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, Case-
Case
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® A sedative drug, also marketed for morning sickness
Valgis® that produced fetal malformation. At the time,
Valgraine®
Valgraine promotional material in some markets emphasized
its safety in pregnancy /
Recently reeintroduced to the market as an
pp
immunosuppresant and is used to treat leprosy.
p y

1971 Diethylstilbe Stilboestrol® Stilboestrol was prescribed for pregnant women up

strol 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 Comment
Name
2005 Co-proxamol Distalgesic® An analgesic combination of dextropropoxyphene and
C l i ®
Cosalgesic® 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® An anti-α4,β1 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
2009 Efalizumab Raptiva® 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/knowledge- Pragmatic/Decision-
oriented question oriented 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. Ada, namun bisa diseleksi
Obat lain atau yang saat analisa statistik
dikonsumsi, pola makan,
usia
 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 Aplastic anemia: phenylbutazone;
populations 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
h lth
healthcare settings
tti
healthcare professionals
Effi
Efficacy i new indications
in i di i
discovered after marketing
including secondary effects
Modifiers of efficacy
concurrent drugs
disease severity
lifestyle
Example
emergency, ambulatory
b l t care
according to training, specialty information
sources
Propanolol as an antihypertensive, captopril in
rheumatoid arthritis, amantadine in Parkinson’s
disease antihistamines in motion sickness
disease,
Antihypertensives to prevent cardiovascular
disease, hypoglycemic agents to prevent
complications of diabetes
A decrease in sodium intake can improve the
efficacy of some diuretics in hypertension
Severe asthmatics do not respond to
metaproterenol without supplementary therapy
Risk of myocardial infarction in women who use
oral contraceptives may be increased by cigarette
smoking