Pharmacovigilance is a scientific discipline concerned with the collection, detection, assessment, monitoring, and prevention of adverse effects of pharmaceutical products. Pharmacovigilance is a branch of Pharmacoepidemiology and is restricted to the study of adverse effects of drugs.

1. PHARMACOVIGILANCE
Dr. P.Naina Mohamed PhD
Pharmacologist

2. INTRODUCTION
 Pharmacoepidemiology is the study of effects of drugs in
large population.
 Pharmacovigilance is a branch of Pharmacoepidemiology
and is restricted to the study of adverse effects of drugs.
 Pharmacovigilance is a scientific discipline concerned with
the collection, detection, assessment, monitoring, and
prevention of adverse effects of pharmaceutical products.
Pharmacovigilance
Pharmakon (Greek) -
Drug
Vigilare (Latin) – To
keep watch

3. AIMS OF PHARMACOVIGILANCE
 Identification and quantification of previously unrecognized
ADRs.
 Identification of patient related risk factors of ADRs such as dose,
age, gender, and underlying disease.
 Continued monitoring of the safety of a product throughout the
duration of its use to ensure that its risks and benefits remain
acceptable.
 Comparing the ADR profile with same therapeutic class drugs.
 Detection of inappropriate prescription and administration.
 Further elucidation of a product's pharmacological / toxicological
properties and the mechanism by which it produces ADRs.
 Detection of significant drug-drug interactions between new
products and agents already established on the market.
 Communication of appropriate information to healthcare
professionals.

4. CLASSIFICATION OF ADRS
 Adverse drug reactions (ADRs) are frequently
classified as ‘type A’ and ‘type B’ reactions. An
extended version of this classification system is
as follows…
Adverse Drug
Reactions
(ADRs)
Type A
(Augmented)
reactions
Pharmacological Pathological Genotoxic
Type B
(Bizarre)
reactions
Type C
(Chronic)
reactions
Type D
(Delayed)
reactions
Type E
(End-of-
use)
reactions

5. TYPE A (AUGMENTED) REACTIONS
 Type A (Augmented) reactions may be caused by exaggeration
of therapeutic effect due to overdose (Pharmacological) or
disease condition like Hepatic and Renal failure (Pathological)
or injury to DNA (Genotoxic) by therapeutic agents.
 They are predictable from the drug’s pharmacology.
 They are preventable.
 They are usually dose-dependent.
 They are readily reversible on drug withdrawal or even simply
after dose reduction.
 Type A reactions are more common than the type B reactions
and they account for over 80% of all reactions.
 They have high morbidity and low mortality
Examples:
 Warfarin induced Bleeding.
 Sulfonylureas associated Hypoglycemia.
 Respiratory depression with Opioids.

6. TYPE B (BIZARRE) REACTIONS
 Type B (Bizarre) reactions or Side effects occurs not through
therapeutic mechanism.
 They are idiosyncratic or immunologic reactions.
 These are less common.
 They cannot be predicted from the known pharmacological
actions of the drug.
 They are not dose dependent.
Examples:
 Anaphylaxis with a Penicillin.
 Hypersensitivity reactions, such as serious skin
reactions with Lamotrigine.

7. TYPE C, D & E REACTIONS
 Type C (Chronic) or ‘continuing’ reactions, persist relatively
for a long time.
Example: Biphosphonates induce Osteonecrosis of the
jaw.
 Type D (Delayed) reactions, become apparent some time
after the use of a medicine. The timing of these may make
them more difficult to detect.
Example: Lomustine may cause Leucopenia, after six
weeks of tretment.
 Type E (End-of-use) reactions, are associated with the
withdrawal of a medicine.
Example: Benzodiazepines may cause insomnia,
anxiety and perceptual disturbances following their
withdrawal.

8. PHARMACOVIGILANCE METHODOLOGIES
 Passive drug Surveillance methodologies
 Spontaneous reports
 Active drug surveillance methodologies
 Enhanced spontaneous reporting
 Stimulated reporting through solicited reports
 Designated sentinel sites (sometimes referred to as
geographic surveillance)
 Ad hoc assembly of a cohort of patients
 Systematic assembly of a cohort of patients
 Case-controlled surveillance (also called disease
registries or disease-specific surveillance)
 Population-based surveillance
 Large automated multipurpose databases

9. PASSIVE DRUG SURVEILLANCE
 Collection of adverse events that come into the company from
all of its offices and any departments or routes, is known as
Passive surveillance.
 Passive surveillance may be done usually as spontaneous
reports.
 Adverse events must be reported to the regulatory agencies
according to established rules and policies.
Advantages of passive surveillance :
 Covers a large population at very low cost.
 Includes all of the company's drugs being used.
 Detects rare events as a signal.
 Helps to identify the risk factors.
 Creates a hypothesis that can be tested with more active
methods

10. LIMITATIONS OF PASSIVE SURVEILLANCE
Limitations of passive surveillance :
 Due to physicians' lack of motivation, lack of knowledge of the procedures
to follow, and concern about their own liability and patient confidentiality
issues, the amount of reports received are generally a small percentage
of those that occur.
 Reports may be received much later than the occurrence, and follow-up
discussions to obtain more complete data will be limited.
 Bias exists in the selection of cases that are reported.
 Data reported are incomplete and usually not well validated.
 Data submitted are often difficult to interpret.
Limitations of passive surveillance (from the company's perspective):
 It is usually difficult to know if a report is a signal.
 It is difficult to know the real numerator or denominator of the event
reported.
 Professionals tend to focus on bad news.
 The attribution of the adverse event to a specific drug is often weak.
 Data submitted are usually incomplete and difficult to interpret.
 If the media or medical literature has focused on a specific event, there
will be an exaggerated number of those events reported.

11. ACTIVE DRUG SURVEILLANCE METHODOLOGIES
Reasons to consider Active Surveillance:
 This is a useful method to capture early data on
drug use after a launch.
 One will learn bad news early, and this will allow the
company to react, plan, and obtain a more
complete understanding of the issue/problem.
 Unanticipated benefits may be learned.
 Passive surveillance techniques are insufficient
today to meet the more rigorous standards of safety
surveillance that have evolved.

12. ENHANCED SPONTANEOUS REPORTING
 The issue of drug alert newsletters or bulletins that
report a potential problem and seek experiences of
other physicians by the company is termed as
Enhanced Spontaneous Reporting.
 A case report of an adverse event published in a
medical journal also serves to understand the
incidence of the event.
 The use of the MedWatch system to stimulate
reporting is another means of enhancing
spontaneous reporting with a toll-free telephone
number placed.

13. STIMULATED REPORTING THROUGH SOLICITED
REPORTS
 Companies usually have arrangements with IMS (a company
that obtains data on drug utilization) to learn about the uses
and extent of how much their drugs are used in various
settings (e.g., hospitals, retail pharmacies).
 The company's follow-up may reveal whether a patient's
discontinuation was due to an adverse event or to other
reasons.
 With the data obtained from all sources, a company will begin
to create its own internal warehouse of data to confirm or deny
the occurrence of new adverse events brought to the
company by regulators or others.
 These data are used to assess whether certain characteristics
are or are not risk factors for adverse events, whether drug-
drug interactions are occurring, and to conduct many other
analyses.

14. DESIGNATED SENTINEL SITES
 The company or a regulatory body itself designates the sites
to be its sentinel sites.
 These sites may be in selected hospitals or clinics chosen for
their expertise and large number of patients whose treatments
would be of particular interest.
 Sites could be chosen on a geographic basis to monitor the
incidence and prevalence of infectious disease, number of
medical or medication errors, or adverse events.
 Other roles of sentinel sites can be to examine various
aspects of physician prescribing behavior, examine aspects of
institutional compliance with use of the company's product,
and conduct various research projects on the safety and
surveillance program itself (e.g., referral patterns to the
sentinel site).

15. EXPECTED ADVANTAGES OF THE SENTINEL SITE
MODEL
 Previously unrecognized serious adverse events would
likely be referred to specialists at the sentinel site.
 The proportion of cases seen at the sentinel site would
be higher than those seen in other settings.
 Information obtained would be more valid and complete
than data received from using other methods.
 Signals would be more rapidly identified and followed-up
than with other methods.
 False-positive case reports of serious adverse events
would be readily identified at the site.
 Causality would be carefully assessed, and the resulting
data would be more valid.
 This approach would enhance the company's ability to
learn about its product in a cost- and time-effective
manner.

16. LIMITATIONS OF THE SENTINEL SITE MODEL
 There will be too little power to detect rare events, particularly
for drugs used to treat only a few or a moderate number of
patients.
 Referrals to specialty programs, such as liver transplant
centers, may mean that sentinel sites will miss those cases of
hepatotoxicity it is hoping to observe.
 Sentinel sites that look at a wide variety of drugs for a
company may be too general and may miss various
aspects/adverse events of specific drugs.
 A sentinel system that is general could be set up as Centers of
Excellence, and their nonspecific approach would probably
identify many false-positive safety signals that would lead the
company to do unnecessary trials.
 The signal-to-noise ratio using general sites may obviate the
benefits they offer.

17. AD HOC ASSEMBLY OF A COHORT OF PATIENTS
 This is a traditional model where a large number of
patients (e.g., 10,000) are enrolled in a trial to learn
about all of the adverse events they experience in
taking the company's drug.
 This is a signal detection activity.
 It was popular in the early 1980s to collect data on
the first 10,000 or so patients who used a newly
approved drug to evaluate the adverse events.
 Very little information on adverse events came from
these trials, and this approach was generally
abandoned.

18. CASE-CONTROL SURVEILLANCE / OBSERVATIONAL
TRIALS
 A case-control surveillance/observational trial involves all
cases of various adverse outcomes that are collected and all
drug exposure reascertainment through interviews or medical
records.
 This is also called an outcome registry because it focuses on
a specific adverse outcome of public policy interest (e.g., birth
defects).
 Observational trials are noninterventional.
 In these trials an investigator “observes and evaluates results
of ongoing medical care without ‘controlling’ the therapy
beyond normal medical practice.”
 These trials do require a protocol, and almost all observational
trials must be reviewed by Institutional Review Boards/Ethics
Committees.
 Other types of comparative observational trials include cross-
sectional trials and cohort trials, both retrospective and
prospective.

19. POPULATION-BASED SURVEILLANCE
 In this methodology, an entire population is monitored
for both positive and negative signals.
 These are longitudinal trials and are often conducted
over many years or even decades.
 The most well known of these is the US Framingham
Study, and others in Finland and Sweden have been in
place for many years.
 The Framingham Study focused on all people in a small
Massachusetts town, and the US Nurses Study focused
on nurses and later added other healthcare personnel.
 These trials were not originally designed or initiated for
pharmaceutical or device products or trials, but for
general medical purposes.

20. LARGE AUTOMATED MULTIPURPOSE DATABASES
 In healthcare groups of United States, Canada and
Europe, there are linkages of electronic medical records
with accounting and billing systems.
 These databases permit linking pharmacy or prescribing
records with information on medical outcomes.
 Large automated multipurpose databases may be
queried for signals of any problem that occurs at a
higher than expected frequency and is associated with a
drug.
 Large pharmaceutical companies often use this method
to test a hypothesis or to confirm a purported signal.

21. IMPORTANCE OF IMPLEMENTING
PHARMACOVIGILANCE
 The effect of medicines might be affected by presence of many
different diseases, drugs, diets and traditional and herbal remedies.
 It is essential that a monitoring system for the safety of medicines is
supported by doctors, pharmacists, nurses and other health
professionals in the country to prevent unnecessary suffering by
patients and financial loss.
 Adverse reactions should be reported on a daily basis through the
Drug Regulatory Authority’s national pharmacovigilance programme.
 Systematic safety monitoring is needed to identify previously
recognized and unrecognized adverse drug reactions of medicines in
the postmarketing period.
 Postmarketing surveillance involves the ongoing processes of risk
identification, risk assessment, and risk mitigation.
 The goal is always the accurate assessment of the benefit versus the
risk of a product in the populations who receive it.

22. ROLES OF THE PHARMACIST
The pharmacists should…
 Educate other healthcare professionals about
prevention, detection and reporting of ADRs.
 Develop policies and procedures for the ADR-
monitoring and reporting program.
 Describe the responsibilities and interactions of
pharmacists, physicians, nurses, risk managers,
and other health professionals in the ADR program.
 Perform patient counseling on ADRs.
 Identify the drugs and patients at high risk for being
involved in ADRs.
 Report serious ADRs to the FDA or the
manufacturer (or both).

23. ROLES OF PRESCRIBERS
 All prescribers need to be aware of ADR reporting
and its important.
 Consider the drug therapy is really necessary.
 Any new symptom(s) experienced by the patients
should be considered as ADR.
 Check the patient’s history of Drug allergy.
 Check about other medications (OTC drugs,
chronic medications, etc) the patient is taking.
 Explain the patients about risk/benefit of the drugs.
 Counsel the patients about proper use of
medicines.
 Watch for ADRs and report them immediately.

24. PREVENTION OF ADRS
 Some ADRs are unavoidable and cannot be prevented.
 However, most ADRs can be prevented by following the basic principles of rational use of
medicines as follows:
 Use few drugs, whenever possible.
 Use drug that well known.
 Do not change therapy from known drugs to unfamiliar one without good reasons.
 Use text books and other reference materials providing information on drug
reactions and interactions.
 Take extra care while prescribing drugs known to exhibit a large variety of
interactions and adverse reactions (anticoagulants, hypoglycemic, and drug affecting
the CNS) with careful monitoring of patients with such reactions.
 Beware of the interaction of drugs with certain food stuffs, alcohol, etc.
 Review all the drugs (including Over the counter, herbal preparations ) used by
patients regularly.
 Be particularly careful when prescribing to children, the elderly, the pregnant and
nursing women, the seriously ill and patients with hepatic and renal diseases.
 Think of adverse drug reaction, when the patients show signs or symptoms not
clearly explained by the course of their illness.
 Consider stopping the drug or reduce the dosage as soon as the ADR is identified.

25. CONCLUSION
 Pharmacovigilance and risk management are an
essential part of pharmaceutical product
development and commercialization.
 Pharmacovigilance and risk management must
extend throughout the product’s life cycle to identify
rare adverse events.
 Pharmacists and Prescribers play important roles in
reporting of ADRs.

26. REFERENCES
 Pharmacovigilance, 2nd Edition
Ronald D. Mann, Elizabeth B. Andrews
 An Introduction to Pharmacovigilance
Patrick Waller
 Cobert’s Manual of Drug safety and
Pharmacovigilance, 2nd edn
Barton Cobert
 Guide to Drug Development: A Comprehensive
Review and Assessment, 1st Edition
Bert Spilker PhD, MD
 Global Clinical Trials Playbook, 1st Edition
Menghis Bairu, Richard Chin

27. REFERENCES
 http://www.fda.gov/downloads/Drugs/Guidan
ceComplianceRegulatoryInformation/Guida
nces/ucm073107.pdf
 http://www.who.int/medicines/areas/quality_
safety/safety_efficacy/S.AfricaDraftGuidelin
es.pdf
 http://ec.europa.eu/health/human-
use/pharmacovigilance/index_en.htm
 http://www.ema.europa.eu/ema/index.jsp?c
url=pages/regulation/general/general_conte
nt_000258.jsp