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FARMAKOEPIDEMIOLOGI
YUNITA
Departemen Farmasi Komunitas
Fakultas Farmasi
Universitas Airlangga
Kuliah Farmasi Masyarakat - 2013

No Recording

X X X

Definisi
pharmaco - drug or medicine
epidemiology - study of the distribution and

determination of diseases in population

pharmacoepidemiology - the study of the use and

effects of pharmaceutical products in populations

The study of the use and effects of medications in large

numbers of people
(Strom)

The Relationship
Health
services
research

Epidemiology

Clinical
Epidemiology
Outcomes
Research

Economics

Health
Economics

Pharmacoepidemiology

(H Guess)

The Relationship
The study of
the effects of
drugs in
humans

- Pharmacokinetics
- Pharmacodynamics

Focus of inquiry
The study of ADR
Post marketing drug
surveillance
Methods of inquiry
The study of the
distribution &
determinants of
diseases in
populations

- Infectious Diseases
- Chronic Diseases

(Strom)

Host Agent Environment Model

HOST
(drug user)
Host factors /
Intrinsic factors

Agents of disease /
Etiological factors
AGENT
(drug)
= the cause of the
disease / contagion / risk
factors

= the recipient of the

causative agent of a
disease of a health
problem

Environmental factors /
Extrinsic factors
ENVIRONMENT
(context of use)
= conditions affecting
survival and transmission
of the causative agent

Host Agent Environment Model

Intrinsic factors
Genetics (e.g. sicle-cell disease)
Age (e.g. alzheimers disease)
Gender (e.g. rheumatoid arthritis)
Ethnic group
Physiological state
Human behaviors, etc
Etiological factors
Excesses or deficencies in nutritional elements
Exposure to chemical agents (e.g. drugs, poison, alergens)
Contact with physical agents, etc

Extrinsic factors
Physical environtment (e.g. geology, climate)
The biological environtment (e.g. human populations, flora, fauna)
The socioeconomic environtment (e.g. occupations, urbanization, economic
development, disruptions from wars and natural disasters), etc

Epidemiology Concepts
Epidemic
An outbreak of a disease, a sudden dramatic increase in the
number of people with the condition or health problem, usually
defined in term of a specific population in a geographic area during
some period
Endemic
The constant presence of a disease or infectious agent within a
given geographic area (or) the usual prevalence of a given
disease within such area.

Number of
cases

Epidemic

Endemic
1 2 3 4 5 6

10

11

12

Time

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Epidemiology Concepts
Mortality rate (MR)
The rapidity with which people in a given population die of a
particular condition
MR = per unit of time
Morbidity
The extend of disease, illness, injury, or disability in a defined
population
Usually expressed in terms of prevalence, attack rates or incidence
rates

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Epidemiology Concepts
Prevalence (P)
Probability that a condition exists in a specific population / probability of

the occurence of a condition

P=

Incidence Rate (IR)

Measure of rapidity with which a new condition develops in a population /
rate at which newly diagnosed patients are identified over time, measured
by actual observation time
IR =
IR are used to study new cases of a diseases. The denominator should not

include individuals who already have the disease, those who had the
disease and no longer susceptible, or those not susceptible due to
intervention, such as immunization

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Drug Approval Process

Human
Subjects

Post-marketing

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Drug Approval Process

Fase I
Pada manusia sehat
Tujuan:
Menentukan metabolisme obat pada manusia
Menentukan rentang dosis aman pada manusia
Memastikan tidak ada efek toksik pada manusia

Perkecualian: pada obat-obat yang sangat toksik, tidak etis apabila diujikan pada manuasa sehat

cytotoxic drug

Fase II
Pada sejumlah kecil pasien yang menderita penyakit yang akan diteliti
Tujuan:
Memperoleh informasi profil farmakokinetika obat
Memperoleh informasi tentang efek yang tidak diinginkan yang umum terjadi
Memperoleh informasi awal sehubungan dengan efikasi obat
Menentukan dosis harian dan regimentasi dosis untuk di tes lebih lanjut pada fase III

Fase III
Pada pasien dengan jumlah yang jauh lebih banyak (umumnya 500-3000 pasien)
Tujuan:
Melakukan evaluasi efikasi obat dengan lebih seksama
Memperoleh informasi lebih detil tentang toksisitas

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Limitiations of Pre-marketing Trials-1

Carefully selected subjects may not reflect real-

life patients in whom drug will be used

Study subjects may receive better care than reallife patients
Short duration of treatment

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Limitiations of Pre-marketing Trials-2

Study size
Studies with 3000 patients cannot reliably

detect adverse events with an incidence of < 1

per 1000, even if severe
Studies with 500 patients cannot reliably detect
adverse events with an incidence of < 1 per
166, even if severe

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Consequences of the Limitations

About 20% of drugs get new black box warnings

after marketing
About 4% of drugs are ultimately withdrawn for
safety reasons

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Epidemiological Study Design

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Farmakoepidemiologi dalam Praktek

1. Evidence-based medicine
2. Adverse drug reaction surveillance
3. Drug utilization evaluation (DUEs)
4. Pharmacoeconomical analyses

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1. Evidence-Based Medicine
The best drug therapy decisions based on sound

evidence
Evidence obtained from pharmacoepidemiological
studies medical literature
Medical literature:
Primer penelitian/studi yang dipublikasikan
Sekunder indexing system, contoh: pubmed
Tersier textbook, compendia, review article

Cochrane Database of Systematic Review

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Hierarchies of Evidence
I
: Properly randomized controlled trial
II-1a
: Controlled trial with pseudo-randomization
II-1b
: Controlled trial without randomization
II-2a
: Cohort prospective study with concurrent controls
II-2b
: Cohort prospective study with historical controls
II-2c
: Cohort retrospective study with concurrent controls
II-3 : Case-control retrospective study
III
: Large differences from comparisons between time and/or
places with and without intervention
IV
: Opinion of respected authorities, based on clinical experience,
descriptive studies, or reports of expert commitees

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2. Adverse Drug Reaction Surveillance

Post Marketing Surveillance (Phase IV)
The identification and collection of information regarding
medication after their approval

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Sejarah
1961: Thalidomide disaster Phocomelia

1968: Committee on Safety of Medicine- UK

WHO Bureau to collect and collate
information on ADR
Other national drug monitoring organization

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Tujuan PMS
1.

Provide valuable information on the use of

drugs in special patient populations
pregnant & breast feeding women (teratogenic & mutagenic effects of

drugs)
the elderly
patients with multiple comorbidities

2.

Long term monitoring of the effects of drugs

adverse drug reaction (ADR) rare ADR occur at rates of 1 in 10,000

or less
tolerance to drugs effects

3.

Knowledge for broader application of medicine

new indication
doses & duration not studied before drug marketing

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Macam PMS
Spontaneous Reporting System
Case Reports
Case-Control Studies
Cohort Studies
RCT
Database Research & Monitoring
Meta-Analyses

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Spontaneous Reporting Systems

Formal reporting systems designed to record, collate,

and analyze the occurrence of ADRs

Commonly used to identify new reactions
The reports were reviewed & analyzed for trends
Health care professionals responsible for reporting
suspected ADRs
Health care institutions responsible in creating &
maintaining the reporting system

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Limitations of Spontaneous Reporting

Systems
1.
2.

3.

4.

5.

Difficulty with adverse event recognition

subjective and imprecise
Underreporting
it has been estimated that rarely more than 10% of serious ADRs and 24% of non-serious reactions are reported to British Spontaneous reporting
program
low reporting rate
Biases
the length of time a product has been on the market, country, reporting
environment, detailing time, quality of data
highest reporting after a new drug is released onto the market
Estimation of population exposure

Impossible to determine the number of patients who have actually

experienced a particular reaction

Difficult to determine the number of patients who have used, or been

exposed to a particular medication

Therefore it is difficult to determine the incidence of the reaction

Report quality

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WHO
All reports are pooled to the WHO International Drug

Monitoring Project, Uppsala, Sweden

Aim:
To identify very rare but serious reaction as early as possible

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MESO - Indonesia
Mengapa Indonesia harus melakukan MESO

(Monitoring Efek Samping Obat) sendiri?

Karena perbedaan ras, iklim, nutrisi, sifat-sifat demografi, dapat

mempengaruhi insidensi dan bentuk ESO

Data dari negara lain tidak selamanya dapat langsung dipakai di
Indonesia

Ada panitia MESO nasional yg bertugas:

Menerima laporan ESO
Menilai laporan ESO yg diterima
Menganalisa data hasil evaluasi
Memberikan rekomendasi tindak lanjut yang perlu dilakukan
Alamat: Badan POM

Jl. Percetakan Negara 23

Jakarta

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3. Drug Utilization Studies

Drug utilization:
The marketing, distribution, prescription, and use of drugs in a
society, with special emphasis on the resulting medical, social, and
economic consequences

(WHO)
Drug utilization studies commonly conducted to monitor
prescribing patterns
Drug utilization studies similar to cohort studies
Subjects exposed to a particular drug are followed for a period to

determine the incidence of an adverse reaction can be easily be

expanded to a prospective cohort model

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4. Farmakoekonomi

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What is Pharmacoeconomics
Research that identifies, measures and compares the

costs (resources consumed) and consequences of

pharmaceutical products and services
(Bootman et al, 1989)

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What is Pharmacoeconomics
Research that identifies, measures and compares the

costs (resources consumed) and consequences of

pharmaceutical products and services
(Bootman et al, 1989)

Two Major Components

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Why do We Need Pharmacoeconomics?

To work out the best way to allocate scarce health
resources

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The Practice
Most industrialized countries government is the

primary payer for healthcare services including

prescription drugs
Pharmacoeconomic guideline by government
Australia, Canada, UK
Nongovernmental guideline US
Australia the first government to implement
pharmacoeconomic guidelines
Australian PBS regulates over 90% of outpatient
prescription dispensed in Australia

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Categories of Costs
Total Cost

Direct Cost

Direct Medical
Cost

Fixed Cost

Indirect Cost

Intangible Cost

Direct Nonmedical Cost

Semifixed Cost

Variable Cost

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Categories of Costs
Direct medical costs:
Associated with the drug and the medical care acquisition costs,

preparation costs, physicians fees, administration of medication, cost of

treating an ADR
E.g. Pharmaceuticals, hospital costs
Direct non-medical cost:
Those relevant to providing the therapy, including transportation to health
care facilities
E.g. Home assistance, travel
Indirect costs:
Result from lost of productivity (time off work due to sick leave)
E.g. Lost work days, early retirement, reduced productivity at work
Intangible costs:
Associated with pain and suffering of disease
E.g. Quality of life

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Perspective
The costs included depend on the perspective of the

evaluation
Perspective of the study should be stated
The point of view from which the study is conducted:
Patients
Providers (e.g. hospitals)
Payer (e.g. governments/insurers/employers)
Employer
Society (societal perspective)

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Outcomes
Clinical outcome
The results of treatment with a drug (+/-)
Humanistic outcome
Look at therapy from patients points of view
How the patient feels, quality of life??

Economic outcome
Cost associated with a therapy

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Interpretation
More effective

Less effective
Less expensive

More expensive

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Types of Pharmacoeconomics Analysis

Cost Analysis
Cost Minimization Analysis (CMA)
Cost Effectiveness Analysis (CEA)
Cost Utility Analysis (CUA)
Cost Benefit Analysis (CBA)

Cost Analysis
Analysis the costs of using a pharmaceutical
The emphasis is on total costs of a treatment
Note: Acquisition cost of a pharmaceutical is a poor

predictor of the total cost

Does not compare treatments or evaluate the efficacy

Example:
Cost comparison of iv antibiotic administration
The costs of preparing and administering several iv

antibiotics in an Australian teaching hospital were

compared.
Standard regimens based on AB Guidelines
Cost included:
Acquisition cost of the drugs
Cost associated with drug delivery
Laboratory monitoring for potential toxicity

Plumridge RJ. Cost comparison of intravenous antibiotic administration. Medical Journal of Australia
1990; 153: 516-8

Cost comparison of iv antibiotic administration

Antibiotic

Dose

Doses Acquisition Delivery Laboratory Total cost

per day cost per
cost per cost per
per dose
dose
dose
dose

Aminoglycosides
Amikacin 500mg
Gentamicin 120mg
Netilmicin 150mg
Tobramycin 120mg

3
3
3
3

$34.82
$0.92
$10.02
$7.20

$9.38
$4.55
$4.55
$4.55

Cephalosporins
Cefotaxime 2g
Cefoxitin
2g

3
4

$18.50
$19.22

$5.63
$5.63

$1.66
$1.66
$1.66
$1.66

Total cost
per day

$45.86
$7.13
$16.23
$13.41

$137.58
$21.39
$46.69
$40.23

$24.31
$24.85

$72.39
$99.40

..
Plumridge RJ. Cost comparison of intravenous antibiotic administration. Medical Journal of Australia
1990; 153: 516-8

Conclusions Derived from the Study

The study highlights the need for hospitals to develop

a global view of intravenous drug administration and

to acknowledge the interrelationships between
departments
The cheapest drug is not always the least expensive
to administer
Relatively expensive antibiotics, particularly those
which are administered infrequently (e.g. daily), do
not require laboratory monitoring and have a low
side-effect profile, can be effective therapeutic
choices

Cost Minimization Analysis (CMA)

Compares two or more pharmaceuticals/treatments

that have equivalent outcomes

The least costly is the best value
Used when the clinical outcomes of the two
treatments are identical in similar populations of
patients
Identical outcome clinical trial (specify!)
Duration of treatment, efficacy, toxicity

The unit of CMA: currency ($, Rp, etc)

Ondansetron vs Tropisetron
Have equal effectiveness in reducing nausea and

vomiting
Outcomes are the same
Choose drug with the lowest total cost:
Acquisition cost of each drug
Consumables for administration
Medical and nursing time

Ranitidine vs Sodium Alginate

Mean cost per patient () Sodium alginate Ranitidine
Study medication
Other GORD drugs
GP consultations
Medications for AEs
Other costs for AEs
Investigations and
outpatient consultations

23.65
72.46
81.01
3.72
174.81

109.16
25.67
71.49
1.20
36.58

116.70

161.75

Total health cost

143.00

188.54

AE = adverse event
Paton S. Cost-effective treatment of GORD a comparison of two therapies commonly used in
general practice. British Journal of Medical Economics 1995; 8: 89-95

Other Examples
Compare the costs of the same drug administered

differently.
E.g. iv therapy given by nurses compared with the same iv therapy

given by doctors

Compare the cost of the same drug given in different

scenarios
E.g. iv antibiotics administered in hospital compared with the same

antibiotic given to outpatients in a clinic or their home

Cost Effectiveness Analysis (CEA)

Compares the relative cost of therapies having different

outcomes, but where outcomes can be compared

Having similar objectives (e.g. prevention or treatment of same

disease)

Outcome is the therapeutic effect

Measure is usually natural units
Units are:
Cost per life year saved
Cost per infection prevented

Example

Misoprostol as prophylaxis for NSAID induced

ulcer
Ceftriaxone vs (Ampicillin + Gentamicin) for sepsis
Ceftriaxone vs Benzylpenicillin for Community
Acquired Pneumonia
The patients should come from patients groups
with comparable baseline demographics and
disease severity

Cost Utility Analysis (CUA)

Compares treatments that yield different levels of health

benefits, and enables effects of treatment on quality of life

and survival to be considered together
CUA measures:
Cost incurred
Effectiveness of treatment
Effect of treatment on quality of life (Quality- adjusted life

years/QALY)

CUA
Similar to a CEA but incorporates a quality of life

component
CUA only suitable for the assessment of chronic diseases
(e.g. cancer, renal disease, diabetes, asthma) acute
conditions of short duration (e.g. infections) do not have
enough impact on quality of life
CUA include an assessment of the patients perception of
their condition and treatment

Assessing Patients Perception

Rating scale
The patient rates their QOL on a scale from 0 (death) 10
(perfect health)
Sickness impact profile (SIP)
Medical outcomes study short form (MOS SF-36)
Nottingham health profile (NHP)
Activities of daily living (ADL) scale
Psycological adjustment to illness scale (PAOS)
Time trade off
The patient decides how much of their life would be willing to

trade off against this decrement in QOL

CUA
Example:

Omeprazole vs Fundoplication for moderate to severe

oesophagitis:
Heudebert GR, Marks R, Wilcox CM, Centor RM. Choice
of long-term strategy for the management of patients with
severe oesophagitis: a cost-utility analysis.
Gastroenterology 1997; 112: 1078-86

Limitation of CUA
Not easy to obtain QOL information QOL assessments

for some conditions do not exist

Only suitable for evaluating chronic diseases acute

conditions (e.g. infections) do not commonly impact on

long term QOL and would not significantly alter QALY

Cost Benefit Analysis (CBA)

Compares costs and outcomes in currency values
Outcomes are not equal
The most difficult type of pharmacoeconomics to perform
Primary problem: putting monetary value on a health

outcome (e.g. pain relief per life years saved)

CBA
Example:

Prophylaxis of hepatitis A, typhoid and malaria in

travellers: a cost benefit analysis
Behrens RH, Robert JA. Is travel prophylaxis worthwhile?
Economic appraisal of prophylactic measures against
malaria, hepatitis A, and typhoid in travellers. British
Medical Journal 1994; 309: 918-22

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Comparison Table
Type Description

Output

Typical Unit

Cost
analysis

Measures total cost of a

healthcare program

Cost

Currency

CMA

Compares 2 interventions
having equal efficacy

(Potential)
cost saving

Currency

CEA

Compares interventions with

different health benefits

Cost per unit

of clinical
outcome

Currency per unit of

outcome
e.g. $ per mmHg drop in
BP

CUA

Measures the cost per life-year

gained, adjusted for quality of
life

Cost per unit

of utility

Currency per unit of utility

e.g. cost per QALY

CBA

Compares interventions with

different health outcomes, in
purely monetary terms

Benefit-to-cost A ratio or a total cost

ration, or
saving in currency units
(potential) cost
savings

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Effectiveness vs Efficacy
Efficacy is the consequence (benefit) of a treatment

under ideal and controlled clinical outcomes and is

the outcome that is measured in RCTs
Assess the benefit and harm of the intervention when all

other factors are controlled

All real live does not behave like an RCTs

Different types of patients, different treatment processes,
different dose, be monitored less intensively
Thus: the intervention is likely to be less effective
Effectiveness: is the therapeutics consequence of a
treatment in real-world conditions
Effectiveness often < than its efficacy

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If a therapy is not clinically effective,

it cannot be cost-effective

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Pustaka
Elliott R and Payne K. 2005. Essentials of Economic

Evaluation in Healthcare. Pharmaceutical Press

Bootman JL, Townsend RJ, and McGhan WF. 1996.
Principles of Pharmacoeconomics. 3rd Edition. Harvey
Whitney
Strom BL. 2000. Pharmacoepidemiology. 3rd Ed. John
Wiley & Sons, pp. 3-15
Waning B, Montagne M. 2001. Pharmacoepidemiology:
Principles and Practice. Mc Graw Hill. pp. 1-15, 131-141,
143-157, 159-167