Transcript Pharmacovigilance

Pharmacovigilance
Dr. Ganesh Uchit , MD
1
Pfizer, India
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
transportation safety office
The Pilot
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
• Perceived Risk is an intuitive estimate of Risk
• Perception of risk in respect to ADRs is not consistent
with other kinds of risk
– Extent and severity are important
• The media play an important role – a two edged sword
– There is a distorted view of the risks of taking medicines
– The risk of death from chloramphenicol is 1 in 20,000 which is
the same as the chance of dying in an air accident
• Everyday life carries appreciable risk
– Motorcycles, cars, skiing, smoking
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
&
Publication
Rewards
Training &
Education
Awareness
Good Reporting Practice
International Organisations
23
WHO Collaborating Centre (Uppsala
Monitoring Centre)
•
•
ADR database
No of reports: more than 3.5 million
Each year increase ~160,000 / year
•
Analysis
•
Output
– Feedback to National Centres
– Signal documents
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
adverse reaction
1 in 100
1 in 200
1 in 1000
1 in 2000
1 in 10000
Numbers of patients to be observed
to detect 1, 2, or 3 events
1
2
3
300
480
650
600
960
1300
3000
4800
6500
6000
9600
13000
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
for India proposed (12
regional centres
India joined WHO-ADR
monitoring programme
(3 centres: AIIMS, KEM, JLN)
2004 – 2008
National
Pharmacovigilance prog.
(2 Zonal, 5 Regional, 24
Peripheral Centres)
2010
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
adults”
Modern
Medicine
Ayur veda
Siddha
Unani
Homeopathy
Folk/ tribal medicine
Corticosteroids
in
Herbal medicines
-Eczema
-Rheumatoid Arthritis
- Bronchial asthma
Deliberate addition of modern
drugs…
Antiepileptics
(60% commercial
samples)
-Sod. Valproate
-Phenytoin
- Carbamazepine
Antidiabetics
-Glibenclamide
-Tolbutamide
Whose is responsible for Pvig….
Pharmaceutical
Industry
Practicing
Clinician
Academia
Nurses &
Paramedics
Pharmacists
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)
 Unexpected SAE




Timeline = 14 calendar days
EC, DCGI & other sites
No pre-screening checklist
No guidance on compensation
(From 30 Jan 2013)





Type of report
Timeline
Additional stakeholders
Pre-screening checklist
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
Whom to report?
Investigator  DCGI, Chairman of EC, Head of Institution, Sponsor,
Sponsor
 DCGI, Chairman of EC, Head of Institution,
EC
 DCGI
[Chairman of Exp. Committee – For death case]
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
99.37
B = Base Amount (8,00,000)
R = Risk Factor
F = Factor (from Annexure I)
Risk Factor
Factor Annexure1
Example of compensation case:
Age
(Years)
R= 4.0
R = 3.0
R= 2.0
R=1.0
R=0.05
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
CDSCONEW
 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%2005-052011.pdf)
"Dying from a disease is sometimes unavoidable. But, dying from an
adverse drug reaction is unacceptable".
-Dr Vladimir Lepakhin
Geneva 2005