Project Management in the Pharmaceutical Industry 16:30 h Project Management and the development of a new medicine Anton Van Kolfschoten 17:15 h Management of the registration of influenza vaccines Dorine Leyssius & Reny ten Haaf 18:45 h FDA Advisory committee Meeting The management of an acceptance test for a new medicine by external stakeholders Jan Jansen Project Management in Drug Development February 2011

Project Management in the Development of New Medicines Anton VanKolfschoten PhD, RegTox, PMP February 22nd 2011

Anton Van Kolfschoten Master in Bio-medical Sciences University of Utrecht; PhD 5 years Research in Pharmacology & Toxicology Solvay Pharmaceuticals/Abbott 29 years Non-clinical safety testing 17 years Project management 12 years PMP since 2010 Project Management in Drug Development February 2011

What Is Drug Development The science of developing a pharmaceutical drug candidate through development, approval, launch, and Life Cycle Management. During Development a drug candidate is tested for safety and efficacy, approved by regulatory authorities and launched. During Development a manufacturing process is established, validated and transferred to a commercial manufacturing facility. Once a drug is launched Development continues to monitor safety and develop new indications and/or improved drug delivery. Project Management in Drug Development February 2011

The Drug Development Process Long, Complex, Costly Only 1 in 10,000 Compounds in Drug Discovery Receive Regulatory Approval PhRMA Profile 2009 Project Management in Drug Development February 2011

Advancing and Sustaining the Pipeline – Guiding Principles In Discovery, a high number of compounds is generated to create the optimal pharmacological profile. During Development, the number of compounds is decreasing due to attrition While a compound progresses in Development, the risk of attrition decreases while the costs of development increase Marketed Drug One Portfolio One Team Phase 3 Cost per Compound Decreasing Risk Phase 2 Phase 1 Jim Tyree and the PPG leadership team have identified the advancement of our pipeline as one of our key strategic priorities in PPG. To achieve our goal of launching one NME/year from internal R&D, it will be important that we continue to increase the quality, quantity and velocity in all phases of our pipeline As we advance our programs through all phases of discovery and development we need to ensure a relentess focus on key issues, driving decisions with data and identifying and executing the incisive expertiments to reduce the cost of failure. This will allow us to learn from success and failure Applying these guiding principles to our work on each individual target and compound wil allow us to create a winning discovery and development portfolio and maximize our chances of success Advanced Preclinical Number of Compounds Source: Abbott Project Management in Drug Development February 2011

Pharmaceutical Industry Challenges Average R&D Spend Per NME Has Been Rising Average R&D spend per FDA Approval (small molecules and biologics)* * Average R&D spend per NME defined as 5 year lagging average R&D spend divided by sum of present period NME and BLA approvals Note: Biologics included only from 1986 onward, biologics approvals assumed negligible in prior periods Source: McKinsey analysis, NME data from multiple publications and statistical sourcebooks Industry R&D spend data from the Pharmaceutical Research and Manufacturers of America, PhRMA Annual Membership Survey, 2006. Project Management in Drug Development February 2011

Challenges for Pharmaceutical Industry Rate of FDA approvals has been decreasing… Project Management in Drug Development February 2011

Development of New Drugs Project Initiation - Strategic Considerations Unmet Medical Need/ Profitability Approvability Feasibility/ Expertise Source: Abbott Project Management in Drug Development February 2011

Scope - example from Abbott Role of DOP and TPP in Pipeline Optimization Set objectives DOP Discovery/ early development Full development File, launch, LCM Pre-R+D Disc. P-C P1 P2a P2b Ph. 3 Reg. Mkt. DOP TPP 1. 2. 3. Requirements or priorities to achieve commercial success Integrated, consistent commercial input for early-stage R&D compounds Framework for assessing attractiveness of emerging asset attributes Disease Opportunity Profile and Target Product Profiles Guide Discovery and Development Decision-Making Scope for New Medicine Source: Abbott Project Management in Drug Development February 2011

Target Product Profile – Scope of Development Requirements for Indication (disease to be treated) Patient population Efficacy in disease Safety for patients Presentation form (tablet, capsule, drops, suppository, injection) Interaction potential with other drugs Costs of goods Reimbursement possibilities Launch conditions Project Management in Drug Development February 2011

High Level Drug Development Timeline Discovery Discovery Pre-clinical Development Pre-clinical Development Clinical Development Clinical Development Application Review for First Market Application for First Market Global Launches Global Launches Marketing Support 3–5 Years 3-5 Years < 1 Year < 1 Year ~7–10 Years ~1 Year ~1 Year ~5–10 Years ~5-10 Years Time to develop a drug = 10 to 15 years Source: Abbott Project Management in Drug Development February 2011

Drug Development Is Comprised of Many Stages R&D Key Milestones First Regulatory Enabling Toxicity Dose Active Substance Code Assigned First Human Dose First Submission Discovery Pre-clinical Development Clinical Development Application for First Market International Launch Program First Launch First Patient Dose Not to scale First Pivotal Dose Project Management in Drug Development February 2011

Probability of Success for various Phases Project Management in Drug Development February 2011

Effectiveness in preliminary screens Preclinical Activities Include in vitro (test tubes) and in vivo (animal) Studies Effectiveness in preliminary screens Potential dosage Metabolites Toxicology and safety Extensive animal studies are conducted to determine if a drug is likely to be safe in humans Toxicology studies are performed for differing purposes Studies performed using Good Laboratory Practices (GLP) and meeting regulatory requirements for duration and power are suitable to submit to regulatory authorities Additional studies are also conducted to gain preliminary data and scientific knowledge Project Management in Drug Development February 2011

What Is Drug-Product Development? From idea… …to drug substance… …to medicine for the patient Drug development turns a laboratory concept into a consistent and well-characterized medical product that can be mass produced. It is the process whereby a compound is discovered, tested for safety and efficacy, approved by regulatory authorities and marketed. It involves physical design and specifications of the product, as well as manufacturing and quality control approaches 90% of new medicines are discovered & developed by industry Source: Abbott Project Management in Drug Development February 2011

Nonclinical Activities Include Developing Manufacturing Process Manufacture of active Pharmaceutical ingredient (API) Process design and development Scale up Validation Manufacture of Drug Product (DP) Formulation for first-in-human (FIH) Formulation design to meet product needs Manufacturing process development Bioavailability The Drug Product must meet bioavailabity requirements to deliver the drug Project Management in Drug Development February 2011

Developing a Dosage Formulation The Process of Taking the Drug and Inactive Ingredients to Produce Stable Dosage Forms that Deliver Safe and Therapeutically Effective Levels of Medicine Upon Administration Source: Abbott Project Management in Drug Development February 2011

Phase 1 Clinical Testing First time in humans (FIH) Healthy volunteers (not patients) Small number of subjects (~20–80) Examples of questions that researcher must answer satisfactorily include: Is the drug safe? Within what dose range? What is the maximum tolerated dose? How quickly is the drug absorbed? Where in the body is the drug distributed? How quickly is the drug eliminated? How difficult is the drug to manufacture? Source: Abbott Project Management in Drug Development February 2011

Phase 2 Clinical Studies Approximately 100 to 300 patients with the targeted disease are tested to determine the drug’s effectiveness to treat disease and short-term side effects Source: Abbott Project Management in Drug Development February 2011

Phase 2 Clinical Studies (cont.) First time in patients who have disease or condition Proof of concept (POC) to see if drug actually works as experimental data suggested Is the drug safe in patients? Is the drug effective within the safe dose range? What is the minimum effective and the optimal dose? Is the drug effective in mild, moderate and severe cases of the disease or condition? Statistical difference from placebo More patients than Phase 1 (n~100s) Phase 2 studies are generally not statistically powered to support registration Source: Abbott Project Management in Drug Development February 2011

Phase 3 Clinical Studies Thousands of patients are tested in clinics or hospitals to determine the drug’s effectiveness and side effects. Phase 3 studies are conducted in many sites around the world and cost tens to a hundred million dollars. Source: Abbott Project Management in Drug Development February 2011

Phase 3 Clinical Studies (cont.) Phase 3 studies involve large numbers of patients (n~1000s) and are conducted at multiple sites in multiple countries. Studies last from months to several years and answer questions such as: Is the drug safe in large populations? Do the benefits of therapy out weigh the safety risks? Does the drug interact with other drugs? Is the drug more or less effective than other competing drugs? Is the drug effective under unusual circumstances? Do patients build up a tolerance to the drug? Is there an explanation for the times when the drug is not effective? Source: Abbott Project Management in Drug Development February 2011

Regulatory Submission and Approval Regulatory submissions seek approval to sell a new drug All data are compiled and submitted for review by the regulatory authorities If regulatory authorities concur that the data prove safety and effectiveness, it will approve the drug, along with official labeling, and guidelines for its administration Submission documents United States (FDA) New Drug Application (NDA): Small Molecules Biologics License Application (BLA): Biologics European Union (EMA) Marketing Application (MA): Small Molecule or Biologic Source: Abbott Project Management in Drug Development February 2011

After Regulatory Approval Regulatory approval is the starting point for many post approval activities and life cycle management improvements to the products such as new indications Product launch Product marketing and education to physicians, patients, and payors Post-market surveillance Follow up on adverse reactions Respond to physicians’ needs Source: Abbott Project Management in Drug Development February 2011

Project Management Team Project Management Compound Project-Team Structure Situation in (former) Solvay Project Management Team Pharmacovigilance/ Safety Team Clinical Pharmacology Team Project Director (P-team) leader Cross-functional Project Team (P-team) Health Economy Team GPRM Team Leader ClinPharm Team Leader Marketing Team GHE Team Leader GPS Team Leader PDS Team Leader Chemical & Pharmaceutical Development Team Research Team Research Team Leader Regulatory Team Leader Regulatory Team Liaison (US/EU) Reg CMC (US/EU) Tech Support (US/EU) Japan, EELA/AMAC Clinical Team Clinical Team Leader Project Management in Drug Development February 2011

Global Project Team (GPT) “The fundamental project working unit for drug development” Sets the strategic direction for the project, makes recommendations to governance bodies and executes the project plan Develops and delivers Target Product Profile (TPP), Product Development Plan (PDP) Product Labeling Risk Management Plan (RMP) Project Communication Purpose and Key Deliverables Source: Abbott Project Management in Drug Development February 2011

Leadership Team Empowers Project Teams and Line Functions Senior Strategic Leadership R&D + Commercial Project Strategy, Planning and Execution Project Team Headcount Budget Science Line Functions Team Members Empowerment Accountability Project Management in Drug Development February 2011

Thank you! QUESTIONS ? Project Management in Drug Development February 2011