Farmakoepidemiologi

YUNITA
Departemen Praktis
Fakultas Farmasi
Universitas Airlangga

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 • Strom BL. 2000.
Pharmacoepidemiology. 3rd Ed.
John Wiley & Sons, pp. 3-15
• Waning B, Montagne M. 2001.
Reading List Pharmacoepidemiology: Principles
and Practice. Mc Graw Hill. pp. 1-
15, 131-141, 143-157, 159-167

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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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History
In an attempt to prevent or reduce the occurrence
of disease → public health professionals realized a
scientific method was needed to assess diseases and
their causes

They needed to develop a logical, standard

approach to counting events (e.g. births, deaths,
diseases) and calculating results from the data

The field of EPIDEMIOLOGY was born in 19th

century to address this need

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The Relationship

Epidemiology Health
services Economics
research

Clinical
Epidemiology
Health
Economics
Outcomes
Research

Pharmaco-
epidemiology

(H Guess)
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The Relationship
The study of the
effects of drugs - Pharmacokinetics
in humans Clinical pharmacology - Pharmacodynamics

Focus of inquiry

The study of ADR

Pharmacoepidemiology Post marketing drug

surveillance

Methods of inquiry

The study of the

distribution & Epidemiology - Infectious Diseases
determinants of
diseases in - Chronic Diseases
populations
(Strom) 6
Host – Agent – Environment Model
HOST = the recipient of the
causative agent of a disease
(drug user) of a health problem
Host factors /
Intrinsic factors

Agents of disease / Environmental factors /

Etiological factors Extrinsic factors

AGENT ENVIRONMENT
(drug) (context of use)
= the cause of the disease / = conditions affecting
contagion / risk factors survival and transmission
of the causative agent
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 Host – Agent – Environment Model
Intrinsic factors
• Genetics (e.g. sicle-cell
disease)
• Age (e.g. alzheimer’s
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
• Incubation Period
• The interval of time between exposure to, or contact with, the causative agent (or risk
factor) and the onset of condition
• Individual incubation period vs epidemic incubation period (the median case of the
epidemic curve)
• The epidemic curve for a specific disease is fairly consistent from outbreak to
outbreak → a distinguishing feature of a disease
• 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’.

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Number of Epidemic
cases

Endemic

1 2 3 4 5 6 7 8 9 10 11 12 Time

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Epidemiology Concepts
• Outbreak
• carries the same definition of epidemic, but is often used for a more limited
geographic area.
• Cluster
• refers to an aggregation of cases grouped in place and time that are
suspected to be greater than the number expected, even though the
expected number may not be known.
• Pandemic
• refers to an epidemic that has spread over several countries or continents,
usually affecting a large number of people.

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Epidemiology Concepts
• Ratio, Proportion, Percentage, Rate

• Mortality rate (MR)

• The rapidity with which people in a given population die of a particular
condition
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑒𝑜𝑝𝑙𝑒 𝑑𝑖𝑒𝑑 𝑖𝑛 𝑎 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛
• MR = per unit of time
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑒𝑜𝑝𝑙𝑒 𝑖𝑛 𝑡ℎ𝑎𝑡 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛

• 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 → at a specific time
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑒𝑥𝑖𝑠𝑡𝑖𝑛𝑔 𝑐𝑎𝑠𝑒𝑠 𝑖𝑛 𝑎 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛
• P=
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑒𝑜𝑝𝑙𝑒 𝑖𝑛 𝑡ℎ𝑎𝑡 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛

• 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
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑒𝑤 𝑐𝑎𝑠𝑒𝑠
• IR =
𝑇𝑜𝑡𝑎𝑙 𝑝𝑒𝑟𝑠𝑜𝑛 − 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑜𝑏𝑠𝑒𝑟𝑣𝑎𝑡𝑖𝑜𝑛 𝑖𝑛 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑎𝑡 𝑟𝑖𝑠𝑘

• 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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Epidemiology Concepts
• Cumulative Incidence (CI)
• Cumulative incidence assumes that all of the subjects were followed for the entire study
period → does not reflect study dropouts or losses to follow-up
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑒𝑤 𝑐𝑎𝑠𝑒𝑠 𝑑𝑖𝑠𝑒𝑎𝑠𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑔𝑖𝑣𝑒𝑛 𝑡𝑖𝑚𝑒
• CI =
𝑇𝑜𝑡𝑎𝑙 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑎𝑡 𝑟𝑖𝑠𝑘

• Case Fatality Rate (CFR)

• Proportion of people with a particular condition who die from it in a specific time period
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑒𝑜𝑝𝑙𝑒 𝑤ℎ𝑜 𝑑𝑖𝑒𝑑 𝑓𝑟𝑜𝑚 𝑝𝑎𝑟𝑡𝑖𝑐𝑢𝑙𝑎𝑟 𝑐𝑜𝑛𝑑𝑖𝑡𝑖𝑜𝑛
• CFR = per unit of time
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑒𝑜𝑝𝑙𝑒 𝑤𝑖𝑡ℎ 𝑡ℎ𝑐𝑜𝑛𝑑𝑖𝑡𝑖𝑜𝑛

• Survival Rate (SR)

• The likelihood of living for a specified time period after the diagnosis of a particular condition

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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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How about VACCINE?
• Laboratory and Animal Studies
• Phase I Vaccine Trials
• A small group of adults, usually between 20-80 subjects.
• If the vaccine is intended for children, researchers will first test adults, and then gradually step down the age of the test subjects until they
reach their target.
• May be non-blinded (also known as open-label in that the researchers and perhaps subjects know whether a vaccine or placebo is used).
• To assess the safety of the candidate vaccine and to determine the type and extent of immune response that the vaccine provokes.
• In a small minority of Phase 1 vaccine trials, researchers may use the challenge model, attempting to infect participants with the pathogen
after the experimental group has been vaccinated.
• Phase II Vaccine Trials
• A larger group of several hundred individuals participates in Phase II testing.
• Some of the individuals may belong to groups at risk of acquiring the disease.
• Randomized and well controlled, and include a placebo group.
• To study the candidate vaccine’s safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery.
• Phase III Vaccine Trials
• Involving thousands to tens of thousands of people.
• Randomized and double blind and involve the experimental vaccine being tested against a placebo (the placebo may be a saline solution, a
vaccine for another disease, or some other substance).
• To assess vaccine safety in a large group of people.
• Vaccine efficacy: 1) Does the candidate vaccine prevent disease? 2) Does it prevent infection with the pathogen? 3) Does it lead to production
of antibodies or other types of immune responses related to the pathogen?

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Limitiations of Pre-marketing Trials
• Carefully selected subjects may not reflect real-life patients in
whom drug will be used
• Study subjects may receive better care than real-life patients
1 • Short duration of treatment

• 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
2 with an incidence of < 1 per 166, even if severe

To detect a significant difference for a low-frequency event, the trial would have to
include 60,000 subjects, half of them in the control, or no vaccine, group (Plotkin SA
et al. Vaccines, 5th ed. Philadelphia: Saunders, 2008).
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Consequences of the Limitations

• About 20% of • About 4% of

drugs get new drugs are
“black box” ultimately
warnings after withdrawn for
marketing safety reasons

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The case of Covid-19 Vaccine
• Emergency Use Authorization (EUA)
• An Emergency Use Authorization (EUA) is a mechanism to facilitate the
availability and use of medical countermeasures, including vaccines, during public
health emergencies, such as the current COVID-19 pandemic.
• Under an EUA, FDA may allow the use of unapproved medical products, or
unapproved uses of approved medical products in an emergency to diagnose,
treat, or prevent serious or life-threatening diseases or conditions when certain
statutory criteria have been met, including that there are no adequate, approved,
and available alternatives.
• Taking into consideration input from the FDA, manufacturers decide whether and
when to submit an EUA request to FDA.
• Once submitted, FDA will evaluate an EUA request and determine whether the
relevant statutory criteria are met, taking into account the totality of the scientific
evidence about the vaccine that is available to FDA.

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Preliminary results suggest that this
drug has little or no effect on
hospitalized patients with covid-19, as
indicated by overall mortality,
initiation of ventilation, and duration
of hospital stay
How the Solidarity Trial works
• WHO helps evaluate drugs
by randomizing their
effects on important
outcomes.
• The WHO Solidarity PLUS
trial involves collaboration
among hundreds of
hospitals in dozens of
countries.
• It began by evaluating four
repurposed drugs, and
now guided by an
independent expert group,
is evaluating three new
drugs in addition to the
local Standard of Care.
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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 trial Clinical trial Cross-sectional regard to
regard to 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
Properly randomized controlled trial
I
Controlled trial with pseudo-randomization
II-1a
Controlled trial without randomization
II-1b
Cohort prospective study with concurrent controls
II-2a
Cohort retrospective study with concurrent controls
II-2c
Cohort prospective study with historical controls
II-2b
Case-control retrospective study
II-3
Large differences from comparisons between time and/or places with and without intervention
III
Opinion of respected authorities, based on clinical experience, descriptive studies, or reports of
IV expert commitees
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2. Adverse Drug Reaction Surveillance
Pharmacovigilance
The science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other drug-related
problem.
(WHO)

Post marketing surveillance is a part of pharmacovigilance (Phase IV)

“The identification and collection of information regarding medication after
their approval”

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Definition
• Adverse drug reaction (ADR)
• A response to a drug which is noxious and unintended and which occurs at
doses normally used in man for prophylaxis, diagnosis, or therapy of disease
or for the modification of physiologic function (WHO)
• Adverse drug event (ADE)
• Any untoward medical occurrence that may present during treatment with a
pharmaceutical product but which does not necessarily have a causal
relationship with this treatment (WHO)
• Medication error
• Any preventable event that may cause or lead to inappropriate medication
use or patient harm while the medication is in the control of the health care
professional, patient, or consumer (NCCMERP)

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ADR & ADE
• An ADR is a type of ADE whose cause can be directly attributed to a
drug and its physiologic properties.
• ADRs occur despite appropriate prescribing and dosing
• ADEs may also be associated with inappropriate use of the drug or
other confounders that occur during drug therapy but are not
necessarily caused by the pharmacology of the drug itself.
• A causal relationship is suspected for an ADR but is not required for
an ADE.
• ADE may also be caused by medication errors

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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 drug’s 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 Evaluation (DUEs)
• 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)
• The prescribing, dispensing and ingesting of drugs
• 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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Next week:
PHARMACOECONOMICS

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