Bridging the Gap - Research into Practice

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

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

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

6. 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. 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. Safe Use of Drugs ? Antibiotics use in pregnancy in Germany 2000/2001 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. Actions in Germany: None

9. Safe Use of Drugs ? The Case of digitoxin-intoxication 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. Actions in Germany: None Hippius M et al. Int J Clin Pharmacol 2001;39:336-343.

10. Safe Use of Drugs ? The case of long acting beta agonists There are two large randomized trials, both showed an increased mortality with salmeterol. Mortality Castle et al. 1993 Salmeterol vs Salbutamol 0.32% vs 0.24% SMART 2002 Salmeterol vs Placebo 0.31% vs 0.24% Number needed to harm (kill): 1250 - 1428 patients Actions in the U.S.: Dear Dr. Letter Black Box Warning Germany: None

11. The Problem is: Who is responsible for Patient Safety? • EU-Regulations • National Law

12. 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. 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. Summary of the Role and the Responsibilities • 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 Marketing Authorisation Holder • 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 Member States Volume 9 - Pharmacovigilance

15. The Problem is: 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

16. 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. Pharmacovigilance Planning • starts PV early, i.e. before the license is granted • is proactive • tries to demonstrate safety, as opposed to looking for harm Tools • Pharmacovigilance Specification • Pharmacovigilance Plan

19. Pharmacovigilance Specification (PVS) • Summary of the identified risks, the potential risks and any important missing information • All 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. • Assessment of trials population vs. patient population (e.g. women, children) • Consideration of class effects for the medicine at time of submission / approval Tsinitis P and La Mache E. Drug Safety 2004;27:509-517.

20. Pharmacovigilance Plan • is based on PV specification • includes appropriate proposals for key issues as identified in the PVS, e.g. epidemiological studies • provides the rationale for such studies, the objectives and mile-stones for evaluation

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

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

23. Conclusions • 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.