1. IBE J. Hasford Munich Bridging the Gap - Research into Practice Prof. Joerg Hasford, M.D., Ph.D. German Pharmacovigilance Study Group IBEDepartment of Medical Informatics, Biometry and Epidemiology, University of Munich, Germany Email:has@ibe.med.uni-muenchen.de Pharmacovigilance Research and Patient Safety Policies

2. IBE J. Hasford Munich Frequency of ADR-related Hospital Admissions Meta-Analysis of 25 publications covering medical departments Median (all):5.8% Median (age > 60):10.2% Mühlberger N, Schneeweiss S, Hasford J. Pharmacoepidem Drug Safety 1997; 6 Suppl. 3: S71-S77.

3. IBE J. Hasford Munich Direct Costs of ADR-related Hospital Admissions in Germany 4.5 Mio Admissions to Medicine Departments / year 5.8% due to ADR 8.7 days median length of stay 310 € costs per day in hospitals (2000) 704,000,000 € / year

4. IBE J. Hasford Munich Preventability of ADRs Meta-Analysis of 14 publications Goettler M, Schneeweiss S, Hasford J. Pharmacoepidem Drug Safety 1996;6 Suppl.3:S79-S90 30.7% (median) of ADRs leading to hospital admission are preventable.

5. IBE J. Hasford Munich Pharmacovigilance The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug- related problem. WHO

6. IBE J. Hasford Munich Pharmacovigilance collects, records, codes ADEs / ADRs analyses and assesses the reports promotes the safe use of drugs creates appropriate structures and means of communication needed to perform its tasks

7. IBE J. Hasford Munich Aims of Pharmacovigilance to improve patient care and safety to improve public health and safety to contribute to the assessment of benefit, harm, effectiveness and risk of medicines to promote education and clinical training to promote effective communication to the public to promote rational and safe use of medicines

8. IBE J. Hasford Munich Safe Use of Drugs ? Antibiotics use in pregnancy in Germany 2000/2001 Actions in Germany:None Tetracyclines count among the 10 most prescribed antibiotics during pregnancy (1/1000 pregnant women). It is well known for more than 30 years that tetracyclines can severely damage teeth and bone structures of the fetus.

9. IBE J. Hasford Munich Safe Use of Drugs ? The Case of digitoxin-intoxication Actions in Germany:None Intoxications with digitoxin count still among the most common causes of ADR-related hospital admissions (12 - 14/10,000 / quarter year). The therapeutic benefit of digitoxin is rather limited, however. Hippius M et al. Int J Clin Pharmacol 2001;39:336-343.

10. IBE J. Hasford Munich Safe Use of Drugs ? The case of long acting beta agonists Actions in the U.S.:Dear Dr. Letter Black Box Warning Germany:None There are two large randomized trials, both showed an increased mortality with salmeterol. Mortality Castle et al. 1993Salmeterol vs Salbutamol0.32% vs 0.24% SMART 2002Salmeterol vs Placebo0.31% vs 0.24% Number needed to harm (kill): 1250 - 1428 patients

11. IBE J. Hasford Munich The Problem is: Who is responsible for Patient Safety? rEU-Regulations rNational Law

12. IBE J. Hasford Munich Market Authorization Holder collect, collate, validate and follow up (SAEs) of all reported suspected Adverse Events screen the relevant world-wide literature at least once / week report all serious suspected ADRs within 15 days submit PSURs company-sponsored Post-Authorisation Safety Studies regularly checks risks and benefits and acts accordingly

13. IBE J. Hasford Munich Drug Authority collect, validate, code, store and analyse reports transmit ADR data to the MA holder inform health care professionals and, when needed, treated patients, of any significant changes Decision Making Communication with all interested parties Evaluation of the actions taken

14. IBE J. Hasford Munich Marketing Authorisation Holder Establish and maintain a system, accessible at a single point in the EU, to collect, collate, and evaluate pharmacovigilance data Meet legal obligations for reporting suspected adverse drug reactions Meet legal obligations regarding the preparation and the submission of PSURs Respond fully to requests from authorities for additional information necessary for the evaluation of the benefits and risks of a medicinal product Ensure the Marketing Authorisation is maintained and reflects the latest information Member States Have in place national pharmacovigilance systems Inform the European Commission, the CPMP, the Agency, the member states and the MAHs of any relevant actions Collect and collate risk / benefit data Provide serious ADRs which have occurred in its territory to the Agency and the relevant MAH within 15 calendar days of receipt Identify and evaluate drug safety alerts and conduct risk / benefit evaluations Provide representation on CPMP, PhVWP and Rapporteurs / Co-Rapporteurs Implement Commission Decisions In case of urgent action to protect public health, suspend the use of the product in the member state’s territory and inform, in accordance with the legislation, the Agency and the European Commission of the basis for action Summary of the Role and the Responsibilities Volume 9 - Pharmacovigilance

15. IBE J. Hasford Munich There are a lot of laws and regulations, but with very little impact on routine medical care, except when a drug is withdrawn from the market. There are too many parties involved, e.g. hospitals, physicians, sickness funds, patients, industry, government institutions, media, juris- diction and the like, but there is No institution solely devoted on Patient Safety The Problem is:

16. IBE J. Hasford Munich Patient Safety Policies October 2004 The World Alliance for Patients’ Safety was launched. AIMS to coordinate international actions and avoid duplication of effort in coping with escalating problems of iatrogenic disease and health care misadventures

17. Edwards RI. The WHO World Alliance for Patient Safety - A New Challenge or an Old One Neglected? Drug Safety 2005;28:379-386.

18. IBE J. Hasford Munich Pharmacovigilance Planning rstarts PV early, i.e. before the license is granted ris proactive rtries to demonstrate safety, as opposed to looking for harm Tools rPharmacovigilance Specification rPharmacovigilance Plan

19. IBE J. Hasford Munich Pharmacovigilance Specification (PVS) rSummary of the identified risks, the potential risks and any important missing information rAll relevant data, e.g. preclinical toxicology, pharmacology, target organ findings, potential for interactions and all clinical data collected during the phases of drug development are evaluated. rAssessment of trials population vs. patient population (e.g. women, children) rConsideration of class effects for the medicine at time of submission / approval Tsinitis P and La Mache E. Drug Safety 2004;27:509-517.

20. IBE J. Hasford Munich Pharmacovigilance Plan pis based on PV specification pincludes appropriate proposals for key issues as identified in the PVS, e.g. epidemiological studies pprovides the rationale for such studies, the objectives and mile- stones for evaluation

21. IBE J. Hasford Munich 4A concerted action with transparent and com- prehensive responsibilities is essential 4Annual reports about the state of patient safety in health care  competition 4Access to the data 4Pharmacovigilance Planning and Risk Manage- ment 4Systematic and continuous use of pharmaco- epidemiologic data bases, e.g. GPRD (UK, PHARMO (NL), MEMO (Scotland) Starting points for improvement

22. IBE J. Hasford Munich 4Low threshold AE-reporting systems 4regional (i.e. at least EU-member state level) ADR and Drug Utilisation monitoring 4Effective strategies to modify physicians’ prescribing and patients’ compliance are urgently needed 4More use of modern information technologies

23. IBE J. Hasford Munich /ADEs are a major public health threat with significant financial cost implications. /Pharmacovigilance has made and will make es- sential contributions to the safer use of medicines. /There is still a considerable gap between the results of Pharmacovigilance research and medical practice. /A concerted action of all parties involved and a reliable and proactive partner are essential to gain the full benefit of pharmacovigilance research. Conclusions