PHARMACOVIGILANCE.pptx

basics of pharmacovigilance for medical graduates and post-graduates.

1. PHARMACOVIGILANCE BY- DR UTSAV SHINGHAL JR-II MD PHARMACOLOGY

2. references Kalaiselvan V, Srivastava S, Singh A, Gupta SK. Pharmacovigilance in India: Present Scenario and Future Challenges. Drug Saf , 2019 Mar; 42(3): 339-46. doi:10.1007/s40264-018-0730-7 Talbot JCC, Nilsson BS. Pharmacovigilance in the pharmaceutical industry. Br J Clin Pharmacol , 2011 May; 45(5): 427-31. doi:10.1046/j.1365-2125.1998.00713.x Skegg DC, Doll R. The case for recording events in clinical trials. Br Med J, 1997 Dec 10; 2(6101): 1523-4. doi:10.1136/bmj.2.6101.1523

3. What is pharmacovigilance? Pharmacovigilance is the science of detection, assessment, understanding and prevention of adverse drug effects or any other possible drug related problems.

4. PHARMACOVIGILANCE: HISTORICAL PERSPECTIVE

5. Pharmacovigilance before 18 th century The study of literature from before 18 th century reveals evidences of man’s awareness towards the possible harmful effects of drugs and therapeutic procedures undertaken for healing various ailments. Few such examples are quoted here. In 1780 BC, the Babylonian Code of Hammurabi gives details of punishment for harm done by medical procedures. According to it, “If a physician make a large incision with the operating knife, and kills him, or open a tumor with the operating knife, and cut out the eye, his hands shall be cut off.”

6. In 10 th century, Salerno medical school was empowered to inspect drugs for possible adulteration and severe penalties were imposed: “whosoever shall have or sell any poison or noxious drug not useful or necessary to his art, let him be hanged.” In 13 th century, the Oath of Apothecaries in Basle, Switzerland mentions the following about the use of drugs by physicians: “drugs should be of such good quality and of such usefulness that he knows, upon his oath, that it will be good and useful for the confection that the physician is making.”

7. In 1599, a charter was issued to make provisions for the supervision of sales of drugs and poisons by King James VI of Scotland. William Spang was the first inspector appointed and he took the responsibility of approving drugs for sale in Glasgow. All these instances indicate the keen interest of man in taking steps to eliminate the adverse effects associated with drugs and therapeutic measures. But the measures taken were localized to a small group of people and organized efforts to involve wider population did not exist.

8. Pharmacovigilance in 18 th century An English physician, William Withering, had published his extensive work on Foxglove in the year 1785. This work was later recognized as the first systematic paper on a medicinal drug with detailed description of adverse effects associated with digitalis treatment. In his book entitled “An account of Foxglove and Some of its Medicinal uses: with Practical Remarks on Dropsy and Other Diseases”, Withering gives a detailed description on methods used for synthesis of digitalis from foxglove in a standardized way, animal tests using turkeys, details of therapeutic effects and symptoms associated with digitalis overdoses.

9. In 1789, Wouter van Doeveren Professor of Medicine at Leiden university and a critic of medical practice of that time, discussed in his academic lecture named Remedio Morbi, the diseases or ailments which affect people as a result of administration of remedies for therapeutic purposes. In 18 th century, Calomel (mercurous chloride) was widely used in America for the treatment of yellow fever. Treatment lead to mercurialism characterized by intense salivation, loosening of teeth, ulceration and gangrene of mouth and cheeks and osteomyelitis of mandible. In spite of the adverse effects physicians continued to use Calomel.

10. Later, Oliver Wendall Holmes said, “if the whole materia medica as it is used now, could be sunk to the bottom of the sea, it would all be the better for the mankind and all the worse for the fishes.” These instances from 18 th century, indicate even the greater awareness of people especially academicians and physicians, who started communicating by various means such as lectures and publications, with regards to the issues related to safe-use of drugs.

11. Pharmacovigilance in 19 th century In 1848, a death of a 15 year old girl as a result of chloroform anesthesia administered for ingrown toe-nail was reported. In response to more deaths following chloroform anesthesia Glasgow Committee was appointed by British Medical Association for inquiry in 1880. The committee concluded that “Chloroform was injurious to heart and in comparison more dangerous than ether.”

12. Later, in 1888 in Hyderabad, Edward Lawrie claimed the safe use of chloroform in 40000 people without any fatality. So, the First Hyderabad Chloroform Commission was appointed to verify the claim and after conducting experiments in 141 animals, the commission concluded that chloroform could be safely used for anesthesia if respiration is carefully monitored. This report was not accepted in England and a Second Hyderabad Chloroform Commission was appointed to reinvestigate. It also included a representative from Lancet. The second commission confirmed the findings of Glasgow Committee.

13. Similarly, in America a statute was passed in 1848 in America to control the quality of drugs when the quinine imported for US army was found to be adulterated. A book, “ THE UNTOWARD EFFECTS OF DRUGS ”, regarding adverse effects was published by L. Lewin in 1881.

14. PHARMACOVIGILANCE IN 20 TH CENTURY The first drug related legislation in US, the Federal Food and Drug Act of 1906, was concerned with the interstate transport of misbranded or adulterated foods and drugs. There were no obligations to establish the efficacy and safety. In 1937, sulfa drugs were considered ‘miracle dugs’ as they killed a wide range of harmful bacteria. One of the manufacturers in 1938 had prepared an elixir of sulfanilamide by dissolving sulfanilamide in diethylene glycol, an excellent but highly toxic solvent. Subsequently, 107 people including 100 children were killed.

15. In June 1938, the Federal Food, Drug and Cosmetic Act was signed in USA. The new law required safety testing of new drugs before marketing and it became essential that new drug application (NDA) must incorporate the safety data. Although a new drug’s safety had to be demonstrated but no proof of efficacy was required.

16. Thalidomide, a hypnotic and an antiemetic drug with no obvious advantages over others, was synthesized in 1953 and was extensively promoted in 1956 under various brand names in Germany, England and other countries and was available as both the prescription and over-the-counter drug. An Australian physician McBride had observed the correlation between the maternal use of thalidomide and congenital malformations in newborns and he sent a letter to Lancet in this regard in June 1961, which got published in December 1961.

17. In November 1961, Dr Lenz from Germany had discussed the similar association in a pediatric conference. Finally, the manufacturer Chemie Grunenthal withdrew thalidomide from the market on 25 November 1961. Later it was reported that nearly 6000-12000 children were born with congenital anomalies due to maternal use of thalidomide and majority of them were born in Germany.

18. In reaction to this catastrophe, the US Congress had passed the Harris-Kefauver amendments to the Food, Drug and Cosmetic Act in 1962. These amendments established the requirement of proof of efficacy as well as the establishment of relative safety in terms of risk-to benefit ratio.

19. Pharmacovigilance: the current status The foundation of WHO International Drug Monitoring Program was laid down in 1971 during the 20 th World Health Assembly. The current international system of pharmacovigilance is based on a report published in 1972 and accordingly the national pharmacovigilance centers work in collaboration with WHO. The WHO Collaborating Centre for International Drug Monitoring is based in Uppsala, Sweden (Uppsala Monitoring Center).

20. Functions of UMC: Provides active support to pharmacovigilance centres in developing countries, Collects pharmacovigilance data from national pharmacovigilance centres , Maintains an international database, Evaluates the efficiency and problems of ongoing national pharmacovigilance programs, Takes measures to further strengthen the national pharmacovigilance programs by providing them with technical and financial support.

21. Pharmacovigilance in india A formal ADR monitoring system was proposed for the first time in India in 1986. It consisted of 12 regional centres each covering a population of 50 million. More concrete efforts in the direction of drug safety monitoring in India began in 1997 when India became the member of WHO International Drug Monitoring Programme , managed by UMC. 6 regional centres were set up in New Delhi, Mumbai, Kolkata, Chandigarh, Lucknow and Pondicherry for ADR monitoring. This programme also could not succeed due to multiple reasons.

22. In November 2004, Government of India launched the National Pharmacovigilance Programme ( NPvP ) with an annual grant of US$ 0.1 million approved for 5 years by World Bank. NPvP started functioning on 1 st Jan 2005. Under this programme , whole country was divided into zones and regions for operational efficiency. Central Drugs Standard Control Organization (CDSCO), New Delhi is at the top of hierarchy followed by two zonal centres viz, Seth GS Medical College, Mumbai and AIIMS, New Delhi.

23. There are 5 regional centres located at Lady Hardinge Medical College, New Delhi Topiwala National Medical College, Mumbai IPGME&R and SSKM Hospital, Kolkata JIPMER, Pondicherry Indira Gandhi Medical College, Nagpur. Then are 28 peripheral centres .

24. The functioning of the programme is to be periodically reviewed by National Pharmacovigilance Advisory Committee- a 16 membered committee appointed by Government of India. The committee will evaluate the pharmacovigilance data collected from various centres and recommend the possible regulatory measures. This programme also could not meet the expectations and was suspended in 2009 when World Bank funding was discontinued.

25. Recognizing the need for improved ADR monitoring in the country MoHFW , Government of India launched a revised ADR monitoring programme on 14 th July 2010 and was named as Pharmacovigilance Programme of India ( PvPI ). Initially, under this programme AIIMS, New Delhi was the National Coordination Centre (NCC). Later, in April 2011, NCC was shifted from AIIMS, New Delhi to Indian Pharmacopoeia Commission (IPC), Ghaziabad. In order to monitor ADRs all over the country, 22 ADR monitoring centres (AMCs) were set up.

26. CURRENT METHODS OF PHARMACOVIGILANCE

27. PASSIVE SURVEILLANCE

28. Spontaneous reports A spontaneous report is an unsolicited communication by healthcare professionals or consumers to a company, regulatory authority or other organizations (e.g. WHO, Regional Centres , Poison Control Centre) that describes one or more adverse drug reactions in a person who was given one or medicinal products and that does not derive from a study or any other organized data collection scheme. This type of reporting is voluntary in nature and may be initiated by health care professional or consumer as and when they become suspicious of any adverse reaction by any medication.

29. Health care professionals (e.g. doctors, nurses, pharmacists) are provided with a form for filling the details of the suspected ADR experienced by the patient along with the details of prescribed medication, patient details and details of the doctor (prescriber). In India, the form used for spontaneous reporting is known as the “Suspected ADR Reporting Form” generated by CDSCO (Central Drugs Standard Control Organization) working under the aegis of DGHS (Directorate General of Health Services), Government of India.

30. In UK, the form used for spontaneous reporting is known as “Yellow Card”. This form is available separately for patients (patient reporting form) and for health care professionals (health care professional reporting form).

31. In US, “Med Watch” form is available in two categories: Form FDA3500-Voluntary Reporting: For use by health care professionals, consumers and patients. Form FDA-3500A-Mandatory Reporting: For use by IND reporters, manufacturers, distributors, importers, user facilities personnel.

32. These filled forms are then notified to the central authority (e.g. DCGI i.e. Drug Controller General of India for India; USFDA i.e. US Food and Drug Administration for USA; TGA i.e. Therapeutic and Goods Administration for Australia; MHRA i.e. Medicines and Healthcare products Regulatory Agency for UK etc.).

33. Case series Case report describes the particular outcome or experience of a person who has been exposed to a drug. These reports are useful for generating hypotheses about effects of drug and may lead to further studies to test these hypotheses. A case series, reports on two or more people with common exposure to a drug or a common outcome.

34. A series of case reports can provide the evidence of association between a drug and an adverse event, but these are generally used for generating hypotheses than verifying an association between drug exposure and outcome. There are certain distinct events which are known to be associated with drug therapy such as Stevens-Johnson syndrome, Toxic epidermal necrolysis, anaphylaxis. Therefore, when events such as these are spontaneously reported, sponsors should place more emphasis on these reports for more detailed and rapid follow-up.

35. Stimulated reporting Stimulated reports are those which have been motivated, prompted, stimulated or induced and occur in certain situations such as notification by health care professional communication (HCPC ), questioning of healthcare professionals by MAH (Marketing Authorisation Holder), public advisory, publication in press. These reports should be considered unsolicited in nature and a form of spontaneous reporting.

36. ACTIVE SURVEILLANCE

37. Active surveillance seeks to ascertain completely the number of adverse events by a continuous preorganized process. An example of active surveillance is the follow up of patients treated with a particular drug through a risk management programme . Patients who fill the prescription for this drug may be asked to complete a brief survey form and give permission for later contact. In general, it is more feasible to get comprehensive data (complete or widespread data) on individual adverse event reports through an active surveillance system rather than through a passive surveillance system.

38. SENTINEL SITES Active surveillance can be achieved by reviewing medical records or interviewing patients and/or physicians in a sample of sentinel sites to ensure complete and accurate data on reported adverse events from these sites.

39. DRUG EVENT MONITORING Drug event monitoring is the method of active pharmacological surveillance. In drug event monitoring, the patients might be identified from electronic prescription data or automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or patient at pre-specified interval to obtain outcome information. Information on patient demographics, indication for treatment, duration of therapy, dosage, clinical events and reasons for discontinuation can be included in the questionnaire.

40. registries A registry is a list of patient with similar characteristics. The characteristic can be a disease (disease registry) or a specific exposure (drug registry). Both types of registries, which only differ by the type of patient data of interest, can collect a battery of information using standard questionnaires in a prospective fashion. Disease registries, such as blood dyscrasias, severe cutaneous reactions, or congenital malformations can help collect data on drug exposure or other factors associated with clinical condition.

41. A disease registry may also serve as a base for case control study comparing the drug exposure among cases identified from the registry and controls selected from either patients with another condition within the registry or patients outside the registry. Drug registries address population exposed to drugs of interest (such as rheumatoid arthritis patients treated with biological therapy) to determine if a drug has a special impact on this group of population. Patients can be followed over a period of time and included in cohort study to collect data on adverse events using standard questionnaires.

42. ADVERSE EVENT and ADVERSE DRUG REACTION

43. ADVERSE EVENT: Any untoward medical experience which may occur during treatment with pharmaceutical product but does not necessarily have a cause relationship with the treatment. ADVERSE DRUG REACTION: A response which is noxious and unintended, and which occurs due to a drug at doses normally used in humans for the prophylaxis, diagnosis or therapy of a disease, or for the modification of physiological function. An ADR, contrary to adverse event, is characterized by the suspicion of a causal relationship between drug and occurrence, i.e. judged as being possibly related to treatment by the reporting or reviewing health professional.

44. For the purpose of reporting, it is important that all adverse events rather than ADRs are collected, as the term ADR imply that the adverse medical event was caused by a drug and if the recorder is not certain whether the event was caused by a drug then it would not be recorded.

45. PHARMACOLOGICAL CLASSIFICATION OF ADR s

46. TYPE-A (or TYPE I or AUGMENTED): This is the commonest type of ADR which is predictable by pharmacological mechanisms, for e.g. hypotension caused by beta-blockers, hypoglycemia caused by insulins. These types of ADRs are dose dependent henceforth severity increases with dose. TYPE-B (or TYPE 2 or BIZZARE): This type of ADR is not expected from the known pharmacological mechanisms, for e.g. hepatitis caused by halothane, aplastic anemia caused by chloramphenicol, neuroleptic malignant syndrome caused by antipsychotics. These type of ADRs are dose independent.

47. TYPE-C (CONTINUOUS DRUG USE): This type of ADR occurs as a result of continuous drug use, e.g. dementia caused by anticholinergics. TYPE-D (DELAYED): This type of ADR is characterized by delayed occurrence even after cessation of treatment, e.g. corneal pigmentation caused by thioridazine, pulmonary/peritoneal fibrosis caused by methysergide .

48. TYPE-E (END OF DOSE): This type of ADR is characterized by withdrawal reactions, e.g. hypertension and restlessness in opioid abstainers, seizures on alcohol withdrawal. TYPE-F (FAILURE OF THERAPY): This type of ADR results from ineffective treatment, e.g. accelerated hypertension because of ineffective control.

49. CAUSALITY CLASSIFICATION (WHO-UMC CLASSIFICATION)

50. Severity classification

51. MILD: No antidote, therapy or prolongation of hospitalization is required. MODERATE: Requires a change in drug therapy, specific treatment or prolongation of hospitalization by atleast one day. SEVERE: Potentially life-threatening, causing permanent damage or requiring intensive medical care.

52. Seriousness classification

53. An adverse event or reaction can be referred to as serious by the investigator if it: results in death is life-threatening requires inpatient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incompetence is a congenital anomaly/birth defect If an adverse event doesn’t cause death, require hospitalization, or threatens subject’s life, it may still be considered as serious if it can jeopardize the patient and may require surgical/ medical intervention.

54. Thank you