochure • Protocol and Informed Consent document • Institutional Review Board/ Research Ethics Committee submissions • Clinical Trial Applications Madhu Davies January 2018

47. Medical Oversight of Clinical Trials Steering committee Data and Safety Monitoring Board (DSMB)Medical Liaison Critical Event Committees Medical Monitoring Clinical Trial Madhu Davies January 2018

48. End of Full Development - assessment • Efficacy (hurdle 1) • Does it work, compared to competitor or placebo. Superiority/non inferiority…Is it no worse (the same) or better? • Safety (hurdle 2) • Safety profile seen to date and risk benefit assessment? • Signal generation • Are other adverse effects emerging? • Population Kinetics • To supplement the core PK data- elderly, organ impaired, paediatrics etc • Commercial Assessment-ongoing • Target Product Profile vs Minimum Acceptable Profile vs actual profile, and commercial viability assessed. Landscape? Madhu Davies January 2018

49. Some specific challenges of late phase development/studies • “Before a new drug or biologic can be marketed, its sponsor must show, through adequate and well-controlled clinical studies, that it is effective” FDA CFR 314.126 Madhu Davies January 2018

50. Some specific challenges of late phase development/studies • Study design! • Specific populations e.g. organ impaired/ timing of paediatric studies • Leaky recruitment and retention in studies • Availability of good principal investigators/sites • Protocol complexity and subject numbers • Patient demand vs site performance vs retention (again) • Cost- e.g. just consider site start up costs: • Starting up a site costs £25,000 - £75,000 • Monitoring a site costs £2000 per month • Missed visits cost on average £250 • A drop out patient costs £20,000 (Source, MRN, 2015) Madhu Davies January 2018