Introduction to

Pharmacovigilance
Mondira Bhattacharya, MD
Senior Medical Director, Global
Pharmacovigilance

Abbott Laboratories

Disclaimer
The views and opinions expressed in this
presentation are solely those of the
presenter and do not necessarily reflect
those of Abbott Laboratories or any of its
affiliated organizations.

Course Overview:
Focus on Postmarketing Safety
History of U.S. Pharmacovigilance (the regulations!)
Definitions: Pharmacovigilance, ICSR, MedDRA, Signal, Risk
General PV Processes: Less data driven; greater emphasis
on regulatory submissions
Spontaneous reporting: ICSRs and Aggregate Reports
Signal Detection and Evaluation: Systematic; Data Driven
Qualitative cases/cases series
Quantitative disproportionality algorithms
Risk Management
Benefit Risk Assessment and its Implications: ongoing
evaluation of a drugs profile

Definition of Pharmacovigilance
Discipline that employs scientific methodologies to detect,
assess and understand adverse events associated with use
of drugs/biologicals/vaccines
Postmarketing activities
Utilizes data gathering from multiple sources: clinical
trials, spontaneous reports, literature,
pharmacoepidemiologic studies, registries
Major task is to identify new safety signals and to better
understand the patterns of recognized signals (risk
factors, severity, outcome)
PV activities contribute to the understanding of the
risk/benefit profile of the drug and to the communication of
changes identified to the existing profile

History of Drug Safety Regulations

1906 Pure Food and Drug Act: Tetanus: contaminated diptheria antitoxin
leading to deaths in children
Required licensing of manufacturers and distributers
Prevented mislabeling of drugs and adulteration of drugs
NO requirement for proof of safety/efficacy.
Next major disaster: Elixir of sulfanilamide used to treat gonorrhea and
pneumococcal infections was newly introduced in a more flavorful dosage
using a solvent which was the antifreeze diethylene glycol.
> 100 deaths
Only charge against the company was that the elixir contained no alcohol.
1938 Food, Drug and Cosmetic Act: requirement for collection of clinical
safety data on and submission of such data to the FDA prior to approval. No
postmarketing safety reporting requirements.

Thalidomide Storm
Thalidomide
(sedative/antiemetic) disaster:
malformed limbs along with
other birth defects reported in
Lancet in 1961
Drug was never approved in
the US for morning sickness
because reports of fetal
malformations were quickly
picked up by the press and
communicated worldwide

Thalidomide Storm: Outcome

Kefauver-Harris Amendment (1962):
A result of the thalidomide disaster
(phocomelia in newborns). Extensive preclinical testing, submission of such data to
FDA (IND) before clinical testing could begin.
Three explicit phases of clinical testing were
defined. Proof of efficacy was required.
Also mandated that pharmaceutical
manufacturers having an NDA must report
AEs to the FDA.

History of U.S. Regulations

Historical Perspective
- 1967: computerization of AE reports
1985 NDA Rewrite : requirement for submission
of spontaneous reports; prior to that these reports
got filed away as part of IND submissions.
1993 MedWatch devices, vaccines
1997 FDA Modernization Act: AERS database
2003 Concept Papers on Risk Management
2007 FDAAA

Adverse Event
Any untoward medical occurrence in a
patientadministered a pharmaceutical
product and which does not necessarily
have a causal relationship with this
treatment.
Can be any sign, symptom, or abnormal
lab result temporally associated with a
treatment.

Spontaneous Reporting:
Sources of Data
Unsolicited reports from health care professionals
or consumers
Includes adverse experiences, medication errors
and product quality complaints sent directly to FDA
through the MedWatch program or via a
manufacturer.
Postmarketing surveillance: compilation of these
spontaneous reports + data from formal clinical
trials + literature reports + pharmacoepidemiological
studies = postmarketing surveillance data

Uses of Spontaneous
Data
Identify new (previously unrecognized) ADRs

Identify risk factors/at-risk populations for

known ADRs
Identify change in reporting of an AE/ADR over time
Identify manufacturing problems
Identify medication errors (wrong dose, wrong
patient, drug interactions, use in the face of clear
contraindications) are common: estimated to
contribute to 44,000-98,000 annual deaths in the
U.S. and are associated with 17-29 billion dollars of
excess expenditure.

Why do we need spontaneous reporting after drug

approval? Why is Clinical Safety Data Inadequate
for Identifying all Risks?
Very restricted patient population(inclusion/exclusion
criteria; concomitant medications restricted)
Too small (few thousand)
Duration of exposure is usually less than 1 year
Often not designed to identify specific change in
incidence of outcomes of the underlying disease
Errors associated with medical prescribing not captured
Public failures of our system:

20% of new drugs get Black-box warnings

4% of new drugs removed from market due to safety
reasons (industry inefficiency)

Greatest Challenge for Spontaneous

Reports: Under reporting

HIPPA Regulations have not helped!

Report Quality: Inclusion of details to establish causality:

diagnostic test results?, progression of disease?, effect of
concomitant medications?, etc.

Biases Affecting Spontaneous Reporting

Nature

of the event

Severity
Uniqueness
Co-morbidity/outcome of disease being treated
Length of time drug is on the market: first in

class vs. later

Weber effect: peak is 1-2 years after approval;
not shown to be true for all classes of drugs
Publicity/media attention
Litigation
Reporting regulations

Triggers for Increased Reporting

300

900

200

No denominator available!
800
700
600
500

150
400
100

Prescriptions
(Thousands)

# of Cases (Initial or Follow-up)

250

Another drug
in class
removed
from market
for safety
reasons

300
200

50
100
0

Ju
l-1
99
9
Se
p- 1
99
9
No
v-1
99
9
Ja
n-2
00
0
Ma
r- 2
00
0
Ma
y -2
00
0
Ju
l-2
00
0
Se
p-2
00
0
No
v-2
00
0
Ja
n-2
00
1
Ma
r- 2
00
1
Ma
y -2
00
1
Ju
l-2
00
1
Se
p- 2
00
1
No
v-2
00
1
Ja
n-2
00
2
Ma
r- 2
00
2
Ma
y -2
00
2
Ju
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2
Se
p- 2
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2
No
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2
Ja
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3
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3
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3

Initial Versions

Follow-up Versions

Prescriptions

Next step - Coding of Events: Medical

Dictionary for Regulatory Activities (MedDRA)
Each event within a report (ICSR individual case
safety report)
To aggregate reported terms in medically
meaningful groupings for the purpose of
reviewing and/or analyzing safety data
To facilitate consistent retrieval of specific cases
or medical conditions from a database
To identify frequency of medically similar
ADR/AEs
To improve consistency in comparing safety data
from multiple sources (clinical trials and
spontaneous reports)

Evaluation of Causality of a Single Case Report: Medical

Assessment and Query = Adverse Drug Reaction (ADR)

Features that may Suggest a Causal Relationship:

Absence of symptoms/condition prior to exposure to drug
Timing of event in relationship to drug administration
suggestive
Evidence of a positive dechallenge and/or positive rechallenge
No mitigating factors identified
Consistency with the drugs known pharmacological and/or
toxicological effects
Supporting evidence from other sources (clinical studies,
nonclinical studies, reports for drugs of the same class)
Event typically associated with a drug effect (i.e. Steven
Johnson Syndrome)

MEDICALLY SIGNIFICANT LIST Examples of

events that require immediate follow-up
Acute respiratory failure/acute

Hepatic necrosis

Acute respiratory distress syndrome

Acute liver failure

Ventricular fibrillation

Anaphylactic shock

Torsade de pointes

Acute renal failure

Malignant hypertension

Pulmonary hypertension
Pulmonary fibrosis

Convulsive seizures

Confirmed or suspected
endotoxin shock

Agranulocytosis
Aplastic anemia

Confirmed or suspected
transmission of infectious agent
by products

Toxic epidermal necrolysis

Stevens-Johnson syndrome

Aggregate Reports: Periodic vs. PSUR

Periodic Report (PADER)

PSUR

(a)

Covers

FDA USA

ICH International

Events

No required events; analysis of

expedited events; non-expedited and
fatal reports

Required events (Overdose, Drug

Interaction); selected events; analysis
of Serious unlisted events

Foreign Reports

Non-included / Optional

Included

Period

Quarterly for 3 yrs. Annual after 3 yrs. Every 6 mos (2yrs), annually (2yrs),
every 3yrs
Not included
Included

Total Exposure
Studies

Targeted safety studies or studies

yielding important safety data that
were initiated during reporting period

Targeted safety studies or studies

yielding significant safety data;
tracked until final report

Regulatory

Actions taken for safety reasons

globally

Actions taken for safety reasons

globally

Label Changes

USPI Changes during the reporting

period

CCDS changes during the reporting

period

(a)

Only medically confirmed cases are used

CLASSIC
PHARMACOVIGILANCE
Adverse Drug Reaction

EX
PE
DI
TE

Review Of Data From All Source

No

Regulators

Aggregate and Present In

Periodic Reports
s
Ye

Change

Bulk of effort was to better characterize

what was known and heavily reliant on
companys own database. Not a very
effective means for identifying signals!

What is a Signal?
Reported information on a possible causal
relationship between an adverse event
and a drug, of which the relationship is
unknown or incompletely documented
previously and which is of enough
interest to justify verification action.
Source: Trinks, Uwe. DIA Conference, Chicago, IL, 2011

How do you find Signals:

many routine activities within PV
Single case of concern (ie:SJS)
Trial results revealing an imbalance in ADRs
between treatment arms
Data mining:
Methodology to identify hidden patterns of association
between use of a drug and an unexpected adverse
reaction
Computer algorithms to analyze records contained in
huge drug safety databases.
Estimated 1000 reports per day are added to FDA AERS
database

Data Mining
It is a prospective, timely methodology for analyzing
these reports to ascertain whether there is an excess
of events of concern with use of a drug
Is now considered an essential adjunct to other PV
activities and needs to be integrated into existing PV
processes.
Databases:
US FDA-AERS:available through FOI Act (5 month lag)
WHO Vigibase: licensing agreement
EMEA Eudra Vigilance:products on EU market; only access
to data on their own products
In house corporate database

Data Mining
Examination of reported AEs using statistical or
mathematical tools to assess for an excess of specific AEs
for a product
Output is generally a score that quantifies the
disproportionality between the observed and expected
values for a given product-event combination
Comparison: assumption for these scores is that the
proportion of specific events is the same across all drugs
This comparison can be modified as appropriate (for
example, for an anti-diabetic drug, the comparison may
be made only to other anti-diabetic drugs rather than all
drugs)
A threshold is arbitrarily set, with scores above this threshold
deemed in excess of expected and meriting further
investigation

Datamining Method
Disproportionality Analysis
Comparison of relative reporting frequencies
AE of interest
All other AEs
Total

Drug of Interest

All Other Drugs

Total

A+C

B+D

A+B

C+D

A+B+C+D

Example:
Proportional Reporting Ratio (PRR) =

A
A+B
C
C+D

> 9,000 event codes (MedDRA Preferred Terms)

> 7,000 drug/biological products by trade names
> 60,000,000 drug-event combinations possible!

Data Mining
Scores are determined using statistical
models
Multi-item Gamma Poisson Shrinker (MGPS)
algorithm
Proportional Reporting Ratio (PRR) method
Neural Network Approach

Results of Data Mining

EBGM: Empirical Bayes Geometric Mean that can
be understood as an average ratio of expected to
observed events
EB05: The lower limit of the 95% CI on the EBGM
Example: if EB05=20, then the drug-event occurred AT
LEAST 20 times more frequently in AERS than expected

Data Mining Signal (Threshold Interval) EB05

>=2:
The drug-event occurred AT LEAST twice as often as
expected. This threshold gives assurance that potential
signals are unlikely to be noise

Interpretation of Data Mining Results

Advantages: large, reproducible, comparable however
only hypothesis generating
Areas of uncertainty:
False associations:
- Drug constantly used with other drugs that do
cause the event
- Outcome/event more related to natural history
of disease than drug
Missed associations:
- Later in drug class under reporting
- Event linked to the disease under reporting
- Event occurs years after initiation of treatment
(cancers, heart disease) under reporting

Signal Evaluation:
Confirm/Refute/Understand a Signal
No confirmation of a causal relationship
between a drug and an AE can be
established through this exercise.
Case series
Review of additional cases; if possible, use standardized
case definitions (formal criteria
for including or excluding a case in the series)
Literature
Epidemiologic studies: natural history; safety studies
Clinical Trial Data

CURRENT
PHARMACOVIGILANCE
Periodic
Reports

Data
Mining

ADRs

Signal
Other
Sources

Clinical
Data
No

Assess Signal

Regulatory
Reporting

Yes

Fully Characterize =
Risk Management

Label & Other

Changes

Altered

Benefit/
Risk Assessment

Risk Management: The Patients

Perspective Stop the Drug!

Risk Benefit Decisions

Every substance is a poison;
it is only a matter of dose
Paracelsus (1493 1541)
and a matter of risk management!

Risk Management View

Risk
Disapprove
Acceptable
risk for
some
patients or
physicians

Risk Management (RM) Zone

Maximum
acceptable
risk for all
patients

Approve
Benefit
Acceptable
benefit for
some patients
or physicians

Minimum
acceptable
efficacy for
all patients

Source: Michael J. Klepper, MD (2006)

Risk Management Plans: Quantify,

Characterize and Communicate Risks
Identify the significant risks and potential risks
of the product
Quantify the risks; identify populations for which risk is not
known or quantified
Identify the subpopulations who face the
important risk
Evaluate early detection and prevention potentials
Strategic safety program designed to meet specific goals and
objectives in minimizing known risks of a product while
preserving its benefits.
Proposed routine PV or active interventions (will include a PPI)
but generally involves other activities (e.g.: change to the label,
certification of prescribers, medication guide, restricted
distribution, etc.)

FDA vs. EMEA

Convergence rather than divergence
Both requiring estimation of risk (pharmacoepidemiology)
with drug, with population, and lowering the thresholds for
identifying risk in the label
RMP in EU is a requirement, though a risk minimization
plan is not
REMS is analogous to a risk minimization strategy and will
become more commonplace in the US. REMS must be

accompanied by a timetable for submission of

assessments.
Both utilizing these documents to shift the discussion to
one of benefit/risk in a more formalized manner.

T.O.U.C.H. Tysabri Risk Minimization

Plan
Monoclonal antibody launched in 2004 for treatment of MS
and Crohns disease
Rare, fatal illness associated with use PML few cases in
2005
Removed and reintroduced in 2007 (for relapsing MS only,
neurologist only) with restrictive prescribing program that has
allowed:
- An efficacious drug to be available for a subgroup of patients with MS under
highly restrictive prescribing conditions
- Estimate the incidence rate and outcome of PML in patients using the drug
- Characterize early clinical presentations of PML
- Possibly reduce the number of fatal cases by working with clinicians to
introduce new therapies
- Collect and characterize other opportunistic infections associated with use
Drug Safety Update March 2010, vol 3
Neurology Today May 2010, vol 10: 17-18

Summary: Changes in Emphasis within

PV
Old Emphasis

Current Practices
Collection, coding timely evaluation of ICSRs and
aggegate periodic reports continue.
Implementation of signal detection methodologies to
allow for identification of signals utilizing large
safety databases; standard processes for signal
evaluation
Comparison to epidemiologic data to understand
incidence/prevalence in population
Conduct more safety studies to answer
new/ongoing safety concerns
Staffing to ensure that qualified persons are
reviewing these data outputs per company
processes
RMPs (including the specific risk minimization
plans) provide opportunity to analyze the large
volume of spontaneous reports in a more focused
manner and require utilization of data from other
sources when risk/safety concerns exist and allows
the company to more formally place them in the
context of benefit/risk

Collection, coding and timely

evaluation and reporting of

individual cases
Reliance on aggregate reports to
identify signals (based primarily on
spontaneous reporting which lacks
quality, estimation of exposure)

Concentration on analysis of
companys own data

Not analyzed in the context of

reporting rates of similar events
with other drugs

Less emphasis on the continued

evaluation of the benefit:risk profile
of the drug

PV and Risk Management: Continuous

Signal Detection: allows us identify what we
do NOT know (the needle in the haystack)
more data driven

Risk Management/Benefit:Risk Assessments:

allows us to characterize better what we do
know and attempt to mitigate the risk and
maintain a favorable profile

Benefit Risk is a Familiar Concept

Questions?