PharmaCon2007 Conference Dubrovnik Croatia

1. Pharmacovigilance Workshop

6. From test tube to the market – PRECLINICAL RESEARCH SYNTHESIS CANDIDATES SAFETY, TOLERABILITY & PHARMACOKINETICS Toxicity testing , reproductive toxicology, carcinogenicity, genotoxicity, toxicokinetics DRUG SCREENING activity & selectivity = Pharmacological profile

7. From test tube to the market – CLINICAL RESEARCH PHASE I PHASE III PHASE II “ First-in-Man Trial” Pharmacokinetics Metabolism Pharmacology Safety (early effectiveness) 20-80 HEALTHY VOLUNTEERS Preliminary data on efficacy for a particular indication(s) Short-term Adverse Drug Reactions Dose range SEVERAL HUNDRED PATIENTS WITH DISEASES OR CONDITION SEVERAL HUNDRED TO THOUSAND PATIENTS Efficacy and safety for overall benefit-risk assessment Product information APPROVAL

8. ? Limitations of Clinical Study Data ? Variable (compliance?) Fixed Dose Flexible; less information Rigorous; more information Conditions Usually present Avoided Concomitant medication and illness All Pregnant, children, elderly excluded Population Years Weeks Duration Thousands to millions Hundreds (rarely thousands) Number of patients Clinical Practice Clinical trials

9. Drug Safety Information Formulation (STRUCTURE ACTIVITY RELATIONSHIP) Preclinical studies (TOXICOLOGY, PHARMACOLOGY, PHARMACOKINETICS) Clinical studies (IDENTIFICATION OF ADRs, CHARACTERISATION, CAUSALITY, FREQUENCY, MANAGING) Pre marketing RARE ADRs? CHRONIC USE? DELAYED ADRs? INTERACTIONS? CHILDREN/ELDERLY?

10. From test tube to the market – CLINICAL RESEARCH PHASE I PHASE III PHASE II “ First-in-Man Trial” Pharmacokinetics Metabolism Pharmacology Safety (early effectiveness) 20-80 HEALTHY VOLUNTEERS Preliminary data on efficacy for a particular indication(s) Short-term Adverse Drug Reactions Dose range SEVERAL HUNDRED PATIENTS WITH DISEASES OR CONDITION SEVERAL HUNDRED TO THOUSAND PATIENTS Efficacy and safety for overall benefit-risk assessment Product information APPROVAL POSTMARKETING SURVEILLANCE

13. Withdrawals from the market as a result of spontaneous reporting 1998 1997 Serious hepatotoxic effect bromfenac 1998 1985 Fatal cardiac arrythmias terfenadine 1992 1992 Haemolytic anemia temafloxacin 1991 1987 Excessive mortality encainide 1982 1982 Onycholysis, renal, liver, bone marrow toxicity benoxaprofen 1975 1970 Blindness practolol Year of withdrawal Year of approval Reason for withdrawal INN

19. The Concept of Pharmacovigilance System

20. Pharmacovigilance – concerned parties Competent Authorities (National Agencies, European Medicines Agency) Healthcare Professionals: Voluntary reporting or Mandatory reporting WHO Pharmaceutical Industry (Marketing Authorisation Holder & Sponsor of Clinical Trials) Patients: Complain or Complain & Report

21. Collect Identify Evaluate Take action INDIVIDUAL REPORTS

27. Collect PSUR Identify Evaluate Take action INDIVIDUAL REPORTS

29. Collect SIGNAL DETECTION PSURs Identify Evaluate Take action INDIVIDUAL REPORTS

30. Signal Detection Today: Large & Complex computerised systems Signal: new, previously unknown safety information

31. Collect SIGNAL DETECTION PSURs Identify Evaluate Take action INDIVIDUAL REPORTS CLINICAL EVALUATION REGULATORY ACTION INFORMATION TO HEALTHCARE PROFESSIONALS AND THE PUBLIC

39. Agency for Medicinal Products and Medical Devices, Ksaverska cesta 4, Zagreb tel. 01/ 46 93 830; fax. 01/ 46 73 275

42. Educational activities

46. Introduction to the Workshop

58. WHO causality classification Probable Unlikely Unlikely Possible No data on dechallenge Possible Possible Dechallenge Probable No Dechallenge i rechallenge Certain Other factors Time relationship

59. Time for exercise!