ADR SURVEILLANCE Noor Cahaya,M.sc,Apt.

Post Marketing Surveillance

NOOR CAHAYA,M.Sc.,Apt.
Program Studi S1 FARMASI FMIPA UNLAM
Penerapan
Farmakoepidemiologi
dalam Kefarmasian
Noor Cahaya, S.Si, M.Sc,Apt.
 INTRODUCTION
To market a drug, the manufacturer must provide
evidence of its efficacy and safety to the US Food and
Drug Administration (FDA)
In premarketing testing, the numbers and type of patient
used to demonstrate a drug’s efficacy and safety are
limited as compared with the numbers and type of patient
who will eventually be prescribed the drugs after it is
marketed
Post marketing surveillance of drug play an important role
to discover an undesirable effect that might present at risk
it provide additional information on the benefit and risk of
the drugs
 Post Marketing Surveillance ??

refers to the monitoring of drugs once they reach

the market after clinical trials.
The majority of postmarketing surveillance concern
adverse drug reactions (ADRs) monitoring and
evaluation.
Other important postmarketing surveillance
components include unapproved or off-label drug
use, problems with orphan drugs, and lack of
paediatric formulations, as well as issues concerning
international clinical trials in paediatric population.
 Should the FDA require all drugs to
undergo post-marketing studies......... ???
44% of Americans take at least one prescription
drug in any given month.
Adverse drug reactions (ADRs) are one of the
leading causes of serious health problems in the
United States.
ADR’s kill more than 100,000 people every year
and injure more than 2 million.
 Need for Post Marketing Studies
Instances of delayed discovery of an adverse
reaction from several drugs that were approved
and marketed.
Avandia, Vioxx and Redux.
FDA & pharmaceutical companies enter into an
agreement to study drugs after they are approved.
Out of 1,259 post marketing commitments, 71.1%
were not started and 18% were ongoing.
 History & Background
1962 Kefauver-Harris Amendment required that safety
and efficacy of a drug should be proved prior to being
approved.
In 1992, Congress enacted the Prescription Drug Users
Fees Act (PDUFA) which requires manufacturers to pay
user fees for new drug applications
 Limitations of Pre-Marketing Studies
 Design issues
 Co-morbid medical problems
 Size of the study
 Special population
 Post marketing studies (Phase IV) becomes very important.
 FDA currently mandates post-marketing studies:
Fast-track products which are used to treat certain life
threatening illnesses
Products for use in children
How are Adverse Drug Events
Reported ...........???
MedWatch is an FDA reporting system founded in 1993.
Reports can be done by phone or by submitting a form.
Pharmaceutical companies are mandated to report
adverse events.
Physicians are not mandated to report: only 1 – 3% of
adverse events are reported by physicians.
This reporting system is inconsistent and somewhat
incomplete
 Benefits of Post-Marketing Studies
 Can detect adverse reactions that occur while the
drugs are being used on a long term basis.
E.g. HIV, protease inhibitors and risk of myocardial
infarction
 Improved treatment and decreased toxicity – e.g.
Interferon Alpha B in chronic Hepatitis C.
 Post-marketing studies can become the first point where
pre-clinical drug safety issues can be analyzed.
 Reveal other disease treatment indications.
Limitations of Post-Marketing Studies

Could be costly
Length of study
Who has the oversight?
How do you determine which drugs undergo post
marketing studies ?
 Cost of Post-Marketing Studies
 2005 cost of developing a new drug was estimated at $51.3
billion
 Funding increased to obtain data from external sources
about drug safety from $5 million to $28 million in 2007.
 In 2008, funding increased to about $9 million for
contracting with companies for post-marketing studies.
 User fees increased to about $400 million in 2008 and of the
$400 million, $300 million would fund post-marketing safety-
related
Cont...

At FDA Center for Drug Evaluation and Research ,

funding for post marketing drugsafety increased
from $54 million in 2006 to $139 million in 2008.
Of the $139 million, $55 million was revenue
generated from the user fees
Source of PMS information

Expert user groups (focus groups)

Customer surveys
Customer complaints and warranty claims
Literature reviews
User reaction during training programmers
The media
 Source of surveillance

Four types of studies are generally used to identify drug effects :

 Controlled clinical trial
 Spontaneous or voluntary reporting
by physician and other health provider and hospital may to alert
FDA and pharmaceutical firms to possible adverse of drugs
 Cohort studies
 Case control studies
pharmacovigilance

Pharmacovigilance (PV) also calledas drug

safety
Pharmakon (in greek) = drug
Vigilare (in latin) = to keep watch
Pharmacovigilance is the science and activities
relating to the detection, assesment,
understanding and prevention of adverse
effects
 aims

To improve patient care and safety

To improve public health and safety
To contribute to the assessment of benefit,
harm, effectiveness and risk of medicines
To promote education and clinical
training
To promote rational and safe use of
medicines
DEFINITION
 A surveillance design to collect adverse drug
reactions following administration of a drug use for
prophylaxis, diagnosis or theraphy of disease or
for the alteration of a physiological process
 Responsible for detecting and responding to
adverse events ssociated with drugs
 ADR (ADVERSE DRUG REACTION)
Any unexpected,unintended,undesired, or excessive response to a drug that :
 Requires discontinuing the drug (terapeutic or diagnostic)
 Requires changing the drug theraphy
 Requires modifying the dose (except for minor dosage adjustment)
 Necessitates admission to a hospital
 Prolongs stay in ahealthcare facility
 Necessitates complicates diagnosis
 Significantly complicates diagnosis
 Negatively affects prognosis or results in temporary or permanent harm,disability or
death
(The American Society of Health-System Pharmacists/ASHP)
 The ASHP definiton includes allergic reactions
(immunologic hypersensitivity response to a drug) and
idiosyncratic reactions (an abnormal response to a drug
that is specific to an individual)
 ASHP excludes the following from this definiton: drug
withdrawal, drug-abuse syndromes, accidental poisoning,
drug overdose complications, side effects
 Side effect is defined as an”expected,well-known
reaction resulting in little or no change in patient
management” that occurs with a”predictable frequency
and whode intensity and occurence are related to the
size of the dose”
DEFINITON ADR (WHO)
Any response to a drug, which is noxious and unintended,
and which occurs at doses used in man for prophylaxis,
diagnosis or theraphy or for modification of physiologic
function
The definiton excludes cases attributed to drug abuse or
overdose (intended or unintended)
The exclusions of the WHO definiton: therapeutic failures
DEFINITION BY KARCH AND LASAGNA
ADR as any response to a drug that is noxious and
unintended and that occurs at doses used in humans
for prophylaxis,diagnosis or theraphy, excluding
failure toaccomplish the intended purpose.
I
DETECTION OF ADVERSE DRUG EVENTS
Sign and symptoms
Signs and synptoms of ADRs are many and varied
and may be similar to signs and symptoms of
disease states or medical conditions
SURVEILLANCE SYSTEM
There are three types of surveillance systems that may be
used to detect ADRs:
1.prospective
2. Concurrent
3. Retrospective
PROSPECTIVE SURVEILLANCE SYSTEM
Prospective surveillance occurs prior to initiation of medication theraphy and
can be accomplished in two ways:
1. monitoring of patients who are at a high risk for experiencing ADRs-risk
factors for ADRs include the following:
Polypharmacy
Extremes of age (e.g neonatal, pediatric and geriatric patients)
Presence of concurrent disease states (e.g impaired renal or hepatic function)
Severity of illness
History of allergy/previous ADR
Pharmacodynamic/pharmacokinetic changes
 PROSPECTIVE SURVEILLANCE SYSTEM
2.monitoring of patients who are receiving medications known to have a high potential
for causing ADRs
The classes most frequently implicated in ADRs include the following:
Anticoagulants (e.g.,heparin and warfarin)
Antimicrobials (e.g., penicillins, cephalosporins, sulfa antibiotics and aminoglycosides)
Antineoplastics.
Cardiac agents (e.g., antiarrhytmics, digoxin,diuretics and antihypertensives)
Central nervous system (CNS) agents (.g., analgesics,anticonvulsants and
sedatives/hypnotics)
Diagnostic agents (e.g., contrast media)
Antidiabetic agents (including insulin)
corticosteroids
PROSPECTIVE SURVEILLANCE SYSTEM
The major advantage of prospective surveillance is that it
isthe most sensitive and specific method for detecting ADRs
However, it has a significant disadvantage in that it is very
labor intensive and involves continous monitoring
Prospective surveillance systems are best accomplished
through the use of decentralized pharmacists and/or
utilization review personnel
CONCURRENT SURVEILLANCE SYSTEM
Concurrent surveillance involves the identification of ADRs close to the time they
occur
There are several methods that can be used to detect ADRs concurrently:
 spontaneous reporting of ADRs by primary care practitioners (such as
physicians and nurses) during the corse of their work using telephone hotlines,
ADR alert cards, report forms,etc.
 Analysis of medication usage evaluation (MUE) studies
 Reporting of suspected ADRs by hospital utilization review/quality assurance
personnel from their concurrent review of patients charts
 Monitoring of orders and patient charts by pharmacy personnel for clues
(often called triggers) that an ADR has occured
TRIGGERS INCLUDE THE FOLLOWING:
Abnormal test results such as serumdrug
concentrations above therapeutic levels and
laboratory test results outside a particular range
or threshold (e.g., platelet count less than 50.000)
Alerting order, which is an order or sequence of
orders that suggests an adverse effect may have
taken place
Monitoring for triggers by pharmacists isa veryeffective wayto
detect ADRs
Alerting orders include the suddendiscontinuation of one or more
medications, an unexpected reduction in dosage, and a tat order
for an antidote or other medication used to manage ADRs, such as
the following:
 atropine - Benztropine - Dextrose 50%
 glucagon – naloxone - dipenhydramine
 Epinephrine – furosemide - phytonadione
 potassium chloride – flumazenil- Protamine
 nitroglycerin - physostigmine
Alerting orders also include nonroutine orders for laboratory tests,
such as the following:
BUN
AST,ALT
PT, PTT, platelet count
Drug serum concentration
Clostridium difficile
Guaiac test
Serum creatinine
Urine protein, cells, casts
Concurrent surveillance has the advantage of
allowing a more through investigation because the
patient, nurse and physician are available for
interviews and are likely to recollect events more
accurately.
Also, this method allows interventions and
management of the ADR to take place in a timely
manner
RETROSPECTIVE SURVEILLANCE SYSTEM
Involves the review of medical records for adverse drug reactions
It is not a desirable approach to monitoring for ADRs, because of the
disadvantages inherent in utilizing retrospective data
These disadvantages include inadequate documentation of events on
medical records and the inability to intervene in a timely manner
Also, ADR programs based solely on retrospective surveillance do not
comply with the Joint Commisions expectations for active monitoring
ASSESSMENT OF ADVERSE DRUG REACTIONS
Once an ADR is suspected through an alerting order
or other means of surveillance, an investigation is
conducted to evaluate causality and assess the
probabilityof a reaction using standardized criteria
and an algorithm developed for objectively rating
potential ADRs
Evaluation of causality determines the medication suspected of
causing the ADR
Assessment of the probability of a medication causing an ADR
depends on evaluation of six criteria:
1. event is a documented, known response to the suspected agent
2. event is not explained by the disease state
3. timing of events
4. serum drug concentration
5. dechallenge (discontinuing suspected agent)
6. rechallenge (resuming suspected agent)
Usually, these citeria are incorporated in an algoritm developed to objectively rate
ADRs
Several algoritms have been developed over the years
one method, the Kramer algoritm, consists of 56 questions with weigted values for
responses, which are totaled to obtain a score.
The score corresponds with one of four categories of probability
Although this algorithm is detailed and thoruhg, it is very complicated and time
consuming to complete
The Jones algorithmwas developed to simplify assessment of probabbility
It consists of a flow chart of questions with diverging pathways depending on response.
The FDA uses this method, but a study reported in the literature did not show a high
correlation of the Jones algorithm with the Kramer algorithm
To simplify the process of assessing probabilit while
maintaining validity and reproducibility, the Naranjo
algorithm was developed
DRUG UTILIZATION REVIEW (DUR)
 DUR
• Suatu program yg mengolah data dari penggunaan obat (DUS)
utk meminimalisasi peresepan yg tidak tepat
• Sampai saat ini DUR berkembang pada penelitian yg merubah
kualitas hidup dan menurunkan biaya kesehatan
• DUR dapat dikatakan juga drug use evaluation dan medication
use evaluation
• DUR membandingkan antara perilaku sesungguhnya dengan
kriteria yg sudah ditentukan
 Proses yang terjadi dalam DUR
• Membuat rancangan struktur dasar
• Mencari persetujuan
• Membuat kriteria penelitian
• Menerapkan kriteriapenelitian
• Membuat pola peresepan
• Membuat pola intervensi
• Menerapkan kembali kriteria
• Merevisi kriteria
STUDY BENEFICIAL DRUG EFFECTS
EFEK OBAT
Ada 4 efek obat yang dapat muncul setelah obat diminum oleh pasien:
1. efek yg tdk menguntungkan dan tdk dapat diantisipasi
sebagian besar efek yg masuk dlm kategori ini ROTD tipe B
2. efek tidak menyenangkan yg dapat diantisipasi
ROTD tipe A dan B
3. efek menguntungkan yg tdk dapat diantisipasi
ex : aspirin utk mengurangi kejadian MI
4. efek menguntungkan yg dapat diantisipasi
efek yg diinginkan dgn mengkonsumsi obat termasuk dlm kategori ini
PRESCRIPTION EVENT MONITORING
PRESCRIPTION EVENT MONITORING
is a well established postmarketing surveillance technique
designed to monitor the overall safety of newly marketed
medicines as used in real-life clinical practice, usually in
cohorts of at least 10000 patients (Cohort event monitoring)
System created to monitor adverse drug events in a
population. Prescribers are requested to report all events,
regardless of whether they are suspected adverse events, for
identified patients receiving a specified drug.
THE OBJECTIVES OF CEM
1. Characterise known reactions

 Mean age
 Gender
 Mean dose
 Treatment duration
 Time to onset
 Seriousness profile
 Incidence
 Outcomes
 Effect on treatment (% withdrawals)
 Part of syndrome?
 THE OBJECTIVES OF CEM
2. Detect signals of unrecognised reactions
3. Interactions with
Other medicines
Complementary and alternative medicines
Foods
4. Identify risk factors so that they can be avoided
Age Duration of therapy
Gender Concomitant disease
Dose Concomitant therapy 52
THE OBJECTIVES OF CEM

5. Assess safety in pregnancy & lactation

6. Estimate risk (including comparative)
7. Provide evidence for effective risk management
 Safer prescribing
 Benefit / harm assessment
 Regulatory changes

53
THE OBJECTIVES OF CEM

8. Detect inefficacy, which might be due to

 Faulty administration
 Poor storage conditions
 Out of date
 Poor quality product
 Counterfeit
54
THE OBJECTIVES OF CEM

9. Hypothesis generation

10. Cohorts for study

55
THE OBJECTIVES

Achieve maximum benefit, least

harm for patients

56
WHAT RESULTS CAN YOU GET?

57
THE FOLLOWING WILL BE SUMMARISED

Cohort description & drug utilisation

Preliminary events data

Preliminary review of deaths

58
IMMP PROCESS
Prescription

Follow-up Patient and

Event information questionnaires Prescription details

Cohort
Relationship
data assessment

NZHIS 59
COX-2 INHIBITORS
CELECOXIB, ROFECOXIB
Preliminary monitoring data

60
COHORT

Prescriptions Patients

Celecoxib 98,975 32,630

Rofecoxib 52,874 26,666

61
 Profile of Ages at First Prescription

25

Celecoxib Rofecoxib

6552
20
5969
5827
4704
4254 4297
% of total known ages

15
3426

3601
3325
10
2289
1939

1477
5
945

468 543 503

213 280

0
< 20 20-30 30-39 40-49 50-59 60-69 70-79 80-89 90 plus

62
IMMP EXAMPLE –COX-2
Age Celecoxib Rofecoxib

Mean 63 58

Mode 59 53

<40 years 6.9% 12.6%

Highly significant

70+ years 32.7% 25.7%

Highly significant
GENDER AND TERM

Celecoxib Rofecoxib

Women 61.6% 60.5%

Short term 6879 (21%) 9843 (37%)

64
ROFECOXIB DOSE
mg/day No. %

12.5 11,695 28.3

25 26,027 63.0

37.5 36 0.1

50 3,546 8.6

65
CELECOXIB DOSE MG/NO./%
100 6,622 8.1
200 65,591 80.5
300 274 0.3
400 8,927 11.0
600 46
800 30

66
IMMP PROCESS
Prescription

Follow-up Patient and

Event information questionnaires Prescription details

Cohort
Relationship
data assessment

NZHIS 67
INDICATIONS FOR USE
( 0R TYPE/SERIOUSNESS OF MALARIA )

Celecoxib Rofecoxib Difference

No. % No. % Chi-square
Patients 6,200 4,536
Inflammatory 211 (3.4) 129 (2.8) P>0.05
Osteoarthritis 1805 (29) 775 (17) P<0.0001
Musculoskel 1668 (27) 1105 (24) P<0.01
Other pain 2479 (40) 2495 (55) P<0.0001

68
 Indications for use
(0r type/seriousness of malaria)

Celecoxib Rofecoxib Difference

No. % No. % Chi-square
Patients 6,200 4,536
Inflammatory 211 (3.4) 129 (2.8) P>0.05
Osteoarthritis 1805 (29) 775 (17) P<0.0001
Musculoskel 1668 (27) 1105 (24) P<0.01
Other pain 2479 (40) 2495 (55) P<0.0001
 Baseline information 1
Questions
1. Current Acid Related Disorder
2. Past ARD
3. NSAID exposure
• Past GI problems
• Direct switch to COX-2
• Concurrent aspirin

4. Past cardiovascular disease

• Hypertension / Heart failure
• MI / Angina
• Dysrhythmia / Stroke - TIA

70
 Baseline information 2

Questionnaire response rate

 Celecoxib: number sent 4635
No. returned with information 3985
(91%)

 Rofecoxib: number sent 3050

No. returned with information 2725
(89%)
 Baseline information 3
No. & % of positive responses to question

CEL ROF Rate ratio

(95% CI)
ARD 2281 1341 1.4
(68%) (60%) (1.27-1.58)

NSAID/ARD 2136 1199 1.4

(62%) (54%) (1.28-1.59)
Switch 1345 824 1.9
(36%) (34%) (0.98-1.21)

Aspirin 352 173 1.4

(9.3%) (6.9%) (1.15-1.69)
Cardiovasc 1361 797 1.2
(36%) (31%) (1.11-1.38)
 Baseline information 4
Cardiovascular disease
Celecoxib Rofecoxib Rate ratio
(95% CI)
Hypertension 843 (22%) 498 (19%) 1.1
(1.04-1.26)
MI/angina 547 (14%) 298 (12%) 1.2
(1.09-1.42)

HF 206 (5.4%) 115 (4.5%) 1.2

(0.97-1.51)
Dysrhythmia 141 (3.7%) 86 (3.3%) 1.1
(0.85-1.44)
Stroke/TIA 40 (1.0%) 17 (0.7%) 1.6
(0.90-2.80)
The events
 Percentage of Total Events
A
cc

0
5
10
15
20
25

id
en
A

33
lim ts
en

13
ta
A ry 273
ut
on
181

om
C ic

22
irc

5
ul
En at
or
y
301

do
cr
198

in D
e/ ied
M
293

et
179

ab
ol
ic

32 17
EN
T
H 22
ae Ey 3
m
at e s
ol
19 12
Celecoxib

H og
ic
ep al
44

at
ob
Im
28

ili
m ar
un y
22

ol
12

og
n=1714

ic
In
8

al
M fe
9

us ct
cu ion
System Organ Class

lo s
32

sk
Rofecoxib

21

el
N et
al
35

eo
pl
21

N as
m
eu
s
n=982

12

ro
lo
12
Profile of Events - Celecoxib and Rofecoxib

gi
Ps ca
l
58

yc
28

hi
R at
ri c
es
78

pi
ra
39

to
ry
103
51

Sk
U in
ro
156

ge
50

ni
ta
l
64
40
 Most common events 1
rates /1000 patients
Celecoxib Rofecoxib

Event No. Rate No. Rate RR

ARD 129 3.4 89 3.3 NS

Rash 86 2.6 30 1.1 2.3 (1.6-3.6)

HF 74 2.3 55 2.1 NS

IHD 57 1.8 38 1.4 NS

 Most common events 2
Celecoxib Rofecoxib

Event No. Rate No. Rate RR

1.6
LRTI 56 1.7 29 1.1
(1.0-2.5)
2.1
Dysrhythmias 49 1.5 19 0.7
(1.2-3.6)
2.8
Angioedema 48 1.5 14 0.5
(1.6-5.1)

Stroke 37 1.1 18 0.7 NS

 Most common events 3
Celecoxib Rofecoxib
Event No Rate No. Rate RR
Diarrhoea 36 1.1 17 0.6 NS
Asthma 34 1.0 13 0.5 2.1 (1.1-4.1)

RF 33 1.0 28 1.1 NS

Vomiting 33 1.0 34 1.3 NS

HT 13 0.3 28 1.1 2.6 (1.4-5.0)

 Signals identified 1
Coughing
Visual field defect / temp blindness
Acute psychiatric events
Pancreatitis
Hepatotoxicity
Psoriasis
Acute urinary retention
 Signals 2
Mouth ulceration
Lower bowel effects
Cardiac dysrhythmias
Cardiac arrest
Myocardial infarction / stroke
Anaphylaxis
Serious skin infection
Acute labyrinthitis
 Signals 3
Interactions
Tricyclics causing arrhythmias
Warfarin causing increased INR (rofecoxib)
 Deaths
Causes by SOC (% of total deaths)

Celecoxib No. (%) Rofecoxib No. (%)

All deaths Causal All deaths Causal
Circulatory 116 (40) 34 (11.6) 68 (38) 23 (12.9)
Malignancy 115 (39) Nil 92 (51) Nil
Respiratory 59 (20) Nil 24 (13) Nil
Renal 23 (8) 18 (6) 8 (5) 8 (5)
Infection 13 (4) Nil 11 (6) Nil
Alimentary 10 (3) 10 (3) 8 (5) 4 (2)
 Risk factors 1
by multiple logistic regression
Renal failure
– Age
– Inflammatory arthritis
Heart failure
– Age
– P/H heart failure
– Inflammatory arthritis
 Risk factors 2
Ischaemic heart disease
– Age
– P/H of any type of heart disease
– Inflammatory arthritis (celecoxib)
Cardiac dysrhythmias
– Age
– Past history of heart failure
– Inflammatory arthritis (celecoxib)
 Risk factors 3
Stroke / TIA
– Age
– Hypertension
– Inflammatory arthritis
Did we reach the objectives?
 Study demonstrates
High compliance
Demographics of cohorts
Background data
– Indication
– Relevant past/current history
Prescribing practices
Early signal identification
Significant events
Comparative rates
Risk factors
 Concerns raised
High volume of prescribing
High doses of rofecoxib
Substantial prescribing to patients at high risk
– very elderly
– history of cardiovascular disease
– history of ARD
Apparent high death rate
 Concerns
High rate of cardiovascular events
– Heart failure
– Dysrhythmias
– Prothrombotic effects
Myocardial infarction
Stroke
Renal infarction
High rate of alimentary events
How do we get results like this?

The principles
 Cohort event monitoring
How is it done?

Two Principles
Identifying patients exposed (cohort) - the
denominator
– as complete as possible
Systematically soliciting adverse EVENTS - the
numerator
– as complete as possible
 1. Identifying the patients
How can this be done?
The cohort of patients is established using the best
source of usage data available
– Dispensings (pharmacies or central records)
– Patient records
Doctors
Clinics
Hospitals
Other
– Programme records
Adequate cohort (10,000 patients)
 IMMP Process
Prescription

Follow-up Patient and

Event information questionnaires Prescription details

Other Rx
Sources

Cohort
Relationship
data assessment

NZHIS
 Cohort size
General aim 10,000 (IMMP 11,000)
Greater numbers required to detect differences
– if events naturally common
– for sub-group analyses
Smaller numbers still produce good data
– fluoxetine <7000
Signals can be identified / confirmed with much smaller
numbers (<1000)
– eg nifedipine & eye pain
 2. Soliciting the events
How can this be done?

Actively asking for the events

Systematically asking for the events

 Soliciting the events
How is it done?
The events are collected using the best
source(s) available
– Survey prescribers (questionnaires or other)
– Survey patients (questionnaires or other)
– Real-time recording*
– Telephone, or visit*
– Record searches (manual, electronic)
– Registers of death or morbidity
– Record linkage with registers or hospital
records
– Intensified spontaneous reporting
– Other
– Several
 IMMP Process
Prescription

Patient and
Follow-up Prescription details
Event information questionnaires
Other Rx
Sources

Cohort
Relationship
data assessment

Other
NZHIS Sources
 Actively & systematically asking
Ask after every treatment

Patients in cohort checked to see that follow-up

information received

Repeat request for missed patients

Make strenuous efforts to avoid missing anyone

 Adverse event (experience)

Definition (WHO)
Untoward medical occurrence
temporally associated with the use
of a medicinal product, but not
necessarily causally related
 It is EVENT monitoring

Any new clinical experience (favourable or

unfavourable) that is worthy of a record in the

patient’s file, regardless of its severity and without

judgement on its causality.

 Events = reactions + incidents
Reactions
1 Definite
2 Probable
3 Possible
Incidents (background noise)
4 Unlikely
5 Unclassified (conditional)
6 Unassessable
 Incidents
(Making music from the noise)
Should represent background morbidity

May contain unrecognised signals

– unexpected profiles

Useful for assessing reporting bias

– as within-drug controls
– as between-drug controls

Unmasking
 Why adverse events?
To identify signals of new reactions

If only known or expected adverse reactions are

reported, unexpected adverse reactions will not
be identified

It is important to identify signals, validate them,

determine the incidence, understand their
significance and identify the risk factors as soon
as possible.

It is not logical to specify the types of events to

be recorded. Unexpected reactions cannot be
identified by recording only the known or
expected.
 Reporting requirements
All new events even if common & minor

Change in a pre-existing condition

Abnormal changes in laboratory tests

Accidents

All deaths with date & cause

Possible interactions
– NB alcohol, OCs, CAMs
 Reasons for stopping
Poor compliance (adherence)

No longer necessary

Change of diagnosis

Inadequate response

Suspected ADR

Death

Lost to follow-up
 Pregnancy
Routine questions about pregnancy and lactation for all women of
child bearing age –computer generated

Pregnancy register established

Time / period of exposure identified

Routine follow-up of all pregnancies after expected delivery date

 Non-serious events
May indicate serious problem

May affect compliance

– nausea
– Rash / pruritus
– Diarrhoea

May be more important than serious reactions

Recording all events is easier than being selective

 CEM in the IMMP
Prospective observational cohort studies on new
drugs in normal clinical practice

Cohorts established from prescription data from

pharmacies

Events data mainly from questionnaires sent to

prescribers
 Compliance
Voluntary / unpaid

Doctors 80%

– Limiting factor is workload

Patients higher

Pharmacists 93%

Good feedback essential

Value appreciated
 ‘Controls’
Controls create an artificial situation

The aim is a non-interventional study in normal clinical practice

Comparators are desirable

– not always possible
– possibility of confounding

A good study of a single drug

– provides valuable data
– has benchmark value
 Record linkage
Linking databases using unique ID

IMMP -routine link with

– NZHIS –identify deaths
– Register of deaths for certified cause(s)

IMMP –special studies

– Suicide & antidepressants
– Reactions of long latency –cancer registers / hospital discharge
diagnoses
– Conditions of interest eg MI
 Cohort investigations
Patient questionnaires
– Eye pain and nifedipine / taste disturbance and captopril

Doctor questionnaires
– Angina and bezafibrate
(confounding by indication)

Reactions of long latency

– Omeprazole

Case control studies (nested)

– Genetic studies
 Don’t ask for too much
The more you ask for, the less you get

A delicate balance

Concomitant therapy

Information can be requested if needed

Unnecessary data increases workload

 Be open minded
Unexpected reactions will occur

Predictions of safety unreliable

Experience based only on spontaneous reporting unreliable

– 2.1 million patient exposures with olanzapine
’no significant safety concerns’

No dominant pre-conceived ideas

All data should be collected & analysed in a totally objective manner

 Cohort event monitoring
Is an early warning system

New drugs (post-marketing surveillance)

Can be used to validate signals

Can be used to characterize reactions

Normal clinical practice, real life situations

 Cohort event monitoring
Exposure in pregnancy / lactation

Death rates

Reasons for stopping therapy

Inefficacy

Limited study period

Reactions of long latency

Events examined clinically and epidemiologically

 The epidemiology
observational cohort studies

prospective

longitudinal

non-interventional

inceptional

dynamic

descriptive
 Analysis
Collation and signal identification

Rates and profiles

– Comparisons by drug, age group, etc
– By system organ class
– Within system organ class
– Individual events

Life table or survival analysis

Multiple logistic regression

– esp. for risk factors
 Advantages of CEM
Provides comprehensive information

Provides near complete information

– On the target population
– Drug utilisation
– Effectiveness
– Risks and how to prevent them

Provides the information needed to

– Handle drug scares
– Minimise harm
– Ensure treatment success
 Advantages of CEM
Stimulates interest in drug safety

Improves spontaneous reporting

Can concentrate resources on drugs of particular importance to a

country or programme

Can be applied regionally

Adaptable
 The essentials

Identify the cohort

Identify the events

With this information, you can find all you need to

know (almost) concerning safety
 PEM references
Mann & Andrews Pharmacovigilance

Title: Pharmacovigilance (2nd Edition) 2007

Publisher: John Wiley & Sons, Ltd.
Author: Mann, Ronald D.; Andrews, Elizabeth B.

Includes chapters on:

PEM in the UK
PEM in NZ