Drug Development Overview CET Square 1 Program November 4, 2014 Carl Siekmann President & CEO BioAdvisory Consulting CFS 11-4--2014

Drug Development CFS 11-4--2014

Drug Development Process Development time for a new drug = 10-15yrs. 1 in 5000 chance of success. Development cost for a new drug = $1.0 + billion New technologies have added cost but have not yet improved productivity of the process. CFS 11-4--2014

Drug Development FDA History 1906 Pure Food and Drug Act Prohibited interstate commerce of misbranded and adulterated foods and drugs. 1938 Food, Drug, and Cosmetics Act (FD&C Act) Toxic sulfanilamide elixir Demonstrate safety prior to market approval Authorized factory inspections 1962 Harris-Kefauver Amendments Thalidomide scare Demonstration of efficacy and safety now required CFS 11-4--2014

Center for Drug Eval. and Research (CDER) Drug Development Office of Commissioner Office of Medical Products and Tobacco Center for Devices and Radiologic Health Center for Drug Eval. and Research (CDER) Center for Biologic Eval. And Research (CBER) FDA CFS 11-4--2014

Drug Development CDER Janet Woodcock, M.D. As part of the U.S. Food and Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs, including biological therapeutics and generic drugs. This work covers more than just medicines. For example, fluoride toothpaste, antiperspirants, dandruff shampoos and sunscreens are all considered "drugs.". CFS 11-4--2014

Discovery Fundamentals Drug Development Discovery Fundamentals 1872 – Ehrlich: Chemo-receptors 1905 – Langley: Receptor/Switch hypothesis. “Lock” and “Key” Analogy : fundamental to DD today Find a molecule (drug) that binds selectively to a target (receptor, enzyme, gene etc.) in the body to trigger a desired biological effect. 1970’s – Advent of Biotechnology “Scientific revolution” Synthesis of therapeutic proteins (keys) New drug target ID methods (locks) Screening technologies for drug-targets matches. CFS 11-4--2014

Drug Development Drug Discovery Understand the disease Underlying patho-physiology at the molecular level. Biochemical pathways Target identification Choose a molecule to target with a drug Target validation Test the target and confirm its role in the disease “Drugable”lead compound identification Find a promising molecule(s) (lead compound) that could become a drug. Lead optimization Alter the structure of lead candidates to improve binding properties Create analogs; test formulations File patents CFS 11-4--2014

Drug Development Pre-Clinical In vitro, in vivo experiments. Two species. Animal toxicity, efficacy, pharmacokinetics (ADME) studies. Scale up manufacturing to pilot plant scale. 5 of 250 molecules survive to enter the clinic. Investigational New Drug (IND) application compiled 1.5 years; $5 million CFS 11-4--2014

Drug Development File IND Pre-IND meeting-FDA (CDER) Submit IND to allow human exposure to experimental drug Preclinical Data ( ADME, Toxicity, Mechanism of Action, Adverse reactions) (GLP) Chemical structure, formulation, manufacturing & control data. (GMP) Clinical Plan (GCP) Apply for priority review. 30 day review. No response, proceed. IND is ongoing file at FDA, tracking drug through NDA process. 1--2014 CFS

Drug Development Phase I Begin 30 days after submission of IND providing no clinical hold notice from FDA. Local IRB approvals required. 20-100 healthy volunteers. Certain life-threatening diseases require patients in Phase I. Determine: safety, pharmacokinetics (ADME), maximum tolerable dose, side-effects. Length: one year. Cost: $1-10 million. 11-4--2014 CFS

Drug Development Phase II No need to consult FDA prior to Phase II. First testing of drug effectiveness in humans (Proof of Concept). Controlled trials in 100-500 patients (placebo or SOC control). Safety and side effects monitored. Dose ranging. Assess minimum effective dose. Results must be statistically significant vs. control group. Length: 2 years. Cost: $10-100 million. 11-4--2014 CFS

Drug Development Phase III End-of- Phase II meeting with FDA. Discuss Ph. III clinical plan. Confirm efficacy/safety in large-scale, multi-center trials vs. control with final dose(s). 1000-5000 patients. Measure long-term efficacy, safety. Side effects. Statistically significant results vs. control. Length: 4-8 years. Cost: $100-800 million. Manufacturing scale-up to commercial scale. Pharmaco-economic outcome studies may be considered for CMS reimbursement. 11-4--2014 CFS

Drug Development CFS 11-4--2014

Clinical Testing (con’t) Drug Development Clinical Testing (con’t) Orphan Drug Act 1983 Patient pop. > 200,000 US. 7 years market exclusivity Special Protocol Assistance (SPA) 50% tax credit on R&D expenses. Prescription Drug User Fee Act (PDUFA) 1992 User Fee paid by sponsor upon NDA submission. $2.2 mil./ 2014. Fee is specifically earmarked for CDER resources to accelerate review process. Expanded safety surveillance. Renewable by Congress every 5 yrs. Greater FDA responsiveness, accountability. 11-4--2014 CFS

NDA (BLA) Submission (100,000+ pages) Drug Development NDA (BLA) Submission (100,000+ pages) CDER: 60 days to accept for review. PDUFA date (10 mo. standard; 6 mo. priority) All preclinical, clinical data: provide evidence drug is safe and effective. Proposed labeling is supported by data. Chemical, manufacturing, and controls (CMC) data. Maintain drug identity, purity, strength. Assay methodology. Manufacturing scale-up: Pre-approval inspection; 3 production batches. Advisory Committee review: Assess risk-benefit; non-binding Approval letter, Approvable letter, rejection letter. Post-market surveillance, Ph. 4 studies. Discovery > Development > NDA review = 10-15 years. $800mil - $1,2 bil. 11-4--2014 CFS

CDER Review Timeline (Standard Application) Drug Development CDER Review Timeline (Standard Application) 11-4--2014 CFS

Drug and Device Development CFS 11-4--2014

Drug and Device Development CFS 11-4--2014

Drug Development CFS 11-4--2014

Drug Discovery Unique Challenges of Drug R&D: Drugs have the potential to do great good or great harm to the human body. The secrets of human biology continue to be shrouded in mystery resulting in recurring surprises and persistent uncertainty. CFS 11-4--2014