This document provides an introduction to pharmacovigilance, which is the study of the safety of marketed drugs. It discusses the importance of pharmacovigilance due to past drug safety issues like the thalidomide tragedy. Key terms related to pharmacovigilance are defined, such as adverse events, adverse reactions, and signals. Methods of pharmacovigilance like passive surveillance, data mining, and active surveillance are described. Important organizations involved in pharmacovigilance include the FDA, EMEA, MHLW, and CDSCO.

1. Basics of PHARMACOVIGILAnce Naganand.Jayakumarswamy

2. iNTRODUCTION Pharmacovigilance :is the study of the safety of marketed drugs under the practical conditions of clinical use in large communities Pharmacovigilance: is concerned with the development of science and regulation in the area of drug safety. Pharmacovigilance aims at the detection, assessment and prevention of adverse effects and other problems related to the use of medicines.

3. Importance of pharmacovigilance-preamble Thalidomide tragedy (1961-62): The greatest of all drug disasters. Thalidomide had been introduced and welcomed as a safe and effective hypnotic and antiemetic. It rapidly became popular for the treatment of nausea and vomiting in early pregnancy. Tragically the drug proved to be a potent human teratogen that caused major birth defects in an estimated 10,000 children Phocomelia was a characteristic feature

5. Other historic violations Sulfanilamide tragedy: Elixir sulfanilamide was an improperly prepared sulfanilamide medicine that caused mass poisoning in the United States in 1937. It caused the deaths of more than 100 people. The public outcry caused by this incident and other similar disasters led to the passing of the 1938 Federal Food, Drug, and Cosmetic Act The thalidomide disaster led,in Europe and else where ,to the establishment of the drug regulatory mechanisms of today. These mechanisms require that new drugs shall be licensed by well –established regulatory authorities before being introduced into clinical use

6. List of a few licenced medicines withdrawn after marketing for drug safety reasons: Secholex(polidexide)-1975 Zomax-1983 Halcion-1991 Kava kava-2001-due to liver toxicity Vioxx(rofecoxib)-2004-due to incresed cardiovascular risks Bextra(valdecoxib)-2005-due to Stevens-Johnson syndrome

7. Glossary of terms Adverse event: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with the treatment. Adverse reaction: WHO technical report:A response to a drug which is noxious and unintended and which occurs at doses normally used in humans for the prophylaxis,diagnosis or therapy of disease or for the modification of physiological function

8. Expected: As opposed to “unexpected”, an event that is noted in the investigatorse brochure or labeling (package insert or summary of product characteristics). Unexpected adverse reaction: the nature or severity of which is not consistent with the domestic labeling or market authorization, or expected from characteristics of the drug. Signal: Reported information on possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than one single report is required to generate a signal depending upon the seriousness of the event and quality of information.

9. Data mining: is used to describe various automated or semiautomated techniques to generate signals from existing databases. For each AE, the calculation of the proportion of that AE as a function of all Aes reported for a drug is calculated and compared with the proportion of that AE for all other drugs in the database Example: liver failure for drug X was reported as 95 times out of the 1,418total AEs for drug X.The proportion is 95/1,418=0.067 and is called “Score” or “Statistic”. This score can be used as a comparison for other drugs in database. For a signal to be generated the score should be >1

10. Classification of adverse effects Type A: (Drug reactions)-Pharmacological adverse effects. Common->1% Dose relationship Suggestive time relationship Reproducible Type B: (“Patient Reactions”) Immunoallergic reactions Idiosyncrasy Rare<1%

11. Unexpected Causality uncertain Not reproducible experimentally Characteristic-serious Type C adverse effects (Statistical effects) Often long latency Mechanism unknown Difficult to reproduce experimentally

12. Methodologies in pharmacovigilance Passive surveillance Spontaneous reporting Case reports Case series Stimulated reporting Active surveillance Comparative observational studies Cross sectional studies Case control study Cohort study

13. Important organisations involved in pharmacovigilance FDA:The Food and Drug Administration (FDA or USFDA) is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments, responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), veterinary products, and cosmetics.

14. EMEA: The European Medicines Agency is a decentralised body of the European Union located in London MHLW: Ministry of Health, Labor and Welfare,Japan CDSCO: The government of India with the assistance of world bank has initiated the National pharmacovigilance programme. The central drugs standard control organization (CDSCO) is coordinating the country wide pharmacovigilance programme under the aegis of Ministry of health and family welfare, DGHS New delhi

15. Uppasala monitoring centre Vigibase: The Uppasala monitoring centre(UMC, on behalf of WHO) has over 3 million AE case reportes from over 75 countries. The data are supplied by national health authorities. Most of the data are from the United states and supplied by the FDA.The UNC does not review or assess the individual cases put into database, but it does pharmacovigilance analyses and signaling.

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