Presentation introduction on new drug development Prof. JanHasker G. Jonkman

INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • Worldwide Sales of Medicines • Costs of Research and Development • New Drug Approvals • Development of a New Drug • Synthesis • New Drug • PharmacologyToxicology • Clinical Pharmacology • Phase I – studies • Phase II – studies • Phase III – studies • Market Authorization • Phase IV – studies • Conclusions

20120404 1/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT Prof JanHasker G Jonkman, Ph.D., F.C.P., F.R.Q.A., R.Ph., Clinical Pharmacologist University of Groningen (NL) Professor Quality Management in Drug Research and Manufacturing JHGJ/gh 20120404 2/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • • • • • • • • • • • • • • Worldwide Sales of Medicines Costs of Research and Development New Drug Approvals Development of a New Drug Synthesis New Drug Pharmacology/Toxicology Clinical Pharmacology Phase I – studies Phase II – studies Phase III – studies Market Authorization Phase IV – studies Conclusions JHGJ/gh 20120404 3/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • • • • • • • • • • • • • • Worldwide Sales of Medicines Costs of Research and Development New Drug Approvals Development of a New Drug Synthesis New Drug Pharmacology/Toxicology Clinical Pharmacology Phase I – studies Phase II – studies Phase III – studies Market Authorization Phase IV – studies Conclusions JHGJ/gh 20120404 4/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) WORLDWIDE SALES OF MEDICINES: BY REGION (2010) Country Sales (billion US $) % of worldwide sales North America 342 39.1 Europe Asia (excluding Japan), Africa and Australia Japan Latin America TOTAL 250 28.6 129 99 53 875 14.8 11.3 6.2 100.0 (Source: PAREXEL R&D Sourcebook, 2011/2012) JHGJ/gh 20120404 5/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) WORLDWIDE SALES OF TOP 10 MEDICINES: BY THERAPEUTIC CLASS (2010) Rank 10 Therapeutic Class Sales (billion US $) Cytostatics Cholesterol & Triglyceride reducers Respiratory agents Antidiabetics Anti-ulcerants Angiotensin-II inhibitors Antipsychotics Autoimmune agents Antidepressants HIV Antivirals % of worldwide sales % of growth (vs 2009) 56.0 6.4 + 6.7 36.4 35.9 34.4 28.0 26.6 25.4 20.7 20.2 15.4 4.2 4.1 3.9 3.2 3.0 2.9 2.4 2.3 1.8 + 2.0 + 7.0 + 12.2 - 6.5 + 4.5 + 9.0 + 14.7 + 3.4 + 13.2 (Source: PAREXEL R&D Sourcebook, 2011/2012) JHGJ/gh 20120404 6/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) WORLDWIDE SALES OF TOP 10 MEDICINES: BY PRODUCT (2010) (1) Rank Product Lipitor (atorvastatin; antilipidic agent) Plavix (clopidogrel; antithrombic agent) Seretide (salmeterol/fluticasone; asthma/COPD) Nexium (esomeprazol; antiulcer) Seroquel (quetiapine; antipsychotic agent) Sales (billion US $) 12.7 Company Pfizer 8.8 Sanofi-Aventis 8.5 GSK 8.4 Astra Zeneca 6.8 Astra Zeneca (Source: IMS Health World Review, 2010) JHGJ/gh 20120404 7/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) WORLDWIDE SALES OF TOP 10 MEDICINES: BY PRODUCT (2010) (2) Rank 10 Product Sales (billion US $) Crestor (rosuvastatine; antilipidic agent) Enbrel (etanercept; antirheumatic agent) Remicade (infliximab; antirheumatic agent) Humira (adalimulab; antirheumatic agent) Zyprexa (olanzapine; antipsychotic agent) Company 6.8 Astra Zeneca 7.3 Wyeth 6.0 6.0 Schering-Plough (Merck&Co) Abbott 5.7 Eli Lilly (Source: IMS Health World Review, 2010) JHGJ/gh 20120404 8/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) WORLDWIDE SALES OF MEDICINES: BY COMPANY (2010) Rank Company 10 Pfizer (US) Sanofi-Aventis (F/Ger) Merck & Co (US) Novartis (Swi) GlaxoSmithKline (UK) Roche (Swi) AstraZeneca (Swe/UK) Johnson & Johnson (US) Eli Lilly & Co (US) Abbott (US) Pharma sales (billion US $) 58.2 40.3 39.8 39.1 36.1 35.6 33.3 22.4 21.1 19.9 (Source: Scrip 100, 2011) JHGJ/gh 20120404 9/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • • • • • • • • • • • • • • Worldwide Sales of Medicines Costs of Research and Development New Drug Approvals Development of a New Drug Synthesis New Drug Pharmacology/Toxicology Clinical Pharmacology Phase I – studies Phase II – studies Phase III – studies Market Authorization Phase IV – studies Conclusions JHGJ/gh 20120404 10/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) COSTS OF RESEARCH & DEVELOPMENT (2010) • World wide expenditure on R&D of new medicines approximately $ 130.000.000.000 per year • Of which costs of clinical research: $ 75.000.000.000 JHGJ/gh 20120404 80/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKETING AUTHORIZATION (13) USA (3) New Drug Application (2) FDA review team: • Chemistry, Manufacturing and Controls reviewer • Pharmacology / Biopharmaceutics reviewer • Pharmacology / Toxicology reviewer • Biometrics / Statistical reviewer • Clinical / Medical reviewer • Bioresearch Monitoring reviewer Continuous questions to applicant during technical review period Pre-approval inspections are conducted (Source: L Vromans) JHGJ/gh 20120404 81/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKETING AUTHORIZATION (14) Comparison EU vs USA (1) EU USA • • • • • • • Top-down approach in evaluation Expert evaluations Raw data only analysed if grounds for doubt are found Some interaction before submission (increasing) Limited company interaction with experts during procedure Accelerated assessment for high medical need products (Source: L Vromans) • • • • • Bottom-up approach in evaluation ISS / ISE, integrated summaries of safety & efficacy FDA always analyses raw data Many meetings before submission Advisory Committee involvement Accelerated development and priority review for high medical need products JHGJ/gh 20120404 82/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKETING AUTHORIZATION (15) Comparison EU vs USA (2) EU USA • • • • Withdrawal if a negative opinion is expected Labelling can not contain detailed study results Action letter evaluation Detailed study results in labelling (marketing!) Approval in US does not automatically imply approval in EU, and vice versa; co-operation between authorities is beginning to take place (e.g on paediatric development) (Source: L Vromans) JHGJ/gh 20120404 83/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKETING AUTHORIZATION (16) Maintenance (1) • Marketing authorization is valid for years JHGJ/gh 20120404 84/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKETING AUTHORIZATION (17) Maintenance (2) Marketing authorization need maintenance: • Variations quality variations to improve production method new indications, new formulations, new route of administration results of pharmacovigilance, new safety information • Pharmacovigilance activities are required; post-marketing surveillance periodic Safety Update Reports one renewal after five years (EU) Risk management Plans (EU: RMP / US: REMS) • Registrations in other countries to extend use of the product (Source: L Vromans) JHGJ/gh 20120404 85/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKET AUTHORIZATION (18) • The new drug (but also during the investigation period) should be manufactured according to another set of key documents: Good Manufacturing Practices (GMP) - 1975 : U.S.A - 1991 : EU JHGJ/gh 20120404 86/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) JHGJ/gh 20120404 87/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKET AUTHORIZATION (19) • After receipt of market authorization continuous, systematic documentation of side-effects: pharmacovigilance (also called ‘Phase V’) JHGJ/gh 20120404 88/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKET AUTHORIZATION (20) • Pharmacovigilance (1) purpose: to provide accurate, complete and timely information about the benefit-risk profile of a medical product throughout its life cycle JHGJ/gh 20120404 89/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) MARKET AUTHORIZATION (21) • Pharmacovigilance (2) each pharmaceutical company need to maintain a system that ensures: - an active, systematic and continuous monitoring of pharmacovigilance cases reviewed - early detection of safety signals - that appropriate actions are taken to minimize risks JHGJ/gh 20120404 90/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • • • • • • • • • • • • • • Worldwide Sales of Medicines Costs of Research and Development New Drug Approvals Development of a New Drug Synthesis New Drug Pharmacology/Toxicology Clinical Pharmacology Phase I – studies Phase II – studies Phase III – studies Market Authorization Phase IV – studies Conclusions JHGJ/gh 20120404 91/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) PHASE IV - STUDIES (efficacy/safety; therapeutic use) • Patients (ambulant GPs; ± 25,000) • Performed after marketing authorization was obtained • Result: practical utility JHGJ/gh 20120404 92/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) JHGJ/gh 20120404 93/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • • • • • • • • • • • • • • • • Sales of Medicines in the Netherlands Worldwide Sales of Medicines Costs of Research and Development New Drug Approvals The Cost per Day of Delay Development of a New Drug Synthesis New Drug Pharmacology/Toxicology Clinical Pharmacology Phase I – studies Phase II – studies Phase III – studies Market Authorization Phase IV – studies Conclusions JHGJ/gh 20120404 94/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) CONCLUSIONS • New drugs: effective and safe • New drug development is expensive and time consuming ($ billion; 10 years) • Many laws and regulations (a.o GCP; GLP) led to  better protection of study participants and study animals  more reliable study data (less scientific misconduct and less fraud)  marketing authorization is extensive, time consuming JHGJ/gh ... INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) NEW DRUG: PATENT LIFE (3) JHGJ/gh 20120404 35/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS... 20120404 22/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) JHGJ/gh 20120404 23/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS • • • •... 13/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) CLINICAL PHARMACOLOGY (2) JHGJ/gh 20120404 14/94 INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.) INTRODUCTION ON NEW DRUG DEVELOPMENT TABLE OF CONTENTS