PHARMACOVIGILANCE

OVERVIEW

What is pharmacovigilance
Pharmacovigilance center in India
History of Pharmacovigilance
Who reports
What to report
How it is categorized
Reporting methods
Reporting timings
Flow of data
Methods to assessment( scales/ algorithms)
Data mining/ software used
MedDRA
Discussion
conclusion

World Health
Organisation

The science and activities relating to the

detection, assessment, understanding and
prevention of adverse effects or any other
drug-related problem
Why pharmacovigilance?
a

Drugs withdrawn from Market due to

severe ADR
Drug

ADR

Company

Year

Rofecoxib

Myocardial infarction

Merck

2004

Cerivastatin

Rhabdomyolysis

Bayer

2001

Cisapride

Cardiac arrythmia

J&J

2000

Astemizole

Cardiac arrythmia

J&J

1999

Bromfenac

Liver toxicity

Wyeth

1998

WHO ALL ARE INVOLVED

The problem of ADRs

ADVERSE DRUG REACTION

SAE

WHAT IS NOT AN AE/SAE?

Surgical procedures planned prior to randomization and

conditions leading to these measures are not adverse events
(medical history)

DIMENSIONS OF AN ADVERSE
EVENT
Adverse
Event

Intensit
y
Mild
Moderat
e
Severe

Seriousn
ess

Serious
Non serious

Expectedn
ess
Expect
ed
Unexpec
ted

Relatedn
ess
Related
Unrelated

OUTCOME OF AN AE & FOLLOW

Follow
Ups
are
Follow
Ups
are
UPS
necessary

necessary
to
toknow
know
outcome
outcome
(ongoing)
(ongoing)
get
getcritical
critical
missing
missing
information
information
(concomitant
(concomitant
med.)
med.)
hospital
hospital/ lab
/ lab
reports
reports
(autopsy
(autopsyreport)
report)
causal
causal
assessment
assessment
(revision
(revision/ /
delayed)
delayed)

AUSAL ASSESSMENT WHO

LGORITHM
Certain
Certain
Probable
Probable
Possible
Possible
Unlikely
Unlikely
Unclassifiable
Unclassifiable

REPORTING METHOD & SYSTEM

THE MINIMUM CRITERIA FOR A

VALID ADR REPORT*

ADR FORM

LAWS, REGULATIONS AND

GUIDELINES

Adv.Event

Record
in CRF

Non -Serious

Serious

Record in CRF

immediately /
within 24 hours/

SUSAR / U.SAE
Report EXPEDITEDLY

within 7
calendar
days

Global Team
HQ
Safety
Review

DSMB

12/17/15

Sponsor
PIs / ECs

EC
DCGI

within 14
calendar days

Safety Profile
Update
17

CURRENT US FDA REGULATIONS

Safety reporting requirements are
specified in Title 21, Code of
Federal Regulations:
Part
Old Drugs (marketed pre310.305
1938)
Part
Safety reporting from INDs
312.302
Part 314.80 Marketed drugs
Part 314.98 Generic drugs
Part 600.80 Therapeutic Biologic
products

ICH-GCP GUIDELINES - III

E2A
E2B
E2B(M)
E2C &
E2C
E2D
E2E

Expedited clinical safety reporting

Safety reporting data elements
specs
Data Elements for Electronic
submission
Addendum PSURs
Post-marketing expedited reporting
standard
Pharmacovigilance planning

AIMS OF POST MARKETING

SURVEILLANCE

SPONTANEOUS REPORT
An

unsolicited communication to a company,

regulatory authority or other organization that
describes an adverse drug reaction in a patient given
one or more medicinal products and which does not
derive from a study or any organized data collection
scheme is called Spontaneous Report.
Strengths

Weaknesses

Cornerstone of PV

Underreporting

Cheap & Easy

Quality of reporting

Encompass all clinical

No denominator

settings
Life-time span
Detection of rare ADRs

Subject to bias
Delayed effects go
undetected

PSUR- PERIODIC SAFETY UPDATE

REPORTS

Its
a
formal,
structured
update
of
the
worldwide
safety
experience
for
a
registered medicinal product
(per
ICH
E2C
standards),
prepared for submission to
regulatory
authorities
at
defined
times
postauthorization

PERIODIC SAFETY UPDATE REPORTS

REPORTING TIMINGS
Schedule Y
(Indian)
o
o

Only New
Drug
Six Monthly
first 2
years
Annual
subsequent
2 years
To be
submitted
within 30
calendar
days

EU Requirements
o
o
o

Even if not
marketed
Six Monthly
first 2 years
Annual
subsequent 2
years
At the first
renewal, and
then
5-yearly at
renewal
thereafter
One PSUR for
each active
substance
To be submitted
within 60 days

US

Requirements
o

Pre-Approval
PSUR 4
months after
application
Post
Approval for
each
approved
NDA/ANDA/B
LA
Quarterly
for first 3
years
Then annual
interval / on
request
Within 30
days of the
close of

Data
Collecti
on

THE FLOW

Data
Evaluati
on

Communicat
ion

Databa
se

Decision
Making

Signal
Detection
&
Evaluation

R/B
Evaluatio
n

PV SOFTWARES & DATABASE

1. Intranet / Internet
based
2. Restricted Access
3. Level privileges

1. ArgusAERS (US
FDA)

4. MedDRA / WHO
integrated

2. Eudravigilance
(EMEA)

5. Company Product
Library

3. ARIS global

6. Time bound process

7. QBS
8. Signal generation
9. Report generation
10.Electronic
submissions

4. Clint race
5. Oracle

MedDRA

Med DRA: medical Dictionary for Regulatory

Activities
MedDRA is a clinically-validated international medical
terminology used by regulatory authorities and the
regulated biopharmaceutical industry.
The

terminology

is

used

through

the

entire

regulatory process, from pre-marketing to postmarketing, and for data entry, retrieval, evaluation,
and presentation.

MedDRA

MedDRA - Structure

The Gains from PV Database

Patients safety & care

Dissemination
information
concerned

to

of
all

Regulatory compliance

Detection of new safety

issues

Changes
in
documents

Ongoing safety review

Regulatory actions

design

ADR detection

Subjective
report

patient
complai
nt

Objective
report

Direct
observation
of event
physical
exam

abnorm
al
findings

Laboratory
test

Diagnosti
c
procedure

NARANJO's ALGORITHM
Question

Don't
know

Yes

No

Are there previous conclusion reports on this

reaction?

+1

Did the adverse event appear after the suspect

drug was administered?

+2

-1

Did the AR improve when the drug was

discontinued or a specific antagonist was
administered?

+1

Did the AR reappear when drug was re

administered?

+2

-1

Are there alternate causes [other than the drug]

that could solely have caused the reaction?

-1

+2

NARANJO's ALGORITHM
Question

Don
t
kno
w

Yes

No

Was the drug detected in the blood [or other

fluids] in a concentration known to be toxic?

+1

Was the reaction more severe when the dose was

increased, or less severe when the dose was
decreased?

+1

Did the patient have a similar reaction to the

same or similar drugs in any previous exposure?

+1

Was the adverse event confirmed by objective

evidence?

+1

NARANJO's ALGORITHM

SCORING
FOR
NARANJO'
s
ALGORIT
HM

Other methods

Methods of assessment

Three broad
categories

Methods of assessment

Desirable Attributes

Drawbacks

Which method to use?

Widely used

Naranj
o

WHO

WHO v/s Naranjo