Postgraduate Course in Pharmaceutical Medicine Session 1 Helicopter

Postgraduate Course in Pharmaceutical Medicine Session 1 Helicopter

Postgraduate Course in Pharmaceutical Medicine Session 1 Helicopter view: Drug development planning through to late stage challenges Madhu Davies January 2018 Madhu Davies January 2018 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 years new drug approvals reached 51,

besting every year since 1950. This tally includes 45 drugs approved by FDAs 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 By contrast.... Madhu Davies January 2018 And then 2017- back up again... (Source Forbes) Madhu Davies January 2018

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 Industry overview and R&D structures Development planning theme Madhu Davies January 2018 What turns C33H34FN2O5 into a blockbuster? C33H34FN2O5

Madhu Davies January 2018 Strateg y Madhu Davies January 2018 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 R&D driving forces Madhu Davies January 2018 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

Therapy area split- 2013 vs 2020 Madhu Davies January 2018 Funding and sources of ideas Old world DIY New world Collaboration 1 Our discovery lab Our scientists Our compound library Our cash (private or shareholders) 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 Madhu Davies January 2018 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 Patent Lifetime Issues Year Effective patent life after NDA, yrs 1966

13.6 1979 9.5 1984 8 1987 ~8 1996 5-8

2008 11.5 Sales of a branded drug typically fall by >50% in the year following patent expiry (Bernstein and Co) 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 Madhu Davies January 2018 Time based competition Peak sales

Patent expiry PROFIT Trials Launch Discovery Generic competition TIME COST Pressure to speed up Madhu Davies January 2018

Discovery and early stage development planning Refer particularly to Introductory, Non-clinical and Clinical Pharmacology Sessions Madhu Davies January 2018 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 What does it take to develop a drug? Madhu Davies January 2018 Integrated drug development & commercialization capabilities Portfolio Management Managing governance and delivery performance management Programme Strategy to support clinical development and commercialization Regulatory Affairs Clinical Operations

Protocol design Medical Writing Operational Delivery

Biometrics & Data Management Regulatory Strategy & Submissions Safety Management Strategy / Analytics

AE reporting Market Research Pharmacovigilance Clinical (TPP) Strategy Quantitative Market Forecast Evidence Analysis Brand Strategy Start-up & TMF

Commercial Operations Medical Affairs Medical Evidence Generation (RWE / HEOR) Market Access & Pricing

Compliance / Safety reporting MSLs Patient support programmes 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 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 Delegation NOT abdication! Pharmaceutical development of their own. Contract Manufacturing (CMO) Etc., etc. Madhu Davies January 2018 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 Davies January 2018 G.E.Blau, J.F.Pekny, V.A.Varma, P.R.Bunch, J.Madhu Prod.

Innov.Manag., 21, 227-245, 2004 Portfolio management- hierarchy Madhu Davies January 2018 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 What might we develop? 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 MoA? e.g. agonists, antagonists, enzyme inhibitors, functional (genomics and proteomics) Development planning Medical Rationale Scientific Rationale Expected MOA Target Identification

Nomination Lead Identification Lead Optimisation Discovery Madhu Davies January 2018 Development The goal? United States Prescribing Information

Why? How? Madhu Davies January 2018 Discovery Refer to Prof Gumbletons 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 Discovery Refer to Prof Gumbletons 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 Nomination: Candidate Drug Profile (Builds to Target Product Profile)

Profile Property Potency in vitro Selectivity Evidence that target inhibition produces phenotypic effect desired Pharmacokinetic properties Metabolic properties Physicochemical properties In vivo activity Toxicology Synthetic route Intellectual property Impact in Development Dose, manufacturing scale Tolerability, toxicity Efficacy, biomarker development, patient

selection Exposure, dose, route Exposure, enzyme induction, drug-drug interactions Bioavailability, formulation, tablet properties Pharmacodynamics, exposure-time for efficacy, disease setting Tolerability, likely side effects Manufacture, cost of goods, F2O Freedom to operate, exclusivity, profit post launch Madhu Davies January 2018 Nomination: Candidate Drug Profile Other Key Requirements

contd Impact in Development Differentiation from competition Competitive position, market position Diagnostic Patient identification Biomarker Surrogate efficacy measure, shorter trials Commercial position

Investment decisions, pricing, ROI Stability Product storage, lifetime Effect in combination Potential restricted use Ethnic variability Restricted use Pharmacodynamics

Dosage regime Clinical plan Trial design, length, cost Back up Risk reduction due to failure of first compound Development Madhu Davies January 2018 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; Purposeefficacy 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 Development planning Madhu Davies January 2018 Safety Toxicology Cross 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 Endpoints- examples Endpoint Pharmacology Proof of concept Surrogate endpoints Outcome endpoints Modelling and simulation (Pharmacometrics) Description Animal Human, Rapid demonstration of pharmacology Human, correlates to

disease severity Human health objective In silico Antihypertensive ACE inhibitor ACE inhibited in plasma DMARD Cytokine Reduction of cytokine and bone markers in serum Reduction in blood Reduced plasma CRP pressure Reduction in target organ Improvement in

damage e.g. stroke rheumatological disease Iterative, learn and confirm, useful throughout the process e.g. predict PK prior to animal screening, PK/PD, effects of food, organ dysfunction, populations Madhu Davies January 2018 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

End of ED assessment contd 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 End of ED assessment contd 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 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 Discovery planning-summary

Madhu Davies January 2018 Madhu Davies January 2018 Late stage (full) development Refer particularly to Clinical Trials, Regulatory, Pharmacovigilance, Statistics, Ethics/ Legal/Health economics Sessions. Madhu Davies January 2018 Discovery planning-summary Madhu Davies January 2018 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 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 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 End of Full Development assessment Efficacy (hurdle 1) Does it work, compared to competitor or placebo. Superiority/non inferiorityIs 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 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

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 Potential solutions- work in progress Consider the needs and motivations of all stakeholders to develop better models of study execution and delivery e.g.: Patients Investigators Regulators Public Payers Investors Your company Madhu Davies January 2018 Use insights gained to develop new study execution models

If the rare resource is the patient, consider patient-centric approaches For example, More thoughtful study design Virtual studies Community based trials Non-site based recruitment tools including social media Etc. Madhu Davies January 2018 Madhu Davies January 2018 Discovery planning-summary Madhu Davies January 2018 Chemistry, Manufacturing,

Pharmacy Drugs approved on the basis of Quality, Safety and Efficacy Quality is about the actual active substance Chemical structure Physical properties (appearance, solubility) Synthetic route Manufacturing process and controls Batch analysis

Analytical procedures Stability Madhu Davies January 2018 Chemistry, Manufacturing, Pharmacy See Dr Smiths lecture Formulation

Description and formulation Manufacturing process and controls Control of excipients Analytical method Proof of structure Purity (identification impurities and amounts) Stability once formulated Certificate of analysis (includes assurance of adherence to GMP) Madhu Davies January 2018 contd Commercial aspects of development stream Refer in particular to Medical Education and Promotion, Ethics/ Legal/ Health

economics Sessions Madhu Davies January 2018 Discovery planning-summary Madhu Davies January 2018 Approval processes Principally: New Drug Application (NDA) Biologics Licence Application (BLA) Marketing Authorisation Application (MAA) Madhu Davies January 2018 Pre launch activities

National Payer/Purchaser adoption - The 4th hurdle Quality of life Health Economics Place in the treatment algorithm Patent positions by country Pricing negotiations by country Final commercial assessment on country- by-country basis Launch planning Post launch obligations and PV requirements Madhu Davies January 2018 Where do things go wrong? CRITICAL challenges are:

Portfolio choices pick the winners Dose must get this right but often dont Target- right disease Recognising the clues BUT if it can go wrong, it probably will Plan with the end in mind Dont draw conclusions that are not supported by the data Follow Quality Methodologies prevent rework

Be very precise about the science Regulatory dialogue If you find yourself in conversations about regulations, make sure you know them. Madhu Davies January 2018 Expanded access Once a product is in phase III Waiting for license review and approval Patients may wish / benefit from continuing on their trial medication Issues arise with blinding if not designed into the study from the start Many ECs require patients to be offered the new medication at the end of the trial Often delivered as open label trial extension Not named patient Madhu Davies January 2018 Product Launch

Once the license is granted, the product may then be officially launched (NB Pricing and reimbursement) All the dossier data with marketing value is published, most phase II and III data is released peri launch The sales team needs education and training Corporate and local affiliate medical, marketing regulatory and other departments need education and training Companies create a major presence at conferences Corporate and local roll out of global commercial platform messaging i.e. promotional campaign needs to be created and approved Madhu Davies January 2018 Product Launch Branding is initiated Purchasing groups are targeted Pricing negotiations commence

Manufacturing and supply chains must be operational Professional bodies are targeted - associations of specialists, patient pressure groups, opinion leaders and prescribing leaders Madhu Davies January 2018 Post launch trials Conditions of approval may include: Post authorization safety studies Post authorization efficacy studies Expansion of knowledge of product by various types of study New indications New data is required soon to maintain noise All new medicines undergo a huge increase in patient exposure, with safety implications Many aspects of the product are unconfirmed or unknown at launch MOA, pharmacology, QoL, Health Economics, maturing AE profile

Madhu Davies January 2018 Pharmacovigilance Refer to Pharmacovigilance Session Requirements Regulatory Marketing

PSURs Yellow card systems Registries Post Authorisation Safety Studies Getting a denominator Sales figures IMS DSRU Madhu Davies January 2018 New Indication New formulation Change of Legal Status Opinion Leader support Signal ID follow up

Regulatory Product awareness Differentiating from competition Commercial Equivalence to competition Academic Safety Conduct A Phase IV Study

New product PASS Efficacy Morbidity / Mortality Refine Practice Refresh Publications Mechanism of action Cost effectiveness Treatment algorithms Madhu Davies January 2018

Lifecycle management-Evergreening Keeping the product patent protected Developing new indications and formulations Delayed release formulations Gels, creams, i.v., epidural etc Combination therapies Expanding indications e.g.

Types of arrhythmias Types of pain Types of infection Prophylactic use New algorithms Madhu Davies January 2018 Structure of the SmPC Information is presented according to a predefined structure Certain information is suitable in different sections but crossreferences are made to avoid repetitive information

Madhu Davies January 2018 Madhu Davies January 2018 Madhu Davies January 2018

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