This document provides a history of pharmacovigilance and discusses key aspects of the field. It begins with important milestones in drug safety regulation dating back to the early 20th century. It then defines pharmacovigilance and describes stakeholders, methods used like individual case safety reporting, and the roles of organizations like the WHO and national regulatory authorities. The document emphasizes the importance of post-market drug safety monitoring to protect public health.

1. PHARMACOVIGILANCE:
A worldwide A master key for drug
monitoring.
By;
VENUGOPAL N
1st M-PHARMACY
PHARMACEUTICAL REGULATORY AFFAIRS
DEPT. OF PHARMACEUTICS.

2. Dying from a disease is
sometimes unavoidable;
dying from a medicine is
unacceptable.
LEPAKHIN V. GENEVA

3. HISTORY
1902
• BIOLOGICS CONTROL ACT (following the death of children caused by contaminated
diphtheria antitoxin vaccines).
1906
• PURE FOOD AND DRUG ACT >>> FDA
1937
• ELIXIR OF SULFANILAMIDE (Contained the poisonous solvent diethylene glycol, no
toxicity tests, killed 100 people) - need to establish drug safety before marketing.
1938
• FEDERAL FOOD, DRUGS AND COSMETICS ACT.
1949
• COUNCIL for INTERNATIONAL ORGANIZATIONS of MEDICAL SCIENCES (CIOMS). By WHO and
UNECO.
1961
• THALIDOMIDE (over 10,000 children in 46 countries were born with birth defects) –
rules for testing and licensing of drugs( clinical trials were also introduced.)

4. 1962
• KEFAUVER-HARRIS Amendments passed which required evidence of drug efficacy and
safety before marketing. (US)
1964
• YELLOW CARD SCHEME – for collecting information on suspected adverse drug
reactions (ADRs) of medicines to provide an early warning of possible hazards. (UK)
1964
• DECLARATION OF HELSINKI – World’s Medical Association best-known policy and was
first adopted as a set ethical principles regarding human experimentation.
1967
• WORLD HEALTH ORGANIZATION (WHO) – It’s resolution 20.51 laid basis for the
International System of Monitoring ADRs.
1968
• MEDICINES ACT – to govern the control of medicines for humans and veterinary,
including manufacture and supply.
1973
• FRENCH PHARMACOVIGILANCE SYSTEM was implemented.

5. 1982
• BENOXAPROFEN – recall when found linked to 3500 side effects and 61 deaths and in
order to prevent the progress of the disaster in further and ensure patient safety.
1991
• EUROPEAN RAPID ALERT SYSTEM – to facilitate early exchange of information
concerning possible safety hazards relating to marketing medicinal products.
2001
• EU Clinical Trial Directive was introduced measures on the safe conduct of the clinical
trials. Volume 9A introduced to standardise post-marketing PV systems in EU.
2009
• MHRA BLACK TRIANGLE scheme to report ALL suspected adverse reaction to
designated black triangle drugs.
2012
• Release of GOOD PHARMACOVIGILANCE PRACTICES (GVPs) to replace Volume 9A. They
expand on the clarity the PV responsibility of marketing authorization holders.

6. 2014
• NEW CLINICAL TRIAL REGULATION signed into force to replace the EU
Clinical Trial Directives 2001 .
• Standardized implementation across member states.
2017
• GVP > New modules on Risk Management and Risk Minimization measures.

7. PHARmACOVIGILANCE
Pharmakon-------in greek----drug
Vigilare -----------in latin------to keep watch
Pharmacovigilance (PV) Drug Safety
Pharmacovigilance is the pharmacological science that aims at the detection,
assessment, monitoring, understanding and prevention of adverse effects,
particularly long term and short term side effects of medicines to ensure drug
safety.

8. TERMINOLOGIES
 SIGNAL & SAFETY SIGNAL
TRIAGE
ADR – Adverse Drug Reaction.
ADE – Adverse Drug Event.
WHOART – WHO Adverse Reaction Terminology is
dictionary for coding adverse reactions.

9. COSTART – COding Symbols for a Thesaurus of Adverse
Reaction Terms developed by USFDA.
MedDRA – Medical Dictionary for Regulatory Activities.
MSSO > Maintenance and support service organization.
VIGIFLOW - a unique collection of international drug safety
data.
VIGIBASE is the WHO web based ICSR(Individual Case Safety
Report) system designed for National Centres Database
consisting of reports of adverse reactions.
DATA MINING - extract information from a data and transform
it into an understandable structure for further use.

11. Limitations of Premarketing Clinical Trials
• Size of the patient population studied.
• Narrow population -often not providing sufficient data
on special groups.
• Narrow indications studied (specific disease).
• Short duration.

12. Benefits of Post-marketing Monitoring
The ability to study the following:
• Low frequency reactions (not identified in clinical trials).
• High risk groups.
• Long-term effects.
• Drug-drug/food interactions.
• Increased severity and / or reporting frequency of
known reactions.

13. ADVERSE DRUG REACTION

14. TYPE A (AUGMENTED) REACTIONS
Reactions which can be predicted from the known pharmacology of the
drug & dose dependent.
TYPE B (BIZARRE) REACTIONS
Cannot be predicted from the pharmacology of the drug & Not dose
dependent.
TYPE C (CONTINUOUS DRUG USE)
May be irreversible, unexpected or unpredictable.
TYPE D (DELAYED) REACTIONS
Occur after many years of treatment. • Can be due to accumulation.
TYPE E (END OF DOSE) REACTIONS
Occur on withdrawal especially when drug is stopped abruptly.

15. SIDE EFFECTS
problem that occur when treatment goes beyond the desired
effect or in addition to therapeutic effect.
SECONDARY EFFECTS
Indirect consequences of a primary action of the drug.
TOXIC EFFECTS
Excessive pharmacological action of the drug due to over
dosage or prolonged use.
INTOLERANCE
Appearance of characteristic toxic effects of a drug in an
individual at therapeutic dose.

16. IDIOSYNCRASY
Genetically determined abnormal reactivity to a chemical.
Restricted to individuals with particular genotype.
PHOTOSENSITIVITY
Cutaneous reaction resulting from drug induced sensitization of the
skin to UV radiation.
TERATOGENICITY
Capacity of a drug to cause foetal abnormalities when administered
to the pregnant mother.
MUTAGENICITY AND CARCINOGENICITY
Capacity of a drug to cause genetic defects and cancer respectively.

17. NEED FOR PV
 Insufficient evidence of safety from clinical trials.
 Medicines are supposed to save lives.
 To KEEP products on the market.
 To protect patients from unnecessary harm.
 To reduce healthcare expenses.
 Ethical thing to do - To know of something that is harmful to
another person who does not know, and not telling, is
unethical.

18. AIM
Early detection of unknown safety problems.
Detection of increases in frequency.
Identification of risk factors.
Quantifying risks.
Communicating information.
Preventing patients from being affected unnecessarily.

20. HOW PV WORK

21. STAKEHOLDERS
A patient may be willing to accept a high risk of side-effects for
benefits of the treatment for a condition that might be considered
trivial by others.
A regulatory agency may consider the burden of the same side effects
to be too high, given their view of the risk–benefit equation.
A governmental or third-party payer might see the issue from an
even different perspective, since a payer may not wish to bear the cost
of the treatment or the cost of treating an adverse event.
It is not surprising that each group may take a different view of the same
evidence.
These pressures may lead to early decisions based on incomplete scientific
data.

22. Withdrawn drugs from the market

23. WHO PROGRAMME FOR INTERNATIONAL
DRUG MONITORING
Started in 1978 known as WHO Program for international
drug monitoring, which is located in Uppsala, Sweden.
 It consists of a network of the
 National Centres
 WHO Headquarters
 Uppsala Monitoring Centre (UMC)
Till now there are 127 full members and 29 associate
members of UMC.

24. UPPSALA MONITORING CENTER
• Located in Uppsala, Sweden, World Health Organization
Collaborating Centre for International Drug Monitoring.
• Principal function to 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.

27. WHO SHOULD REPORT SAFETY DATA ?
Physicians
Pharmacists
Pharmaceutical companies qualified persons
(Pharmacovigilance/Regulatory manager)
Investigational products (clinical trials)
Post-approval reporting – Individual Case Safety Report
(ICSR), Periodic Safety Update Report (PSUR)
In many countries patients are encouraged (but not obligated)
to report side effects

28. WHAT TO REPORT?
• On an ADR or lack of efficacy connected with the use of a medical
device/ drug product.
• On ADRs occurring in the course of the use of a drug , from drug
overdose whether accidental or intentional
• From drug abuse / misuse / non-approved use
• From drug administration during pregnancy.
• Every single problem related to the use of a drug.
• ADRs associated with radiology contrast media, vaccines,
diagnostics, drugs used in traditional medicine, herbal remedies,
cosmetics, medical devices and equipment.

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

30. METHODS OF PV
1. Individual case safety reports
2. Clinical review of case reports
3. Cohort event monitoring
4. Longitudinal electronic patient records
5. Spontaneous reporting
6. Periodic Safety Update Reports (PSUR)
7. Expedited report
8. Record linkage

31. Individual Case Safety Reporting
This reporting systems involve the recording and reporting
clinical observations of a suspected Adverse Drug Reactions
(ADRs) with a marketed drug.
It is Voluntary Reporting OR spontaneous reporting.
 There are slight differences in this reporting system among
the various countries but the ideology are the same.
In India form used for reporting is known as” Suspected
Adverse Drug Reaction Reporting Form”.
In UK “Yellow Cards” and in USA “Med Watch forms” are
used

32. .
The Yellow Card Scheme is the
main ADR reporting scheme in
the UK and was introduced in
1964 after the thalidomide
tragedy
Highlighted the urgent need for
routine monitoring of medicines.
It receives more than 20,000
reports of possible side effects
each year.
.
• Serious AE’s, product
problems and
medication errors IN to
MedWatch
• Timely safety alerts OUT
to our audiences

33. CLINICAL REVIEW OF CASE REPORTS:
The quality of reports is variable , large national and
international organizations collect hundreds of
thousands of reports each year , every one of which
can’t possibly be reviewed by the available experts.
Even if each report could be reviewed , important
reporting patterns would be missed.
Computational have therefore been developed to help
highlight the most urgent problems .

34. COHORT EVENT MONITORING:
Cohort Event Monitoring (CEM) systems for intensified
follow up of selected medicinal products.
The main limitations are its restriction to small subset of
medicinal products , the relatively small fraction of the
population covered.

35. LONGITUDINAL ELECTRONIC PATIENT
RECORDS:
It is extremely valuable method.
They cover large populations, provide detailed
information on both exposed and unexposed patients.
Information is extracted directly from the computer
systems in which physicians store patient’s data.
Privacy protection for patients and physicians is of the
utmost importance.

36. SPONTANEOUS REPORTING:
The reporting might be directly to the company , or it could be
to the regulatory authority.
Main limitation is under reporting.
 However , their main purpose is not the quantification of the
frequency, but identification of signals.
When becoming aware of a serious adverse drug reaction ,
health care providers, pharmacies, pharmaceutical companies
shall report to the health authority.
 Time frame of reporting , report within a specific time frame
upon knowing of any serious ADR.

37. REPORTING METHODS AND TEMPLATE
Shall submit reports by post, fax or internet .
A verbal report is acceptable in urgent situations, but
written submission should be completed before the
deadline.
Additional information on a serious ADR report, not
available at the time of the initial report , should be
provided in follow up reports.

38. PERIODIC SAFETY UPDATE REPORTS (PSUR):
Pre marketing clinical trials may not be sufficient to reflect the product
safety profile.
Therefore medically advanced countries impose the “post marketing drug
safety monitoring period ” on new drugs.
License holders shall proactively collect post marketing safety data,
prepare PSUR and submit them to the health authority.
According to the “regulation of medical products under safety monitoring”
,if pharmaceutical companies fail to submit PSUR as required , then the
health authority may reassess the safety of the concerned product.
The last PSUR should be submitted before the expiration of the drug safety
monitoring period.
The “summary bridging report” provides summarized information of the
PSURs.

39. EXPEDITED REPORT
If there has been spontaneous reporting of a suspected
ADR to a pharmaceutical company , there are legal
obligations on the company to report serious reactions
within a specified time frame to the regulatory authority.
Based on the results of drug safety assessment , license
holders shall report to the health authorities in an
expedited manner.

40. RECORD LINKAGE:
Bring together a variety of patient records .
A specific example is prescription event monitoring
scheme.
It is less expensive but time consuming method.

41. The Minimum Requirements for a functional
Pharmacovigilance System
A National Pharmacovigilance Centre with
designated staff (at least one full time), stable basic
funding, clear mandates, well defined structures and
roles and collaborating with the WHO Programme for
International Drug Monitoring.
• The existence of a National spontaneous reporting
system with a National Individual Case Safety Report
(ICSR) form i.e. ADR reporting form

42. • A National Database or system for collating and
managing ADR reports
• A National ADR or Pharmacovigilance Advisory
Committee able to provide technical assistance on
causality assessment, risk assessment, risk management
case investigation and where necessary crisis
management including crisis communication
• Clear communication strategy for routine communication
and crises communication

43. ICSR Processing Workflow

44. How does pharmacovigilance help
THE PUBLIC
• Pharmacovigilance helps save
thousands of lives each year.
By monitoring the adverse
effects of drugs right from the
lab to the pharmacy and then
on for many years,
pharmacovigilance keeps
track of any drastic effects of
drugs. This way, it prevents
harm to patients using those
drugs.
DRUG MANUFACTURERS
• Pharmaceutical companies spend
millions of dollars and a considerably
long-time in developing new drugs and
conducting clinical trials before the drugs
are approved and launched in the market.
But after all this, if there are adverse
effects to the drugs, the company again
loses millions of dollars in sales and
litigations.
• Furthermore, the reputation of the
company is also severely damaged.
Pharmacovigilance monitors the
development of the drug across various
stages and assesses its effectiveness after
its launch for many years. This way it may
reduce the adverse risk from drugs,
thereby aiding the drug manufacturers.

45. Pharmacovigilance in USA
Post marketing safety reports
• 15-days alert report
• Periodic adverse event report
Spontaneous report.
 FDA MedWatch
Safety Signal.

50. FAERS
FDA ADVERSE EVENT REPORTING SYSTEM
 Computerized database
 Spontaneous reports
 Includes all US marketed products.
 Broad patient population.
 Detection of events not seen in clinical trials.
 Contains human drug and therapeutic biologic reports
 > 9 million reports since 1969
 Over 1.4 million new reports in 2016.

51. Pharmacovigilance In EU
EudraVigilance, the EU reporting and data- warehouse system for
case reports;
The EU Rapid Alert and Incident Management Systems for timely
and adequate responses to new safety data;
The Pharmacovigilance Risk Assessment Committee (PRAC),
which provides recommendations on all aspects of
pharmacovigilance and risk management;
Good pharmacovigilance practices (GVP) and other standards;
Periodic safety update report (PSUR)
POST-AUTHORIZATION SAFETY STUDIES (PASS)

52. Pharmacovigilance In INDIA
In India, for the monitoring of Adverse Drug Reaction (ADR’s)
there were three main centres identified:
1. A National Pharmacovigilance Centre in the Department of
Pharmacology, All India Institute of Medical Sciences (AIIMS),
New Delhi.
2. WHO special centers in Mumbai (KEM Hospital).
3. Jawahar Lal Nehru Hospital, Aligarh Muslim University, Aligarh.
The mentioned centers monitor the Adverse Drug Reactions
(ADRs) of the drugs available in market.
This effort was ineffective

53. Second time from the 1st of January 2005, the WHO
sponsored and World Bank-funded National
Pharmacovigilance Program for India was established.
The National Pharmacovigilance Program (PvPI)
recognized in January 2005, and supervised by The Central
Drugs Standard Control Organization (CDSCO), Directorate
General of Health Services under the aegis of Ministry of
Health & Family Welfare, Government of India in
collaboration with Indian Pharmacopeia commission,
Ghaziabad.

54. Zonal centers
1) KEM located in the Department of Pharmacology, AIIMS,
New Delhi
2) The South-West zonal centre located in the Department of
Clinical Pharmacology, Seth GS Medical College.
 Meanwhile established information centres which collate
information from all over the country and send it to the
Committee as well as to the Uppsala Monitoring centre in
Sweden

56. CONCLUSION AND CONSIDERATIONS FOR FUTURE
• For all medicines there is a trade-off between the 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 risk of harm, however, is less when medicines are used by an informed
health profession and by patients who themselves understand and share
responsibility for their drugs.
• 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. This is the role of
PHARMACOVIGILANCE.

57. 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
Monitoring of established(generic) products.

58. The following summarize some of the priority areas that need
to be addressed either at a national or international level:
Detection of ADRs
Assessment of ADRs
Prevention
Communication.