by Dr. Vishal Pawar MD Pharmacology a complete and comprehensive view of Pharmacovigilance around the world and in india

1. BY DR. VISHAL PAWAR
JR II
DEPT. OF PHARMACOLOGY 1

2. • Pharmacovigilance (PV) Etymological roots : pharmakon (Greek) means
drug and vigilare (Latin) means to keep awake or alert, to keep watch
WHO Definition
Science, activities relating to detection, assessment, understanding and
prevention of adverse effects or any other drug related problems
Side Effect
Any unintended effect of a pharmaceutical product occurring at doses
normally used in man which is related to the pharmacological properties
of the drug e.g. sedation with anti histaminics
Adverse Event / Adverse Experience
Any untoward medical occurrence that may present during treatment
with a pharmaceutical product at the same time, does not necessarily
have a causal relationship with this treatment 2

3. Adverse Reaction (ADR)
A response to a drug which is noxious and unintended, and which occurs
at doses normally used in man for the prophylaxis, diagnosis, or therapy
of disease, or for the modification of physiological function
Active surveillance system
Collection of case safety information as continuous pre-organized
process
Spontaneous reporting
System whereby case reports of adverse drug events are voluntarily
submitted from health professionals and pharmaceutical manufacturers
to the national regulatory authority
Signal
Reported information on a possible causal relationship between an
adverse event and a drug, the relationship being unknown or
incompletely documented previously 3

4. 4
Adverse Event
Intensity
•Mild
•Moderate
•Severe
Seriousness
•Non Serious
•Serious
•Expected
•Unexpected
CausalityExpectation
•Related
•Un-related

5. 5
Poor knowledge of Pharmacology, adverse effects of drugs
Irrational use of drugs, poor prescribing patterns
Promotional activities by pharmaceutical company detailers
Lack of authentic sources of information
Liberal drug outlets and unhealthy pharmaceutical practices
Liberal OTC and self medication practices
Ignorant, illiterate public

6. Pharmacological classification by Rawling and Thompson:
6
Type A (Augmented)
Type B (Bizarre)
Type C (Chronic)
Type D (Delayed)
Type E (End of use)
Type F (Failure)

7. Type A (Augmented) (dose related)
• Related to exaggerated pharmacological effects of drug
• Eg. Hypoglycemia with Insulin, hypotension by beta blockers, NSAID’s
induced gastric ulcers
Type B (Bizzarre)
• Unexpected, unpredictable, related to patient factors like genetic
predisposition
• Eg. Penicillin hypersensitivity, malignant hyperthermia
Type C (Chronic)
• Uncommon, irreversible, unexpected, unpredictable
• Due to long term use of drugs
• Eg. Hypothalamic pituitary adrenal axis suppression by corticosteroids
Type D ( Delayed)
• Time related
• Eg. Teratogenesis, Carcinogenesis like clear cell cancer of female
reproductive tract 7

8. Type E (End of use/ withdrawal)
• Occurs due to sudden discontinuation of the drug after long term therapy
• Eg. Adrenocortical insufficiency due to sudden withdrawal of
corticosteroids, MI due to beta blocker withdrawal
Type F (Failure of therapy)
• Common, Dose related
• Often caused by drug interactions
• Eg. Inadequate dosage of an oral contraceptive particularly when used
with specific enzyme inducers
• FDA monitors safety of human and veterinary drugs, biologics, medical
devices, foods, cosmetics, & other products
• Centre for Drug Evaluation and Research (CDER) regulates
prescription drugs
8

9. • Encourage active surveillance
• Consider special activities and expertise required for the detection of
safety concerns related to vaccines, biologicals, herbal medicines,
biotechnology products and investigational drugs
• Improve signal detection systems by facilitating availability of ADR data
• Revisit definitions of terms used within field of PV including definitions of
specific ADRs to ensure reliability and universal understanding of data
obtained through ADR reporting systems
• Develop and implement ADR detection systems
9

10. PREVENTION
• Improve access to reliable, unbiased drug information at all levels of
healthcare
• Improve access to safer and more effective medicines for neglected
diseases prevalent in developing communities
• Encourage awareness of drug safety and rational drug use among health
professionals and the public
• Integrate PV activities into national drug policies e.g. standard treatment
guidelines, essential drugs lists and clinical practice
• Improve regulation and PV of traditional and herbal medicines
• Develop systems which assess the impact of preventive actions taken in
response to drug safety problems 10

11. COMMUNICATION
• Improve communication, collaboration between key partners in PV
• Principles of good communications practice in PV and drug regulation
should be encouraged
• Different solutions are likely to be developed in different countries and
• regions, and the experience should be shared
• Develop better understanding of patients, their expectations of
medicines and their perception of risk, in order to facilitate programmes
that will inform public on benefit and harm associated with medicine
• Develop sustained, active relationships with media
11

12. Post-marketing monitoring or PV or Phase IV clinical studies
• Provides information about long-term safety of drug
• Safety in extremes of age, special population like pregnant and nursing
women
• Information about Type B ADR’s, rare ADR’s
• In India, mandatory to submit Post Marketing Surveillance (PMS)
Report within 2 years of marketing drug
12

13. • Limited value of animal experiments, Clinical trials
• ADRs constituting enormous burden on society
• Cost of drug related morbidity, mortality exceeding that of drug itself
• 30-50% of ADRs are preventable
• Early detection and prevention can help make drug therapy lot safer
• Rare or delayed serious reactions are likely to remain unnoticed
13

14. • 1881  systemic recording of illnesses associated with pharmacotherapy
started much later and a book in this regard was published by L. Lewin.
• 1937  Unexplained death of hundreds of children. Elixir of
sulfanilamide dissolved in diethylene glycol killing 107 children
• 1938  Stimulus for food and drug Act (drug safety) for stringent action
regarding safety requirement and testing of a new drug before
marketing.
• Thalidomide disaster in 1962
• 1968  WHO established a system for collecting reports of ADR
14

15. NEWER CHALLENGES FACED TODAY
• Illegal sale of medicines and drugs of abuse over Internet
• Increasing self-medication practices
• Widespread manufacture and sale of counterfeit and sub standard
medicines
• Increasing use of traditional medicines outside confines of traditional
culture
Recently, PV concerns have been widened to include:
• Herbals
• Traditional and complementary medicines
• Blood products
• Biologicals
• Medical devices
• Vaccines
15

16. 16
Rational and safe use of medical drugs
Encourage their safe, rational, more effective, cost effective use
Educating and informing patients
Assessment and communication of risks and benefits of drug
Promote understanding, education and clinical training in PV and its
effective communication to the public
Improve patient and public healthcare and safety in relation to use
of medicines
Contribute to regulatory assessment of benefit, harm, effectiveness
and risk of medicines

17. • Established in 1968
• As of October 2008, 89 countries had joined
• It consists of a network of the
i. National Centres
ii. WHO Headquarters
iii. Uppsala Monitoring Centre
17

18. 18
Identification and analysis of new adverse reaction signal
Provision of the WHO database
Information exchange between WHO and National Centres
mainly through Vigiflow
Publication of periodical newsletters, guidelines, books
Provision of training and consultancy support to National Centres

19. • Located in Uppsala, Sweden, World Health Organisation Collaborating
Centre for International Drug Monitoring
• Principal function  manage international database of ADR reports
received from National Centres
• Works by collecting, assessing and communicating information from
member countries' national PV programs in regards to benefits, harm,
effectiveness and risks of drugs
• Annual meetings for representatives of National Centres
• Producing WHO Drug Dictionary and WHO Adverse Reaction
Terminology
19

20. 1. Pharmacovigilance Specification
2. Pharmacovigilance Plan
3. Pharmacovigilance Methods
20

21. Pre Clinical Studies
• Toxicity tests
• General pharmacology
• Effect of hepatic and renal dysfunction,
• Drug interactions, and
• Other toxicity-related information or data
Animal Tests
- Acute toxicity - Kinetics
- Carcinogenicity - Organ damage
- Mutagenicity - Species specificity
- Teratogenicity - Dose dependence
21

22. Clinical Studies
• Adverse events (AEs) / Adverse drug reactions
• Identified and potential interactions, including food-drug and drug-
drug interactions
• Epidemiology of indication(s) and important adverse events
• Pharmacological class effects
• Limitations of the human safety database
22

23. 23
Monitoring center
Investigator
Global HQ
Sponsor’s Safety Officer
Death and
life-threatening,
Associated (by
Investigator)
Cases
Immediately or
within 24 hours
to entry site
immediately or
within 24 hours
immediately or
within 24 hours
immediately or
within 24 hours

24. 24
Patient
Health
Professional
Regional
Centre
Manufacturer
Hospital
National
Centre

25. • Relationship between the drug treatment and occurrence of an
adverse event
• Defined: structured and standardised assessment of individual
patients/case reports of the likelihood of involvement of suspected
drug in causing particular event in a given patientWHO assessment
scale
• Methods
25
Naranjo's scale European ABO system
Karch and Lasagna's scale Kramer scale
Bayesian Neural network Yale algorithm

26. • Data collection & Data management
• Signal detection
• Risk assessment and quantification
• Benefit/ Risk assessment
• Actions to reduce risk or increase benefit
• Communication of risks or interventions
• Audit
26

27. • Passive surveillance
a) Spontaneous reporting
b) Case series
c) Large linked administrative database
d) Electronic medical records
• Intensified reporting
• Active Surveillance
• Comparative Observational Studies
• Targeted Clinical Investigations
• Descriptive studies
27

28. Spontaneous reporting
• Identification of safety signals once a drug is marketed
• Is voluntary for health professionals
• Most useful where reaction is unusual and unexpected
• And where ADRs occur in close temporal relation with start of
treatment or increase in dose
• Provide important information on at-risk groups, risk factors, and
clinical features of known serious ADRs
28

29. Reports for regulatory authorities are in form of
• Expedited adverse drug reaction (ADR) reports
• Periodic Safety Update Reports (PSURs)
• Underreporting is an important limitation
• Causes being lack of awareness of time, ill filled report forms,
misconception that the medicine caused the event
• Reporting rates cannot be used to reliably estimate incidence rates
29

30. Case series
• Provide evidence of association between drug and adverse event
• More useful for generating hypotheses than for verifying an association
between drug exposure and outcome
• Reports of events like SJS, Anaphylaxis should undergo detail and rapid
follow up
Large linked administrative database
• Eg. Medicaid in USA and Ontario provincial database
• Contain data on millions of subjects
• Completeness of details, such as diagnoses, are questionable in many
circumstances
• May not be representative of the whole population
Electronic medical record
• Large number and detail of variables are available like use of tobacco
products and nonprescription drugs, symptoms and signs,
• Can be combined to generate new diagnoses or adverse events,
• Hypotheses which are not restricted to existing diagnoses, can be
explored 30

31. • To encourage and facilitate reporting for new products, methods
used are
• Onine reporting of adverse events
• Systematic stimulation of reporting of adverse events based on a
pre-designed method
ACTIVE MONITORING
• 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 to obtain outcome information
• More detailed information can be collected
• Limitation - poor response rates
31

32. • A registry is a list of patients presenting with the same characteristics
• Used as information gathering and hypothesis generating tool
• Particularly on drug exposure during pregnancy and for orphan drugs
• Can act as population basis for linkage studies
COMPARATIVE OBSERVATIONAL STUDIES
• Are key component in evaluation of adverse events
• Cross- sectional studies - primarily used to gather data for surveys or
for ecological analyses
• Case-control studies - used to investigate whether there is an
association between a drug (or drugs) and one specific rare adverse
event, as well as to identify risk factors for adverse events
• Cohort studies - incidence rates of adverse events in addition to the
relative risks of adverse events are calculated
32

33. • Evaluate MOA for adverse reaction
• Pharmacodynamic and pharmacokinetic studies
• Investigate potential drug-drug interactions and food-drug interactions
DESCRIPTIVE STUDIES
• These are primarily used to obtain background rate of outcome events
• Establish prevalence of use of drugs in specified populations
33

34. • Reported information on a possible causal relationship between an
adverse event and a drug
• Relationship being unknown or incompletely documented previously
• Usually more than a single report is required to generate a signal
• Depending upon seriousness of event and quality of the information
• Describes the first alert of a problem with a drug
• Cannot be regarded as definitive
• Indicates the need for further enquiry or action
• The automated systems used to generate signal is called as data
mining 34

35. DATA MINING
Application of statistical techniques, e.g. predictive modeling,
clustering, link analysis, deviation detection and disproportionality
measures, to databases to generate signal
35
Formulation of
hypothesis of
association
Method of
highlighting
potential ADR and
safety issues of a
drug needing
further
investigations
Signal
Generation
Assessment of
available data
Improved
knowledge
about suspected
ADR and
indicates need
for early
warning or
intervention
Signal
strengthening

36. SNIP criteria
Strong signals that are judged to be New, clinically Important, and
have potential for Prevention, be given priority for further evaluation
Methods of signal detection
• Spontaneous reporting system
• Hospital based surveillance system
• Prescription- event monitoring
• Case reports in literature
• Epidemiological studies
Aim of statistical aids
• To provide means of comparing the frequency of a medicine - event
combination
• With all other such combinations in the database under consideration
• With potential for early detection of signals of possible medicine -
event association
36

37. Evaluation of drug safety issue
• Causality assessment
• Identifying other possible cause
• Assessing the risk to individual and public
• Benefit/ Risk assessment is continued throughout life of a drug
• Guidelines to assess risk/ benefit differ from country to country
Key elements
• Description of target disease, populations being treated, purpose of
intervention
• Degree of efficacy, presence of alternative therapy
• Type of risk and identification of risk factors
• Consideration of all benefits and risks by indication and population
37

38. Actions to reduce risk or increase benefit and Communication
• Contraindicate use of drug in specific group
• Reducing maximum authorized dose
• Contraindicating concomitant use of interacting drug
• Monitoring early warning signs
• Educating practitioners and consumers
• Withdrawal of drug
AUDIT
• To evaluate outcomes of the interventions
• To plan future activities
38

39. Other issues relevant include
• Substandard medicines
• Medication errors
• Lack of efficacy reports
• Use of medicines for indications that are not approved and for which
there is inadequate scientific basis
39

40. • 1986: ADR monitoring system consisting of 12 regional centres each
covering population of 50 million, was proposed for India
• 1989: 6 regional centers : Delhi, Mumbai, Calcutta, Pondicherry,
Lucknow, Chandigarh
• 1997: India joined WHO Monitoring Programme based in Uppsala,
Sweden
• 2004: The WHO sponsored and World Bank funded National
Pharmacovigilance Program (NPP) for India was made operational
• NPP was to be overseen by National Pharmacovigilance Advisory
Committee
40

41. • 2009: World bank funding ended and programme was temporarily
suspended
• Late 2009: workshop org by AIIMS, Dept. of Pharmacology and
CDCSO when a framework of new programme was formulated
• July, 2010: Recognizing the need for improved ADR monitoring in the
country, under the aegis of Health Ministry, a nation-wide revised
ADR monitoring programme was launched and named as
Pharmacovigilance Programme of India (PvPI)
41

42. • Provides a system to collect the data and use the inferences
• To recommended regulatory interventions, besides communicating
risks to healthcare professionals and public
• Indian Pharmacopoeia Commission (IPC) under the Ministry of Health
and Family Welfare has been functioning as the National Coordination
Centre (NCC) for PvPI since April 2011
• Medical colleges and hospitals are cornerstone of PvPI
• Under PvPI, ADRs are being identified and spontaneously reported by
the healthcare professionals of Adverse Drug Reaction Monitoring
Centres (AMC)
42

43. • Currently, 179 Medical Council of India approved teaching hospitals
and corporate hospitals have been identified as AMCs across the
country
• These AMCs are responsible for collecting adverse event as per
Standard Operating Procedure (SOP)
• Performing follow up if require for the completeness of ADR reports
• Uploading these reports in net- based software used for ADR
reporting called as Vigiflow
• These drug safety information/Individual Case Safety Reports
(ICSRs) are collected in predesigned suspected ADR reporting forms
• Broadly consisting of 4 sections i.e., patient’s information, suspected
adverse reaction, suspected medication(s), and reporter’s
information
43

44. • Under PvPI, AMC plays a vital role in collection and follow-up of ADR
reports from healthcare professionals
• At present there are 400 AMCs under this programme and
categorized into four zones i.e., North, South, East and West
• Making this one of the largest Pharmacovigilance Programme in the
world
• PvPI have also extended its reach to other National Health
Programmes within country
• Integrating with Revised National Tuberculosis Control Program,
National AIDS Control Organization
• Has collaborations with Central Drugs Standard Control Organization
(CDSCO)
44

45. • Education and Training on PV at Regional Training Centres
• India, with a current population of 1.27 billion, is the fourth largest
producer of pharmaceuticals in the world
• With more than 6000 licensed manufacturers and over 60,000 branded
formulations in the market
• Over 5 years, has played a significant role in creating awareness among
healthcare professionals about reporting ADRs
• Having more than 1,49,000 ADRs reported till December 2015
• Currently, the contribution of India to the WHO global Individual Case
Safety Reports (ICSRs) database is 3%
• Its trying to create sufficient database on ADRs, awareness among
healthcare providers of government, corporate hospitals
45

46. Communications
• Website : websites of CDSCO (www.cdsco.nic.in) and NCC (www.
ipc.gov.in) are important tools for communication to the stakeholders
and public seeking specific information
• Media : communicate the findings in national newspapers, electronic
media, etc., on regular basis
• Newsletter: unique among healthcare professionals because it focuses
on the ADRs related information
• Scientific Journals
• Helpline Facility to Provide Assistance in ADR Reporting
• Android Mobile Application for Adverse Drug Reaction Reporting
46

47. • Co-ordination among clinician, pharmacist, and nurse appears vital in
contributing each of their respective expertise and experience to
promote the rational use of medicines
• The reason for poor reporting may also include financial incentives,
ignorance (only serious ADRs are to be reported), apprehension of
reporting serious ADRs, and lack of time or over load
• In year 2013, India’s contribution to WHO–UMC’s global drug safety
database was 2%
• India was 7th in position among top 10 counties contributing to
global drug safety database
• Awareness about the ADR reporting among the healthcare providers
can improve the rate of reporting across the country
47

48. • Wide misconception that ‘natural’ means ‘safe’
• There are examples of traditional and herbal medicines being
adulterated or contaminated
• With allopathic medicines, chemicals such as corticosteroids, non-
steroidal anti-inflammatory agents and heavy metals
• Self-medication further aggravates the risk to patients
• When used in conjunction with other medicines there is potential of
serious adverse drug interactions
• These products should be governed by standards of safety, quality and
efficacy that are equivalent to those required for other pharmaceutical
products
48

49. • New vaccines for pandemic diseases such as HIV/AIDS and malaria are
in the later phases of development
• Vaccines and biologicals require modified systems of safety monitoring
often administered to healthy children, particularly used within a
national immunization programme
• The skills and infrastructure to deal with genuine adverse events are
essential in preventing or managing misplaced fear
• Caused by false or unproven signals from patients and health workers
that might adversely affect immunization cover
49

50. • Eg. concerns about safety of whole-cell Pertussis resulted in dramatic
reductions in vaccines coverage and a resurgence of Pertussis in
many countries
• Contamination of blood and blood products by infectious organisms
such as HIV and hepatitis B
• Quality of screening and sterilization procedures and appropriate
selection of donors are linked to the risks of contamination
• Such safety issues related to the use of plasma-derived medicinal
products fall under PV programmes
50

51. • Drug safety monitoring is an essential element for the effective use of
medicines and for high quality medical care
• PV is a clinical discipline in its own right - one that contributes to an ethos
of safety and serves as an indicator of standards of clinical care practised
within a country
• 3 approaches that might serve to increase awareness and interest in drug
safety among clinicians, and to address research issues are
• Education, training and access to reliable information
• Health professionals are more likely to identify and report important ADRs
if they have confidence in their ability to diagnose, manage and prevent
such reactions
• National PV centres and training institutions play a central role in this by
encouraging inclusion of the principles and methods of PV
• And the study of iatrogenic disease at UG and PG levels in schools of
medicine, pharmacy and nursing
51

52. • For all medicines there is a trade-off between benefits and the potential for harm
• To minimize the harm, it is necessary that medicines of good quality, safety and
efficacy are used rationally, and that the expectations and concerns of the patient
are taken into account when therapeutic decisions are made
• The discipline of PV has developed considerably since the 1972 WHO technical
report, and it remains a dynamic clinical and scientific discipline
• It has been essential to meet the challenges of the increasing range and potency of
medicines (including vaccines), which carry with them an inevitable and sometimes
unpredictable potential for harm
• When adverse effects and toxicity appear - particularly when previously unknown
in association with the medicine - it is essential that they should be analysed and
communicated effectively to an audience that has the knowledge to interpret the
information 52

53. • This is the role of PV. Much has already been achieved
• PV activities are expanding around the world
• This is reflected in the increasing number of national PV centres that
have been established in recent years
• There are still many countries where no formal systems for PV are in
place
• To ensure that the existing centres are effective, their impact on
public health and health costs should be measurable and the benefits
demonstrable
• Only then will widespread support and long term sustainability of PV
centres be assured
53

54. The following is a summary of some of the serious challenges facing PV
programmes in the next ten years
• Globalization
• Web-based sales and information
• Broader safety concerns
• Public health versus pharmaceutical industry economic growth
• Attitudes and perceptions to benefit and harm
54

55. • Very concept of detection of an ADR can jeopardize their economics
• Should realize that ADR monitoring can be a source of revenue
generation if a new indication is found for the drug
• Can be tackled by giving conditional clearance for marketing of a new
drug
• Enforcing strict drug regulations
• So that Fraudulent and counterfeit drugs do not find a way into the
market
55

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