Pharmacovigilance

Dr. Ganesh Uchit , MD

Pfizer, India
1
 DISCLAIMER
The presentation is intended for educational purposes only and does not
replace independent professional judgement.

Statements of fact and opinions expressed PowerPoint slides are those of the
individual presenter and should not be attributed to the employer or any
organization/society with which the presenter is affiliated
 Overview

• Introduction & Terminology

• Why Pharmacovigilance?

• Pharmacovigilance Practices: International & Indian

• PVPI

• Drug Safety Issues in Clinical Trials

• Summary
Medicine Safety

To undergo treatment
you have to be very
healthy, because apart
from your sickness
you have to withstand
the medicine.

Molière
 Would you travel with this plane?

New Airbus 390

The plane company's The Pilot

transportation safety office
Would you use this
medicine?
 Authority
inspections

Resourceful
consumer

Media

2010
Version 2.0
Refresher training-Nordic office employees
What is Pharmacovigilance?

Pharmakon: “drug;”
vigilare: “to keep awake or alert, to keep watch.”

“Detection, assessment, understanding and prevention

of any adverse event or other medicine-related problem”
Pharmacovigilance

Science and activities relating to the detection,

assessment, understanding and prevention of adverse
effects or any other drug-related problem
Pharmacovigilance

“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.” [WHO Technical
Report No 498 (1972)].
Case 1

• A patient was seen by you on Monday. He had

complaints of fever, running nose, throat irritation
and cough since Sunday.
• He was prescribed antipyretics + antihistamine +
antibiotic
• He returns on Thursday. There is a bandage
around his wrist. He also has abrasions on his
hands and legs. He says he met with a minor road
accident – a cyclist rammed into him from behind.
• His cold and fever have subsided

Is this an adverse event?

 Pharmacovigilance

• An adverse event (AE) is any untoward medical

occurrence in a patient or clinical investigation subject
administered a pharmaceutical product and which does
not necessarily have a causal relationship with this
treatment.
• Serious ADR
• Severe ADR
• Unexpected ADR
Why Pharmacovigilance

New Medicines
Pre-marketing safety data
• Animal Experiments: Relevant?
• Clinical Trials: Complete?

Established Treatment
• Efficacy, safety & cost are of interest to the community

Clinical Trials
Intended for objective demonstration of clinical efficacy
• What if we do not do any
Pharmacovigilance
Facts about safety of Medicines
• Approximately 5.3% of hospital admissions associated
with ADRs
• Higher rates found in elderly patients who are likely to be
receiving multiple medications for long-term illnesses
• Nearly 10–20% of acute geriatric hospital admissions
are related to ADRs
• Antiinfective drugs – children and
• CV drugs – adults & elderly

Ref : The Annals of Pharmacotherapy n 2008 July/August, Volume 42

Facts

Nearly 7% of medication errors potentially harmful but

preventable ADRs
Adverse Drug Reactions are among the top ten causes of
mortality
Perception of Medical Risk
 The Importance of Choice

• Risk communication is about choice – for the doctor and

patient it is about shared decision making – pharma
companies play a part in providing information

• Sharing opinions, values and information maximises trust

and support

• Many factors, some of which may appear irrational,

influence patient choice
– personal experience, social networks, behavioural norms, media
reporting, fear, trust in technology, a desire to take control

• Risk perception will alter with disease state

 “The certainty
of
reasonable
uncertainty”
“The Tip of the iceberg”
Reported AEs

Under reporting of AEs

Illusion versus Reality !

 Predictable

AE

ADR
Unpredictable
Improving A E
Reporting
Feedback Training
&
&
Education
Publication
Rewards

Awareness

Good Reporting
Practice
International Organisations

23
WHO Collaborating Centre (Uppsala
Monitoring Centre)

24
25
Safety Signal Detection

“A report or reports of an event with an unknown causal

relationship to treatment that is recognised as worthy of further
exploration and continued surveillance”
 Why do we need PV?
Number of patients one would need to observe to have a 95% chance
of detecting 1, 2, or 3 cases of an adverse reaction at a given
incidence of the reaction can be gauged from this table:

Expected incidence of Numbers of patients to be observed

adverse reaction to detect 1, 2, or 3 events
1 2 3
1 in 100 300 480 650
1 in 200 600 960 1300
1 in 1000 3000 4800 6500
1 in 2000 6000 9600 13000
1 in 10000 30000 48000 65000

Oxford Textbook of Clinical Pharmacology and Drug Therapy, 3rd Edition, 2002
 Lancet Oncol 2010; 11: 627–36

Lancet Oncol 2011; 12: 65–82

BMJ 2012;344:e2697 doi: 10.1136/bmj.e2697

(Published 24 April 2012)
 Pharmacovigilance in India

1986 1997
ADR monitoring system India joined WHO-ADR
for India proposed (12 monitoring programme
regional centres (3 centres: AIIMS, KEM, JLN)

2004 – 2008
National
Pharmacovigilance prog.
(2 Zonal, 5 Regional, 24
2010
Peripheral Centres)
 Pharmacovigilance Programme
of India (PVPI)

Pharmacovigilance programme of India (PVPI) was

launched in July 2010.

Goal

To ensure that the benefits of use of medicine

outweighs the risks and thus safeguard the health
of the Indian population
PvPI - Programme governance and reporting structures

http://www.cdsco.nic.in/pharmacovigilance_intro.htm last
accessed on 09/08/2012
Benefit & risk: evolving concepts

One man's meat is another man's poison !!!

 Some examples…

• Clioquinol- subacute myelo-opticoneuropathy

(SMON) in Indians
(Wadia NH. Some observations on SMON from Bombay. J Neurol
Neurosurg Psychiatry. 1977 ;40(3):268-75.)

• Phenylpropanolamine (PPA)- Hemorrhagic

stroke
in Indian patients
(Prasad et al. Phenylpropanolamine-induced intraventricular hemorrhage.
Neurol India. 2003;51(1):117-8.)
 Clioquinol induced SMON in Indians

• About 10,000 cases of SMON reported

from Japan over a 15 year period (1960-
1975)
• What was the prevalence in India?
– A retrospective record based study (1967-71)
 Out 5,168 records, 2 cases compatible
with SMON
– A prospective study (1972-77)
 7 cases of SMON
 Only one case definite -----“Drug not banned
for
Modern Medicine
Ayurveda
Siddha
Unani
Homeopath
y
Folk/ tribal
 Corticosteroids
in
Herbal medicines
-Eczema
-Rheumatoid Arthritis
- Bronchial asthma

Deliberate addition of
modern drugs…

Antiepileptics
(60% commercial
samples) Antidiabetics
-Glibenclamide
-Sod. Valproate
-Tolbutamide
-Phenytoin
- Carbamazepine
 Whose is responsible for Pvig….

Pharmaceutical
Industry Practicing
Clinician

Academia

Pharmacists
Nurses &
Paramedics
 Process in Pharmacovigilance
• Collect and record of AEs / ADRs
• Causality assessment and analysis of ADRs
• Collate and code in database
• Compute risk-benefit and suggest regulatory
action
• Communicate for safe use of drugs
among stakeholders
Adverse Event reporting
Form
 Process in Pharmacovigilance
• Collect and record of AEs / ADRs
• Causality assessment and analysis of ADRs
• Collate and code in database
• Compute risk-benefit and suggest regulatory
action
• Communicate for safe use of drugs
among stakeholders
Compute risk-benefit ratio

One man's meat is another man's poison !!!

 Suggest Regulatory Action
• Suggest warnings and alerts for
regulatory
agency
Widening Scope in Pharmacovigilance

ADR reports of new drugs

- Medication errors and irrational use of medicines

- Herbal, traditional and complimentary medicines
- Substandard medicines and counterfeit medicines
- Blood products, biologicals, medical devices and vaccines
Drugs recently banned in India

• Rosiglitazone
• Sibutramine
• Rimonabant
• Nimesulide (Under 12 years)
• Cisapride
• Phenylpropanolamine
• Gatifloxacin and
• Tegaserod
Drug safety concerns - Europe since 1995

Eur J Clin Pharmacol (2008) 64:743–752

Drug Safety Issues in Clinical Trials

Old requirements New requirements

(Before 30 Jan 2013) (From 30 Jan 2013)

 Unexpected SAE  Type of report

 Timeline = 14 calendar days  Timeline
 EC, DCGI & other sites  Additional stakeholders
 No pre-screening checklist  Pre-screening checklist
 No guidance on compensation  Guidance on compensation
What to report? All SAEs during clinical trial

Who should report? Investigator, Sponsor, Ethics Committee

Investigator = Within 24hrs of occurrence & due analysis report

within 10 calendar days of occurrence
What is the timeframe? Sponsor = Within 10 calendar days of occurrence
EC = Within 21 calendar days of occurrence
What is the format? Appendix-XI

Investigator  DCGI, Chairman of EC, Head of Institution, Sponsor,

Whom to report? Sponsor  DCGI, Chairman of EC, Head of Institution,
EC  DCGI
[Chairman of Exp. Committee – For death case]

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Reporting Timeframe

 within 24hrs of occurrence – for Investigator

 within 10 calendar days of occurrence (Analysis report) - for Inv.& Sponsor
 within 21 calendar days of occurrence – for EC

 Too stringent
 occurrence Vs. awareness
 Hard copy submission Vs. Electronic submission
 Timeline is not in tune with international norms
What is compensation?
‘the act or process of making amends for something’ or
something, typically- money,
awarded to someone in recognition of loss,
suffering or injury’.

Both Schedule Y and the ICMR guidelines specify that

this be an essential element of the Informed consent
document (ICD). Research participants who suffer
physical injury as a result of their participation are
entitled to financial or other assistance to compensate
them equitably for any temporary or permanent
impairment or disability, according to the guidelines
Categories

• Injury occurring to the clinical trial subject

• Injury occurring to the trial subject is related to the clinical trial
• Clinical trial related death of the subject
Condition For Compensation
• Free medical management as long as required
• Financial compensation & Free medical management.
• Financial compensation to his/her nominee(s) & Free medical
management
Consequences of not abiding to the condition of compensation
• Show cause notice
• Suspend or cancel the clinical trial and / or restrict Sponsor
including his representative(s) to conduct any further clinical trials in
the country
• Any other action deemed fit under the rules
 C 1 = A × B (1 – F/100)

‘A’ = income of the deceased/injured per month from which a deduction

(50 % in case of death and 40% in case of injury) should be made in
regard to the amount which the deceased would have spent on himself
by way of personal and living expenses. The balance, which is
considered to be the contribution to the dependent family, constitutes
‘A’.

‘B’ =age of the deceased and period of his/her active career. A table of
multipliers (Annexure 1) has been provided from which an appropriate
multiplier should be selected with reference to the age of the deceased.

‘F’= Risk factor of the subject and should be assessed by the

investigator of the study from the above mentioned scale of 0 to 100.
For the purpose of calculation of the compensation F should not be
more than 50.

Ambiguous !
How to use the formula

Compensation = B x F x R B = Base Amount (8,00,000)

99.37 R = Risk Factor
F = Factor (from Annexure I)
Risk Factor
Factor Annexure1

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Example of compensation case:

Age R= 4.0 R = 3.0 R= 2.0 R=1.0 R=0.05
(Years)
18 7,290,088 - - - -
25 6,985,126 - - - -
35 6,345,899 4,759,424 - - -
55 4,365,422 3,274,067 2,182,711 - -
65 3,200,000 2,400,000 1,600,000 8,00,000 4,00,000
Pharmacovigilance
Promotes:

Systematic & rational use

Boost confidence for
safety
Safety Communications - A Patient Perspective

“Wonder Pills”
Sir, My wife has been prescribed pills. According to the
accompanying leaflet, possible side-effects are: sickness,
diarrhoea, indigestion, loss of appetite, belching, vertigo, abdominal
cramps, dizziness, stomach ulcers, bleeding from intestine or blood
diarrhoea, ulcerative colitis, sore mouth and tongue, constipation,
back pains, inflammation of pancreas, mouth ulcers, skin rashes,
hair loss, sensitivity to sunlight, drowsiness, tiredness, impaired
hearing, difficulty with sleeping, seizures, irritability, anxiety,
depression, mood changes, tremor, memory disturbances,
disorientation, changes in vision, ringing in ears, bad dreams, taste
alteration, allergic reactions, swelling due to water retention,
palpitations, impotence or tightness of the chest.
Should she take them?
Yours faithfully,
A D. O,
Hertfordshire. Information withheld due
to data privacy
Letter to the Editor,1996
56
References

 Central Drugs Standard Control Organization. Good Clinical Practices for

Clinical Research in India. 2001. Available from:http://cdsco.nic.in/
 January 30.01.2013 (GSR 53 E)
 Feb 01.02.2013 (GSR 63 E)
 System of Pre-screening for submission of reports of SAEs to C
DSCO
NEW

 Minutes of 63rd DTAB 16.05.2013

 Draft Guidelines For Industry on Reporting Serious Adverse
Events occurring in Clinical Trials  (
http://www.cdsco.nic.in/SAE%20GUIDELINES%2005-05-2011
.pdf
)
"Dying from a disease is sometimes unavoidable. But, dying from an
adverse drug reaction is unacceptable".
- Dr Vladimir Lepakhin
Geneva 2005