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 18TH CENTURY
• The study of literature from before 18th 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 10th 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 13th 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 18TH 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 18th 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 18th 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 19TH 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.

15. PHARMACOVIGILANCE IN 20TH 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.

16. • 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.

17. • 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.

20. • 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.

21. • 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.

22. PHARMACOVIGILANCE: THE CURRENT STATUS
• The foundation of WHO International Drug Monitoring Program was laid down in
1971 during the 20th 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).

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

24. 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.

25. • 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 1st 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.

26. • 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.

27. • 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.

28. • Recognizing the need for improved ADR monitoring in the country MoHFW,
Government of India launched a revised ADR monitoring programme on 14th
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.

29. CURRENT METHODS
OF
PHARMACOVIGILANCE

30. PASSIVE SURVEILLANCE

31. 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.

32. • 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.

34. • 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).

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

39. • 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.).

40. 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.

41. • 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.

42. 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.

43. ACTIVE SURVEILLANCE

44. • 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.

45. 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.

46. 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.

47. 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.

48. • 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.

49. ADVERSE EVENT
AND
ADVERSE DRUG REACTION

50. • 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.

51. • 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.

52. PHARMACOLOGICAL CLASSIFICATION OF ADRs

53. 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.

54. 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.

55. 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.

56. CAUSALITY CLASSIFICATION
(WHO-UMC CLASSIFICATION)

58. SEVERITY CLASSIFICATION

59. • 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.

60. SERIOUSNESS CLASSIFICATION

61. • 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.

62. THANK YOU