Lecture 2

-research and development -manifacturing -commercial

-discovery -development (clinical development/product development)

-clinical studies and clinical trial supplies -marketed products

-product launch -product marketing -sales

Devoted to inventing medicines that allow patients to liver longer, healthier and more productive lives

• Unmet medical needs and health economics (eg new HCV drugs vs liver transplant) • Projected market demographics (e.g. an aging population; evolving health of population) • Evolving disease profiles (e.g. addressing chronic conditions)

• Addressing competitive environment • Shareholder value • Growing the business • Maximizing market share, sales, profits, and ROI

-hospitals and physicians and clinics

o Cancer/Oncology o Cardiovascular Diseases o CNS Disorders o Psychological Disorders o Prophylactic Vaccines o Gastrointestinal Disorders o Respiratory Disease o Blood Disorders o Dermatological Disorders o Diabetes & Obesity/Metabolic Disorders o Infectious Diseases/AIDS

-target id -target validation -assays and lead ID -lead optimazation -candiate selection -pre-clinical profiling -development candidate/ NME

• Basic Research • Knowledge • Bioinformatics • Genetic Links • Biochemistry • Pathways

• Target Disease Link • Reverse Genetics • Animal Kock out • Animal Data • Health Databases

• Binding Assays • Enzyme Assays • Cell-based Assays • Compound Library Screens • Hit ID • De novo design • Animal models/ • In vivo pharmacology assay development

• Small molecule: • Med chem • Structure Activity Relationship • (SAR) • QSAR • Modelling docking • PK – pharmacokinetics • ADME –adsorption, distribution, metabolism • In vitro ADME • In vivo ADME

• Patent applications • Target potency and exposure requirements • Free-drug levels • Pre-clinical general and safety pharmacology • NOAEL (no adverse effect level) targets • Cross-species PK • PK scaling: Human dose and exposure levels • Back-up candidate defined • TPP – target product profile drafted

• Scale-up process • Pre-formulation studies • GLP Toxicity testing – rodent and non-rodent species • TPP – finalized • Research, Medical and Marketing Agree to develop

• IND – investigational new drug filing with FDA • Major Investment Decision • Product Development Team assumes responsibility

-development team -phase 1 clinic -phase 2 clinic -phase 3 clinic -new drug app/nda/bla -post market monitoring

• Medical, Marketing, Research, Patents • Long term animal toxicology – reprotox; carcinogenicity • CMC – chemistry manufacture and control - GMP • Scale-up process • Pharmaceutics/ Formulation • Clinical PK/ pharmacology • Statistics • Safety/ Pharmacovigilance • Clinical Development Plan: Trial protocols – GCP

• Small number of subjects • Single dose escalation healthy human volunteers • Single Dose PK • Human PK • Multiple ascending dose PK • Confirm safety and human PK • Drug – Drug Interactions studies

• Small to medium number of patients (~50-100) • Multiple Ascending Dose • Safety and PK in patient population • Assess treatment durations • Effect (PD) in patients • Assess clinical biomarkers • Establish dose and duration for testing in phase III

• RCT- randomized controlled clinical trial • In large number of patients • Blinded studies • Registrational trials • Two trials confirm efficacy and safety relative to comparator (placebo or existing treatment) • Establish superiority or non-inferiority to comparator

• NDA – New Drug application • BLA – Biologics Licensing application • Drug supply complete • FDA review (1-2 years!) and approval • Drug registration • Submission in other jurisdictions

• Lon-term Side effects • FDA Adverse Event Reporting System (FAERS) • Phase IV studies – special populations • Post marketing commitments • Pediatric Studies