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FARMAKOEPIDEMIOLOGI
Kuliah Farmasi Masyarakat - 2017

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)

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The Relationship

Epidemiology Health
services Economics
research

Clinical
Epidemiology
Health
Economics
Outcomes
Research

Pharmaco-
epidemiology

(H Guess)

The Relationship
The study of
- Pharmacokinetics
the effects of
drugs in
Clinical pharmacology - Pharmacodynamics
humans

Focus of inquiry

The study of ADR

Pharmacoepidemiology Post marketing drug

surveillance

Methods of inquiry

The study of the

distribution &
- Infectious Diseases
determinants of
diseases in
Epidemiology - Chronic Diseases
populations
(Strom)

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Host Agent Environment Model

HOST = the recipient of the
causative agent of a
(drug user) disease of a health
Host factors / problem
Intrinsic factors

Agents of disease / Environmental factors /

Etiological factors Extrinsic factors

AGENT ENVIRONMENT
(drug) (context of use)
= the cause of the = conditions affecting
disease / contagion / risk survival and transmission
factors 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

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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 Epidemic
cases

Endemic

1 2 3 4 5 6 7 8 9 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

ogy Concepts

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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

Animal Studies
Phase I
Phase II
Human
Phase III Subjects

Drug Approval
Phase IV 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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Epidemiological Study Design

Study Design

Controlled Uncontrolled
assignment assignment

Experimental Observational
studies studies

Community Individual
Descriptive Analytical
assignment assignment

Sampling with Sampling with

Community Cross-
Clinical trial regard to regard to
trial sectional
disease exposure

Case-control Cohort

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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. Difficulty with adverse event recognition
subjective and imprecise
2. Underreporting
it has been estimated that rarely more than 10% of serious ADRs and 2-
4% of non-serious reactions are reported to British Spontaneous reporting
program
low reporting rate
3. 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
4. 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
5. 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 Indirect Cost Intangible Cost

Direct Medical Direct Non-

Cost medical Cost

Fixed 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)

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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

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Cost comparison of iv antibiotic administration

Antibiotic Dose Doses Acquisition Delivery Laboratory Total cost Total cost
per day cost per cost per cost per per dose per day
dose dose dose

Aminoglycosides
Amikacin 500mg 3 $34.82 $9.38 $1.66 $45.86 $137.58
Gentamicin 120mg 3 $0.92 $4.55 $1.66 $7.13 $21.39
Netilmicin 150mg 3 $10.02 $4.55 $1.66 $16.23 $46.69
Tobramycin 120mg 3 $7.20 $4.55 $1.66 $13.41 $40.23

Cephalosporins
Cefotaxime 2g 3 $18.50 $5.63 - $24.31 $72.39
Cefoxitin 2g 4 $19.22 $5.63 - $24.85 $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

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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

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Ranitidine vs Sodium Alginate

Mean cost per patient () Sodium alginate Ranitidine

Study medication 23.65 109.16

Other GORD drugs 72.46 25.67
GP consultations 81.01 71.49
Medications for AEs 3.72 1.20
Other costs for AEs 174.81 36.58
Investigations and
outpatient consultations 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

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

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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)

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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

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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
(Quality Adjusted Life Year)

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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 Measures total cost of a Cost Currency
analysis healthcare program
CMA Compares 2 interventions (Potential) Currency
having equal efficacy cost saving
CEA Compares interventions with Cost per unit Currency per unit of
different health benefits of clinical outcome
outcome e.g. $ per mmHg drop in
BP
CUA Measures the cost per life-year Cost per unit Currency per unit of utility
gained, adjusted for quality of of utility e.g. cost per QALY
life
CBA Compares interventions with Benefit-to-cost A ratio or a total cost
different health outcomes, in ration, or saving in currency units
purely monetary terms (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

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