From Adverse Events to Risk management

1. From Adverse Events to Risk management Munir Anwar Ph. D Chief Operating Officer Martin Dow limited

2. Why Pharmacovigilance? • Started with the administration of plants as medication in old ages….

3. Why Pharmacovigilance? • : Thalidomide disaster. • : WHO resolution laying basis of monitoring of adverse drug reactions (ADRs). • : WHO Research Centre for monitoring ADRs setup. 1995 : EMEA

4. From ADRs to risk management From : The detection, evaluation, understanding and prevention of adverse drug reactions of marketed drugs (PV). To : The risk management of drugs during their whole lifecycle.

5. Risk management • Risk management : identification and implementation of strategies to reduce risk to individuals and populations • Risk assessment : identification, evaluation of the nature and severity of risks associated with the use of a product. • Pharmacovigilance specification :summary of the known risks of a drug, the potential for unidentified risks.

6. Risk management • Tools • Collection of adverse Events from clinical trials and Adverse Reactions from market. • Management of cases collected : evaluation, coding, causality assessment, reporting. • Global evaluation : written summary, Summary of clinical safety, Periodic Safety Update Reports (PSUR). • Pharmacoepidemiology.

7. Risk management • Premarketing phase • Registration / Approval • Marketing phase

8. Premarketing phase

9. Health Professional Ambition • At the end we need to get a product with known risk profile and benefit which outweigh the risk.

10. Risk assessment in clinical trials Requires : • Drug knowledge : pharmacology, pharmacological class… • Disease indication understanding : Disease : evolution, complications Population treated : age, concurrent illness, concomitant usual treatment. Objective : • To define the background rate of events. • Pharmacovigilance tools

11. Premarketing risk assessment • Preclinical studies • Photosensitivity : drugs which absorbed light between 290 and 700nm are at risk, photoinstability. • In vivo / in vitro test required. • Toxicity • Allergy. • Carcinogenicity / mutagenicity. • Pharmacokinetics : drug localized in skin and / or eyes? • Pharmacological class / indication • Adverse events collection

12. Drug interactions • Absorption • Metabolism • Elimination • Pharmacodynamic interactions

13. Drug interactions Antacids : block absorption of many drugs interval of 2 hours between intake. • Elderly population will be tested. Drug – food interaction Grapefruit juice inhibits intestinal CYP CA4 which affects drug metabolism

14. Drug interactions Drug – disease interaction : Renal disease Liver disease

15. Drug interactions Interaction on the target organ: Addition of effects Anticoagulants Aspirin Clopidogrel

16. Post-marketing risk management Tools : Routine pharmacovigilance practices including : • Collection • Evaluation • Reporting • Periodic Safety Update Reports • Signal generation

17. Post-marketing risk management Should take into consideration : • The assessed risk • The epidemiology of the disease : • Incidence / prevalence • Severity / disability • Evolution • Cost • The Drugs available. • In some cases further studies are needed (morbidity-mortality…)

18. Definition of an Adverse Event The International Conference on Harmonization (ICH) definition of an adverse event is "any untoward (undesirable) medical occurrence in a patient ... administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment."

19. WHY REPORT Adverse Events? Serious adverse events (SAE's) resulting from the use of thalidomide were not immediately reported from 1957 to 1961. This occurred prior to the implementation of federal regulations governing the reporting of adverse events associated with pharmaceutical products. As a result, 10,000 children in 12 countries were born with deformities. Risk benefit Ratio is always change. SAE reporting will help it to understand better

20. WHY REPORT Adverse Events? • In 1994, the FDA learned from the National Institute of Health (NIH) that 22 patients who were treated with high doses of IV immunoglobulin (IGIV) were experiencing aseptic meningitis syndrome (AMS). • As a result, the FDA directed IGIV manufacturers to include a precaution statement about the occurrence of the syndrome. • Due to diligent reporting, physicians and patients were made aware of a potential threat to patient safety.

21. WHY REPORT Adverse Events? • There are several implications of NOT reporting AE's: • Patient safety is compromised. • Failure to report adverse events may result in a regulatory • violation and/or legal penalties. • The drug may have to be removed from the market. • Clinical trials may have to be discontinued. • A pharmaceutical company's reputation may be • destroyed. • You could also be personally accountable for non- • compliance to global regulations. • Current Safety profile for the drug will not be reflected in • product label.

22. Importance of Adverse Event Collection • Patient Safety • Regulatory Compliance • Product Information • Prescriber confidence • Impact on Corporate Assets

23. Adverse Event Reporting Required Information • “R” eporter Information • "E" vent Information • "P" atient Information • "P" roduct Information

24. “R” eporter Information • Name, Address, Telephone/Fax • Reporter Classification • Health care professional • (certified medical professional) • Consumer • Secondary reporter or contact • Relatedness opinion

25. “E” vent Information • Describe the adverse event(s) providing relevant details - labs, diagnosis • Explain what happened and when it happened • Specify how long the event occurred • Describe what action was taken (drug discontinued) • Describe the outcome of the event(s)

26. “P” atient Information • Patient’s Initials (unique identifier) • - follow up • Demographics (age, race, gender) • - data analysis • Medical History • - case assessment

27. “P” roduct Information • Product Name • Trade and Generic Names • Manufacturer • Dose / Dosage Form • Therapy Dates / Duration • Indication for Use

28. Serious Adverse Event An adverse event is considered serious if the event results in any of the following: • A patient's death. • A life-threatening situation (an immediate danger of dying). • Inpatient hospitalization (or prolongs an in-patient hospitalization). • Severe or permanent disability. • Congenital anomaly. • Or is deemed as serious for other reasons by the reporter (use when no other serious criteria/indicator applies but the event is of serious medical consequence)..

29. 15 Essential Fields

37. Step forward • What our authorities should do? • Issue guidelines • Capacity building of staff • Reporting format • Reporting medium (web based, 7/24) • What to report • All complaints ??? • ADRs in the prescribing information? • ADRs first time reported • Who to report ? • Manufacturer • Physician • Patient • How to respond to reports?

38. Conclusion • Evaluation of safety does exist during the whole life of a drug. • Risk management should help the correct prescription and use of a drug. • Risk management means that the benefits outweigh the risk.

39. Thank you Contact : munir.anwar@martindow.com