PHARMACOEPIDEMIOLOGY

Topics
Introduction: The Contribution of Epidemiology to the Study
of Drugs
The Drug Approval Process
Premarketing
k
Clinical
l
l Research
h
Post marketing Surveillance Methodologies (Randomized
Clinical trial, Observational epidemiologic surveys, CaseCase
control study, Cross-sectional study, Cohort study)
Meta analysis in Pharmacoepidemiology
Pharmacoeconomy Analysis
The Role of Epidemiology in Pharmaceutical Research,
Development and Marketing
Development,

What is
Pharmacoepidemiology?

Pharmacoepidemiology can be defined as the

application of epidemiologic knowledge,
methods, and reasoning to the study of the
effects (beneficial and adverse) and uses of
drugs in human populations.

What
h is the
h aim??

To describe, explain, control, and predict the

effects and uses of pharmacologic treatments
in a defined time, space, and population.

Efficacy, Safety, Economy

Pharmacoepidemiology as a tool to know:

Efficacy
Clinical evaluation of a drug in the premarketing
phase has limitations, mostly due to ethical,
practical, and economic reasons.

Safety
Adverse Drug Event

Economy
Evaluate the cost and effects of a pharmaceutical
product

What is Adverse Drug

Experience?

Adverse Drug Experience

Adverse Drug Experience is defined in US federal regulation
21 CFR (Code of Federal Regulations) 314.80 as:
Anyy adverse event associated with the use of a drugg in
humans, whether or not considered drug related, including
the following:
an adverse event occuring in the course of the use of a
drug product in proffesional practice;
an adverse event from drug overdose whether accidental
or intentional;
an adverse event occuring from drug abuse;
an adverse event occuring from drug withdrawal;
and any significant failure of expected pharmacological
action

Drugs Withdrawal
Gone, but not forgotten
Year

Name

Trade Name

Comment

1961

Thalidomide

Distavel
Valgis
Valgraine
Valgraine

A sedative drug, also marketed for morning sickness

that produced fetal malformation. At the time,
promotional material in some markets emphasized
its safety in pregnancy /
Recently reeintroduced to the market as an
pp
and is used to treat leprosy.
p y
immunosuppresant

1971

Diethylstilbe
strol

Stilboestrol

Stilboestrol was prescribed for pregnant women up

to 1970s. It induced cervical and vaginal cancer in
the female children of treated mothers as well as
genital malformation in its previous indication to
prevent miscarriage.
Recently reeintroduced to the market rarely to
treat prostate cancer and breast cancer in
postmenopausal woman

Year

Name

Trade
Name

Comment

2005

Co-proxamol

Distalgesic
C l i
Cosalgesic

An analgesic combination of dextropropoxyphene and

paracetamol
t
l which
hi h h
has b
been withdrawn
ithd
b
because off it
its
toxicity in overdose. Some patients found it beneficial
to them, despite little evidence for acute analgesia
benefit compared
p
to p
paracetamol alone.

2010

Sibutramine

Reductil

Withdrawn in EU Jan 2010 due to the required post

marketing surveillance SCOUT study showing excess
cardiovascular mortality

2011

Pioglitazone

Actos

Withdrawn in France June 2011 due to increased risk of

bladder cancer

Molecular Drug Withdrawal

2005 natalizumab Tysabri

2009 Efalizumab

Raptiva

An anti-4,1 integrin monoclonal antibody which

was withdrawn before European approval but
after FDA approval when 3 cases of progressive
multifocal leukoencephalopathy had occurred
amongst 3000 treated in RCT and 5000 treated in
all At the time,
all.
time EMEA rules were tighter than FDA
rules
Withdrawn if EU Feb 2009 due to 3 cases of
progressive
p
g
multifocal leukoencephalopathy
p
p y

Basic molecular and cell biology research have now come of age
Recombinant DNA
DNA, production of monoclonal antibody etc
Although different from traditional pharmacologic agents, products based on
biotechnology should be evaluated in the pharmaceutical context rather than the
production techniques that are employed.
Because of their unique production techniques used and their different mode of action,
it is likely that news pharmacoepidemiology methodologies will need to developed.

List of approved and withdrawn drug

(
(FDA,
2006))
Name

Duration

Rofecoxib

1999-2004

Fenfluramine

1979-1980

Temafloxacin

1992-1992

Troglitazon

1999-2000
1999
2000

Alosteron

2000-2000

Supofen

1985-1987

Ci
Cisapride
id

1993 2000
1993-2000

Grepafloxacin

1997-1999

Rapacuronium

1999-2001

The need for Post Marketing

S
Surveillance
ill
(PMS) arises
i ffrom
the limitations of Phase I, II, and III
clinical trial

Comparison between Premarketing and Postmarketing Study

Parameter

Pre marketing Study

Post marketing Study

Alat/tools

Uji Klinik Fase 1-3

Uji Farmakoepidemiologi

Orientasi

Explanatory/knowledgeoriented question

Pragmatic/Decisionoriented question

Informasi yang didapat

Efikasi Obat

Efektivitas Obat (focusing

on the effectiveness of the
drug under usual clinical
circumstances)

Subjek penelitian

Hasil seleksi ketat

Tidak terlalu ketat

Kemungkinan lain

Dapat dihilangkan, mis.

Obat lain atau yang
dikonsumsi, pola makan,
usia

Ada, namun bisa diseleksi

saat analisa statistik

Main Areas of Inquiry Addressed in

P
Postmarketing
k i Studies
S di
Area of Inquiry

Example

L
Long-term
t
effects
ff t
manifest after long periods of use

Use of exogenous estrogen during

menopause and endometrial cancer

manifest
f after
f llong llatency periods
d

Adenocarcinoma
d
off the
h vagina d
due to
diethylstilbestrol

Low-frequency effects
can only be detected in large
populations

Aplastic anemia: phenylbutazone;

Colitis: clindamycin;
Jaundice; halothane

Eff ti
Effectiveness
i customary
in
t
practice
ti
patients

Children, pregnant or elderly women

therapeutic situations

with concurrent pathologies and several

simultaneous
l
treatments, flexible
fl bl dosages,
tolerance, noncompliance, non-response
emergencies, ambulatory care

Area of Inquiry

Example

h lth
healthcare
settings
tti

emergency, ambulatory
b l t
care

healthcare professionals

according to training, specialty information

sources

Effi
Efficacy
i new indications
in
i di i
discovered after marketing

Propanolol as an antihypertensive, captopril in

rheumatoid arthritis, amantadine in Parkinsons
disease antihistamines in motion sickness
disease,

including secondary effects

Antihypertensives to prevent cardiovascular

disease, hypoglycemic agents to prevent
complications of diabetes

Modifiers of efficacy
concurrent drugs

A decrease in sodium intake can improve the

efficacy of some diuretics in hypertension

disease severity

Severe asthmatics do not respond to

metaproterenol without supplementary therapy

lifestyle

Risk of myocardial infarction in women who use

oral contraceptives may be increased by cigarette
smoking