PHARMACOVIGILANCE

JACOB JESURUN R S
Who is this?
1950s……West Germany……
The wonder drug…….
Disaster strikes
Angel Without Wings
The great wall that Frances was….
Hitting the Headlines
The Honour
 PURPOSE OF THIS PRESENTATION
•To PRESENT the case for the importance of
pharmacovigilance
•To EMPHASIZE its growth and potential as a
significant discipline within medical science
•To EXPLAIN its basic structure and
functioning
• to DESCRIBE its impact on patient welfare
and public health.
OVERVIEW
• Definition
• Introduction and Need for PV
• Terminologies in PV
• ADR Burden
• Aims of Pharmaco-vigilance
• Stake Holders in PV
• History of Pharmacovigilance
• WHO Programme for International Drug Monitoring
• PVPI
 contd…..
• Tools in PV
• Few More Crucial Terms in PV
• Types of Reporting
• What to report?
• Sneak peek into the CDSCO ADR reporting forms
• Causality Assessment
• Questions to be asked while planning a treatment
• Reported Examples
• Reporting Culture
• PV in other parts of the world
• PV in India
• PV The Need of the Hour
• HAEMO-VIGILANCE
• MATERIOVIGILANCE
THE MAGIC BULLET
EFFICACY VS TOXICITY
 DEFINITION
• Pharmacovigilance (PV) is defined as the science and activities
relating to the detection, assessment, understanding and prevention
of adverse effects or any other drug-related problem.

• Adverse event (AE) reporting involves the receipt, triage, data

entering, assessment, distribution, reporting (if appropriate), and
archiving of AE data and documentation.
Introduction and Need for PV
• Pharmacovigilance is an arm of patient care.
• Aims at making the best use of medicines for the treatment or prevention of
disease.
• Will identify the risks and the risk factors in the shortest possible time so that
harm can be avoided or minimized.
• When communicated effectively, this information allows for the intelligent,
evidence-based use of medicines and has the potential for preventing many
adverse reactions.
• This will ultimately help each patient to receive optimum therapy, and on a
population basis, will help to ensure the acceptance and effectiveness of public
health programmes.
Contd……….
• Significant harm to a few patients can destroy the credibility,
adherence to and success of a programme.
• Rumours and myths about the adverse effects of medicines can
spread rapidly and are difficult to refute in the absence of good data.
• Pharmacovigilance can provide these data.
• It can also provide evidence of other types of medicine-related
problems including treatment failure, counterfeit medicines, poor
quality medicines, interactions between medicine and food and the
incorrect use of medicines.
• Good pharmacovigilance practice can generate the evidence that will
inspire public confidence and trust.
 ADR BURDEN
• Over 2 million serious ADRs yearly.
• Over 1 lakh ADR related deaths yearly.
• 4th leading cause of death ahead of Pulmonary disease,
Diabetes, AIDS, Pneumonia and Accidents.
• Nursing Home patients ADR rate 3,50,000.
• Ambulatory patients ADR rate unknown.
• More than 50 percent of the approved drugs in the United
States were associated with some type of adverse effect not
detected prior to approval, much more in developing
countries.
 RISK FACTORS ASSOCIATED WITH ADRs
•Extremes of age
•Multiple pathologies
•Multiple drugs(Polypharmacy)
•Mismanagement of drugs
•Altered drug-handling capacity
•Drug allergy or previous H/O ADRs
•H/O Smoking
•H/O Substance Abuse
RECOGNITION AND REPORTING OF THIS ARRHYTHMIA IN ASSOCIATION WITH
TERFENADINE, ASTEMIZOLE, CISAPRIDE, GREPAFLOXACIN, AND MIBEFRADIL
ULTIMATELY LED TO THE REMOVAL OF THESE MEDICATIONS FROM THE MARKET.
 DRUGS WITHDRAWN(examples..)
DRUGS REASON FOR WITHDRAWAL

SIBUTRAMINE(2010) MI and Stroke

TERFENADINE(1998) Prolonged QTI and VT

TOLCAPONE(1998) Hepatotoxicity

ROFECOXIB(2004) MI and Stroke

LUMIRACOXIB(2008) Hepatotoxicity

PERGOLIDE(2007) Heart Valve Damage

 EXAMPLES OF SERIOUS ADRs
• Anemia - Chloramphenicol , Chloroquine, Isoniazid, Primaquine

• Angioedema - ACE inhibitors : Captopril, Enalapril, Lisinopril

• Bone fractures –Esomeprazole, Lansoprazole, Omeprazole

• Blood clots - Birth control drugs (all forms including patches and pills)
Drospirenone/ethinyl estradiol Norelgestromin/ethinyl estradiol

• Confusion and drowsiness - Sedatives, including many antihistamines

Diphenhydramine , Antidepressants (especially in older people)
Amitriptyline Imipramine
 Contd………
• Decreased production of white blood cells, with increased
risk of infection - Clozapine, Cyclophosphamide,
Mercaptopurine Methotrexate, Vinblastine ,Propylthiouracil

• Renal damage – Ibuprofen, Naproxen, Aminoglycoside,

Gentamicin Tobramycin, Cisplatin, Methotrexate,
Amphotericin B, Gentamicin, Tetracycline

• Hepatic damage -Acetaminophen (use of excessive doses) ,

Isoniazid Iron supplements (in excessive
amounts),Duloxetine, Tetracycline
• Muscle tissue destruction (rhabdomyolysis) Statins
Atorvastatin Simvastatin
• Stomach or intestinal ulcers (with or without bleeding)
NSAIDs Aspirin Ibuprofen Naproxen Anticoagulants
Heparin Warfarin Bisphosphonates Alendronate
Risedronate
• Toxic epidermal necrolysis Some antibiotics Penicillins
Quinolones Anticonvulsants Phenytoin Valproic acid
• Ventricular tachycardia Antiarrhythmics: Amiodarone,
Procainamide Sotalol ,Antipsychotics, Chlorpromazine
,Haloperidol, Lithium.
 TERMINOLOGIES IN PV
An adverse drug reaction (ADR) is ‘a response to a medicine which is noxious and
unintended, and which occurs at doses normally used in man’. In this description it is of
importance that it concerns the response of a patient, in which individual factors may play
an important role, and that the phenomenon is noxious (an unexpected therapeutic
response, for example, may be a side effect but not an adverse reaction).
2. An unexpected adverse reaction is ‘an adverse reaction, the nature or severity of which
is not consistent with domestic labelling or market authorisation, or expected from
characteristics of the drug’.
3. A drug or medicine is ‘a pharmaceutical product, used in or on the human body for the
prevention, diagnosis or treatment of disease, or for the modification of physiological
function’.
4. A side effect is ‘any unintended effect of a pharmaceutical product occurring at doses
normally used by a patient which is related to the pharmacological properties of the drug’.
Essential elements in this defi nition are the pharmacological nature of the effect, that the
phenomenon is unintended, and that there is no deliberate overdose.
5. An adverse event or experience is defined as ‘any untoward medical occurrence that
may present during treatment with a medicine but which does not necessarily have a
causal relationship with this treatment’. The basic point here is the coincidence in time
without any suspicion of a causal relationship.
Contd…..
• 6. A serious adverse event(SAE) is any event that:
❖ Is fatal.
❖ Is life-threatening.
❖ Is permanently/significantly disabling.
❖ Requires or prolongs hospitalization.
❖ Causes a congenital anomaly.
❖ Requires intervention to prevent
permanent impairment or damage.
PV encompasses……….
•Prescription Medications
•Herbals
• Traditional and complementary medicines
• Blood products (Haemo-vigilance)
• Biologicals
• Medical devices (Materio-vigilance)
• Vaccines.
 Other issues relevant to PV
• Sub-standard medicines
• Medication errors
• Lack of efficacy reports
• Use of medicines for indications that are not approved and for which there is
inadequate scientific basis
• Case reports of acute and chronic poisoning
• Assessment of drug-related mortality
• Abuse and misuse of medicines
• Adverse interactions of medicines with chemicals, other medicines, and food.
• Radio-contrast dyes
• ARs due to Malfunctioning Devices
• Adverse effects of Blood and Blood products
 AIMS OF PHARMACOVIGILANCE
• Improve patient care and safety in relation to the use of medicines
and all medical and paramedical interventions,
• Detect problems related to the use of medicines and communicate
the findings in a timely manner
• Improve public health and safety in relation to the use of
medicines,
• Contribute to the assessment of benefit, harm, effectiveness and
risk of medicines, encouraging their safe, rational and more effective
(including cost-effective) use, and
• Promote understanding, education and clinical training in
pharmacovigilance and its effective communication to the public.
 STAKE HOLDERS IN PV
• Policy makers at all levels of healthcare, particularly those
concerned with drug policy
• Staff and consultants in national drug regulatory authorities
• Healthcare practitioners including Doctors, Nurses and
Pharmacists
• Pharmaceutical industry executives and scientists
• Professional staff in national pharmacovigilance centres
• Editors of medical and scientific journals
• Health epidemiologists
Contd…………..
• Health economists
• Professional staff of poison and drug
information centres
• Health administrators
• Consumer groups and patient support groups
• Legal advisors in health care
• Schools of health sciences, and
• The concerned layperson.
 Brief History
1961 Thalidomide
Disaster

1963- 16th World Health Assembly-

Resolution
1968-WHO Pilot research
project for International
Drug Monitoring
Consultation
Meeting-1971

WHO Technical Report-

Formation of “WHO Program for
International Drug Monitoring”
WHO Program for International Drug Monitoring

The WHO Programme for

International Drug Monitoring is a
worldwide collaboration of more
than 150 countries whose aims
are the safer use of medicines for
patients everywhere and building
a global culture of patient safety.
UPPSALA MONITORING CENTRE-SWEDEN
 PVPI
• Pharmaco-Vigilance Programme of India
• Launched by the Ministry of Health, Government of
India, through the Central Drugs Standard Control
Organisation(CDSCO) on
• 23rd November 2004.
• Consists of a network of ADR Monitoring
Centres(AMCs), all reporting online and directly to the
programme HQ at the IPC, Ghaziabad.
 Objectives
• Monitor ADRs in the Indian Population.
• Create awareness among health-care professionals about the importance of
ADR reporting in India.
• Monitor benefit-risk profile of medicines.
• Generate independent, evidence-based recommendations on the safety of
medicines.
• Support the CDSCO for formulating safety-related regulatory decisions for
medicines.
• Communicate findings with all key stakeholders.
• Create a national centre of excellence at par with global drug safety monitoring
standards.
Pharmaco-vigilance Programme of India(PVPI)
Data flow at PVPI
 Signal
•Reported information on a possible causal
relationship between an adverse event and a
drug, the relationship being unknown or
incompletely documented previously. Usually
more than a single report is required to generate
a signal, depending on the seriousness of the
event and the quality of the information.
- WHO Definition.
 ICSR
• Individual Case Safety Report
• Four Elements:
- Identifiable patient
- Identifiable reporter
- A suspect drug
- An adverse event
 ADR Coding
• The terminologies developed within the WHO programme
for coding adverse reactions and medicines.
• MedDRA (Medical Dictionary for Drug Regulatory
Activities) has replaced the World Health Organization
Adverse Reaction Terminology (WHO-ART) in developed
countries.
• WHO-ART remains the mainstay of communicating
adverse reactions in most developing countries within the
International Programme.
 TYPES OF REPORTING
Spontaneous Reporting:
• Sentinel method in Drug Safety Surveillance.
• Spontaneous reports are termed spontaneous as they take place during the
clinician's normal diagnostic appraisal of a patient, when the clinician is drawing
the conclusion that the drug may be implicated in the causality of the event.
• Spontaneous reporting system relies on vigilant physicians and other
healthcare professionals who not only generate a suspicion of an ADR, but also
report it.
• It is an important source of regulatory actions such as taking a drug off the
market or a label change due to safety problems.
• Spontaneous reporting is the core data-generating system of international
pharmacovigilance
 Expedited Reporting
• This refers to ICSRs (individual case safety reports) that involve a serious and
unlisted event (an event not described in the drug's labeling) that is considered
related to the use of the drug.
• Spontaneous reports are typically considered to have a positive causality, whereas a
clinical trial case will typically be assessed for causality by the clinical trial
investigator and/or the license holder.
• In most countries, the timeframe for reporting expedited cases is 7/15 calendar
days from the time a drug company receives notification (referred to as "Day 0") of
such a case.
• Within clinical trials such a case is referred to as a SUSAR (Suspected Unexpected
Serious Adverse Reaction).
• If the SUSAR involves an event that is life-threatening or fatal, it may be subject to a
7-day "clock".
• Cases that do not involve a serious, unlisted event may be subject to non-expedited
or periodic reporting.
 Clinical Trial Reporting
• SAE (serious adverse event) reporting from clinical trials
Safety information from clinical studies is used to establish a drug's safety
profile in humans
Key component that drug regulatory authorities consider in the decision-
making as to whether to grant or deny market authorization (market approval) for a
drug.
SAE reporting occurs as a result of study patients (subjects) who
experience serious adverse events during the conducting of clinical trials. (Non-
serious adverse events are also captured separately.)
SAE information, which may also include relevant information from the
patient's medical background, are reviewed and assessed for causality by the study
investigator.
This information is forwarded to a sponsoring entity (typically a
pharmaceutical company) that is responsible for the reporting of this information, as
appropriate, to drug regulatory authorities.
 Aggregate Reporting

• Aggregate reporting involves the compilation of safety data

for a drug over a prolonged period of time (months or years),
as opposed to single-case reporting which, by definition,
involves only individual AE reports.
• The advantage of aggregate reporting is that it provides a
broader view of the safety profile of a drug.
• The most important aggregate report is the Periodic Safety
Update Report (PSUR) and Development safety updated
report (DSUR).
 Tools in PV
• VIGIFLOW

• VIGIBASE

• VIGILYSE
1) VIGIFLOW:
• VigiFlow is a web-based Individual Case Safety
Report (ICSR) management system.
• Available for use by national pharmacovigilance
centres of the WHO Programme for International
Drug Monitoring.
• New module for vigiflow – e-reporting.
2) VIGIBASE:
• VigiBase is the unique WHO global database of individual case
safety reports (ICSRs).
• It is the largest database of its kind in the world, with over 14 million
reports of suspected adverse effects of medicines, submitted, since
1968, by member countries of the WHO Programme for International
Drug Monitoring.
• It is continuously updated with incoming reports.
• Alongside its data management and quality assurance tools, the
VigiBase system is linked to medical and drug classifications such
as WHO-ART, MedDRA, WHO ICD, and WHODrug. These
classifications enable structured data entry, retrieval and analysis at
different levels of precision and aggregation, which are vital in order
to enable effective and accurate analysis.
3) VIGILYSE:
• Is a powerful search and analysis tool that provides
access to more than 14 million ICSRs in VigiBase
• Submitted by over 120 countries.
• VigiLyze includes data on allopathic medicines,
traditional medicines (herbals), as well as biological
medicines, including vaccines.
• Results from VigiLyze are generated instantly in
tabular and graphical formats.
 What to report???
•All adverse effects of new drugs( Black Triangle
Drugs in UK)
•All serious adverse effects
•Rare adverse effects of existing drugs
•All ADRs in children
•Unsure whether to report- Report
•All suspected ADRs during pregnancy
ADR REPORTING FORM - FILLING
PATIENT INFORMATION(1-4)
1) INITIALS OF THE PATIENT – MOHAN LAL – ML

2) AGE( WHEN THE REACTION OCCURRED) / DATE OF BIRTH.

3) GENDER. ( M/F)

4) WEIGHT. ( IN KG).
SUSPECTED ADVERSE REACTION(5-7)

• 5) DATE OF REACTION STARTED -

• 6) DATE OF RECOVERY -

• 7) DESCRIBE REACTION -
SUSPECTED MEDICATIONS( 8- 15)
• 8) THE DETAILS OF SUSPECTED MEDICATIONS:
- DRUG NAME( BRAND/ GENERIC)
- MANUFACTURER
- BATCH NO/ LOT NO
- EXPIRY DATE
- DOSE USED
- ROUTE USED
- FREQUENCY
- DATES OF THERAPY STARTED AND STOPPED
- INDICATION
• RECHALLENGE DETAILS:
- YES – IF REACTION REAPPEARED AFTER RECHALLENGE.
- NO – IF REACTION DOES NOT REAPPEAR AFTER
RECHALLENGE.
- UNKNOWN – IF EFFECT OF RECHALLENGE IS NOT
KNOWN.
- NA – IF RECHALLENGE IS NOT APPLICABLE AS IN THE
CASE OF ANAPHYLAXIS REACTIONS.
- REINTRODUCED DOSE - MENTION THE DOSE AND DATE
OF RECHALLENGE.
• 11) CONCOMITANT DRUGS:
- ALL CONCOMITANT DRUGS
- SELF MEDICATIONS
- OTC DRUGS
- ALTERNATE MEDICINE

12) RELEVANT TESTS/ LAB DATA: WITH DATES.

13) OTHER RELEVANT HISTORY: COMORBIDS, ALLERGIES, ADDICTIONS,

PREGNANCY.
• 9) DECHALLENGE DETAILS:
- YES – IF THE REACTION ABATES AFTER DECHALLENGE.
- NO – IF THE REACTION DID NOT ABATE AFTER
DECHALLENGE.
- UNKNOWN – IF THE EFFECT OF DECHALLENGE IS NOT
KNOWN.
- NA – SINGLE DOSE – VACCINES, TEST DOSE,
ANAESTHESIA.
- TREATMENT CONCLUDED BEFORE THE REACTION
OCCURRED.
- PATIENT DECEASED BEFORE DECHALLENGE.
- REDUCED DOSE – MENTION REDUCED DOSE AND
DATE.
• 14) SERIOUSNESS OF THE REACTION:
• DEATH( Mention cause and date of death too).
• LIFE THREATENING.
• HOSPITALIZATION/ PROLONGED.
• DISABILITY.
• CONGENITAL ANOMALY.
• REQUIRED INTERVENTION TO PREVENT PERMANENT
DAMAGE/ IMPAIRMENT.
• OTHERS: CONDITIONS WHICH MIGHT LEAD TO ANY OF
THE ABOVE.
15) OUTCOMES:
- FATAL
- CONTINUING
- RECOVERING
- RECOVERED
- UNKNOWN
REPORTER ( 16-18)
• 16) NAME AND PROFESSIONAL ADDRESS: CONFIDENTIALITY WILL BE
MAINTAINED.

• 17) CAUSALITY ASSESSMENT: TO BE DONE BY REPORTER IF TRAINED IN CA.

• 18) DATE OF REPORT:

MANDATORY FIELDS
• PATIENT INITIALS.

• AGE AT ONSET OF REACTION.

• REACTION TERM(S).

• DATE OF ONSET OF REACTION.

• SUSPECTED MEDICATION(S).

• REPORTER’S INFORMATION.
ESSENTIAL FIELDS
• GENDER
• DOSE
• DATE OF THERAPY STARTED
• INDICATION OF USE
• SERIOUSNESS
• OUTCOME
• DECHALLENGE INFO
• RECHALLENGE INFO
• DATE OF REPORT
 CAUSALITY ASSESSMENT-WHO UMC
• The WHO-UMC system has been developed in consultation with the National
Centres participating in the Programme for International Drug Monitoring
• It is a practical tool for the assessment of case reports.
• It is basically a combined assessment taking into account the clinical-
pharmacological aspects of the case history and the quality of the documentation
of the observation.
• Since pharmacovigilance is particularly concerned with the detection of unknown
and unexpected adverse reactions, other criteria such as previous knowledge and
statistical chance play a less prominent role in the system.
• It is recognised that the semantics of the definitions are critical and that individual
judgements may therefore differ.
• There are other algorithms that are either very complex or too specific for general
use.
• This method gives guidance to the general arguments which should be used to
select one category over another.
WHO-UMC CAUSALITY ASSESSMENT SCALE
 OTHER ASSESSMENTS
•Severity Assessment- Hartwig Scale

•Predictability Assessment- Developed criterion

for determining predictability of an ADR

•Preventability Assessment- Modified Schumock

and Thornton scale
 Questions to be asked while planning a treatment option
(by the doctors, nurses, pharmacists, patients, care takers)
• Has the disease been correctly diagnosed?
• Is up-to-date, useful information available to the prescriber
and patient about the positive and negative effects of the
treatment and also comparative information about other
options?
• What are the hoped-for benefits of the drug and the chances
of their happening?
• What is the patient’s opinion of the tension between the
chance of benefit and the risk of harm?
• Has the right dose of the right strength of the right
formulation of the right medicine been prescribed?
 Contd……….
• What are the risks of the treatment producing an adverse
effect?
• What is the potential seriousness and duration of possible
adverse effects?
• Is the patient taking anything else which might interact
badly with the medicine or prevent it working at all?
• Is there any medical, genetic, allergic, social, psychological
or other condition that might cause a bad reaction to the
medicine?
• Is the manufacturing source of the medicine approved and
reliable?
 Contd……….
• Does the patient understand how to take the medicine
safely?
• Will the patient take the medicine exactly as advised?
• Will the patient know how to recognize adverse effects and
know what to do?
• Does the doctor, nurse or pharmacist have the knowledge
to diagnose and treat an adverse effect?
• Is there some reliable system for tracking, recording and
reporting the positive or negative results of treatment, and,
if there is, will it be used?
 PV ELSEWHERE
• UK Committee on Safety of Medicines(UK-CSM) Yellow Card
Scheme
-ADROIT- Adverse Drug Reactions Online Information Tracking
• US- FDA- ADR Registry
• EUDRA Vigilance- European Union
• The Pharmaceuticals and Medical Devices agency of Japan-Adverse
drug reporting System
• Korean FDA-ADR Registry
• The Malaysian Adverse Drug Reaction Adverse Committee
(MADRAC)
• Australian Adverse Drug Reaction Advisory Committee( AD-RAC)
THE FORMER- PV is the need of the hour.
THE LATTER- PV is just waste of time