Farepid 2018

Universitas Sanata Dharma
FARMAKOEPIDEMIOLOGI
Aris Widayati, M.Si., Apt., PhD
Integrating academic excellence and humanistic values








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Epidemiologi?
13
 Definisi?
 Peran epidemiologi dalam farmakoepidemiologi?

Discussion questions
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 Why is John Snow called “The father of

Epidemiology”?
 What is epidemiologic surveillance, and why it is
important for public health?
 What was the role of epidemiology in
determining the cause of the Legionnaires’
disease outbreak in Philadelphia USA?
 What has epidemiology contributed to people’s
understanding of the causes of heart disease?
15

Image: http://www.sciencemuseum.org.uk/broughttolife/people/johnsnow.aspx

Source: http://www.ph.ucla.edu/epi/snow/1859map/lambeth_waterworks_a2.html
Image: http://www.historyisnowmagazine.com/blog/2014/4/5/body-snatchers-and-dickens-london-shocking-tales-of-
crime-in-19th-century-britain#.U6QoV_ldVuI=
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Source: Wood engraving by Smyth of London in 1844, published as a supplement in the Illustrated London
News, January 11, 1845. in Barker F and Jackson P., London 2000 Years of a City & It's People, 1974.

High resolution maps: http://www.ph.ucla.edu/epi/snow/highressnowmap.html

Interactive visualisation of the 1854 cholera outbreak, data of which was based on the original map prepared by
Snow:http://www.evl.uic.edu/kreda/vis/snowcholera/
Source of water Total number of Number of cholera

houses supplied deaths
Southwark & 40,046 1263

Vauxhall
Lambeth 26,107 98
Other 256,423 1422

23

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Istilah – istilah dalam Epidemiologi

25
 Endemic
 Endemic outbreak
 Pandemic
 Incidence rate
 Prevalence rate


Examples of notifiable epidemiology
study (after the John Snow study) 27
 Framingham Heart Study (FHS)  Risks of heart

disease (1948), 5.000 respondents
 Richard Doll and A. Bradford Hill (Doll and Hill) 
risk of smoking on lung cancer (1952), 40.000
respondents (doctors)
 Legionnaire’s disease (1976)

Desain studi Epidemiologi

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 Studi intervensi (eksperimental)

 Murni
 Kuasi / semu
 Cohort
 Case control
 Cross-sectional #

29

Tugas Kelompok (20%)

30
 Buat kelompok dengan anggota 5-6 orang

 Cari artikel di jurnal yang menggunakan desain
case-control atau cohort
 Buat ringkasan dari artikel tersebut
 Lakukan kajian / berikan pembahasan tentang
desain penelitian yang digunakan

Cross-sectional Design
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Efek + (A)
FR +
Efek – (B)
Populasi /
sampel
Efek + (C)
FR -
Efek – (D)
Resiko Prevalensi
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 Prevalensi suatu penyakit dalam populasi yang

berkaitan dengan faktor risiko yang diteliti/faktor
risiko tertentu
 RP = A : C
A+B C+D

Cohort Design
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 Contoh: pada study Doll and Hill

 Smoking and lung cancer
 40.000 physicians
 Observation 7 years: per-year  which physicians

had dead and what was the cause of death

Desain Cohort
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Subyek
(dengan
efek negatif)
FR + FR -
Efek + (A) Efek – (B) Efek + (C) Efek – (D)

Relative Risk (RR)

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 Insidensi penyakit dalam populasi yang terkait

dengan faktor risiko yang diamati
exposure Number of Number of Incidence per
samples death after 7 1000
years
Smoking 25.769 133
Non-smoking 5.439 3
 RR = [A / (A+B) ] : [ C/(C+D)]

Modified Cohort
36
 Retrospective Cohort
 Experimental (“intervention”) Cohort

Case-control design
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FR + (A)
Efek +
(case)
FR – (B)
Populasi /
sample
FR + (C)
Efek -
(control)
FR – (D)
Example of case-control study (1)

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 Reye’s syndrome case  children recovered

from viral infection (in 1980s in USA)
 Hypothesis: medications on the viral infection
diseases lead to Reye’s syndrome
 Case group?
 Control group?
 Data?
 Risk  Odds ratio (OR) ?

Odds Ratio (OR)

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 OR = (A/B) : (C/D)  ?

The use of epidemiologic study of
Reye’s syndrome for health policy 40
 From the results of the Reye’s syndrome case-

control study in 1980s in the US
 FDA put warnings label on aspirin products
 Pediatricians were recommended to use
acetaminophen instead of aspirin for viral infections

Example of case-control study (2)

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 Study on breast cancer in 1980s  exploration

on the link between breast cancer and oral
contraceptive
 Consisted 351 female breast cancer patients in 8
hospitals; controls were 351 women.
 Data: had ever taken oral contraceptives and
how many years

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Contraceptive use Breast cancer cases Controls OR

No use 235 273 1.0
< 1 year 27 26 1.2
1-4 years 43 29 1.7
> 4 years 46 23 2.3

Experimental / intervention study

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 Do an experiments / intervention (“perlakuan”).

 Mostly adopted for the Clinical studies and
Pharmacoepidemiology studies
 Clinical studies phase I to IV
 Pharmacoepidemiology studies
 Intervention group and control group (placebo /

inactive substance)  Randomized (double blind)
control trial (RCT)
 True experimental  randomization
 Quazy experimental  no randomization  ex: because
of ethical issues!
Example of intervention study (1)

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 Polio vaccine in 1954 in USA

 In 1952  21.269 cases of polio were reported in
the US (even the President of the USA!)
 Result: the incidence of polio among those were
given vaccine was less than half than those who
received a placebo.
 Oral vaccine were then developed in 1960s by
Albert Sabin

Example of intervention study (2)

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 The aspirin study in 1983, involved 22.000 physicians in

the US
 Hypothesis:
 whether aspirin reduced mortality from heart disease
 whether beta carotene decreased the incidence of cancer.
 Applied RCT design – received medicines and placebo 
until 1995
 Results:
 aspirin reduced heart attack (the study was halted before
1995)  aspirin reduced heart attack significantly
 No significant differences in reducing incidence of cancer
between trial group and control group

Example of Ethical issues in
experimental / intervention study 46
 Memberikan perlakuan pada subyek yang

diharapkan / hipotesisnya memberikan
penyembuhan pada kelompok perlakuan, tapi
membiarkan pada kelompok kontrol.
 Menekan faktor risiko pada kelompok perlakuan,
sementara membiarkan kelompok kontrol
terpapar faktor risiko yang merugikan.
 Mencobakan satu perlakuan yang belum pasti
efeknya pada manusia (bisa negatif)

Ethical issues
47
 The rules on ethic issues was developed to response

an ethical abuse on an experimental study in humans
conducted during the World War II
 In 1932 , Tuskegee study
 400 Black men in Macon County, US, had suffered
syphilis
 Objective of the study was to observe the cause of this
disease
 In 1940s, Penicillin was discovered  they did not
received the treatment
 The Tuskegee case was explored in 1972!

Intervention study design / Clinical trial

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 RCT – parallel design

 RCT – cross over design

RCT – parallel design

49
A
Patients Inclusion
criteria
B
Randomization

RCT – cross over design

50
Washed-out period
Randomization
A A
Patients Inclusion
criteria
B B

Blinding in RCT
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 Keeping trial participants, the investigators, the

assessors are unaware with the given intervention
 will not influenced by the intervention
 Performance bias / co-intervention bias
 Ascertainment bias
 Types of blinding
 Open label trial  no blinding
 Single blind
 Double blind
 Triple blind
 Quadruple blind

Tahapan penemuan dan pengembangan
obat
Fase 4
Registrasi Proses pendaftaran obat jadi

Dilanjutkan dengan uji klinik fase 4
Bisa sampai Tahap mempelajari bagaimana senyawa

6 tahun Uji Klinik aktif tersebut bekerja pada manusia
(Fase 1, 2, 3)
Bisa sampai Uji Pre-klinik Tahap mempelajari bagaimana

4 tahun (hewan uji, desain senyawa aktif tersebut bekerja
formula) (ADME, dosis, toksisitas, formula, dll)
Bisa sampai Penemuan senyawa dan Tahap menemukan dan

25 tahun karakteristiknya mempelajari suatu senyawa
(struktur, sifat, dll)
Clinical Trial / Uji Klinik

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Phase Phase Phase Phase

I II III IV

Tahap uji klinik (fase 1,2,3)
Fase 1 Fase 2 Fase 3
• apakah senyawa • bagaimana • apakah senyawa

aktif tersebut efikasi senyawa tersebut efektif
aman digunakan tersebut pada (dibandingkan
pada manusia? manusia? yang telah ada)
• 20 – 100 orang • 100 – 500 • 500 – 5000
SEHAT PASIEN PASIEN
• Data: ADME, • Data: ADME • Data:
dosis, efek pada pasien, perbandingan
farmakodinamika rasio manfaat dengan senyawa
yang lain dan risiko, lain yang telah
keamanan ada, penegasan
rasio manfaat
dan risiko
Apakah ada Registrasi

potensi lain? (-/+)
Declaration of Helsinki (1964)
(Revisi: 2002, 2004, 2008)
1. Eksperimentasi klinis harus memenuhi prinsip

moral dan ilmu pengetahuan, dan hanya boleh
dikerjakan atau diawasi oleh orang yang
mempunyai keahlian.
2. Manfaat yang hendak diperoleh penderita harus

jauh melebihi risiko yang terkandung

3. Penderita harus diberitahu tentang seluk beluk

penelitian yang hendak dijalani, dan ia harus bebas
untuk menolak/menerima keikutsertaannya dalam
penelitian.
4. setiap saat penderita boleh menarik diri atau

peneliti harus segera menghentikan penelitian bila
timbul gejala yang mengancam kesehatan dan jiwa
penderita.

Protokol uji klinik

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 Latar belakang
 Tujuan umum dan tujuan khusus
 Kriteria pemilihan pasien
 Prosedur dan tatalaksana perlakuan / intervensi
 Kriteria penilaian respon
 Rancangan uji
 Besar sampel
 Randomisasi subyek
 Written informed consent
 Pemantauan pelaksanaan uji
 Pencatatan dan pengelolaan data
 Prosedur penyimpangan protokol
 Rencana analisis data
 Administrasi / dokumentasi data dan proses

Ethical aspects on clinical trials

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 Ethical clearance approval

 Voluntary participation of the proposed
participants
 Written informed consent
 Assurance of participants’ safety
 Confidentiality of patients’ identity and data

The role of statistics in epidemiology
and clinical trial 59
Information:
 Cause – effects
Data  Risk factors
 Disease cures

Why statistics?  Uncertainty of science

60
 In 1995, NEJM published the Nurses Health Study

(a Cohort study)
 Monitored 122.000 nurses for 14 years  increased
risk of breast cancer in woman taken HRT after
menopause
 Just one month later, JAMA published another (a
study (a Case- control study)
 500
women with breast cancer and 500 healthy
women for control  no increased risk from the
HRT taken for menopausal
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HRT 
decrease risk
of CVDs and
osteoporosis
Avoiding the
risk of breast
Taking the risk cancer by not
of breast using HRT, but
cancer by exercise, diet,
using HRT aspirin, etc

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 In 1997 (USA) should women ages 45 to 49 be

screened using mammography?
 Studies have shown that women over 50 with
mammography screening  reduced breast cancer;
but not in the younger women!
 The NCI panel expert concluded that the benefits
did not justify the risk and the cost  recommended
a younger woman to have personal consultation
with their physician for making a decision in doing X
ray screening.

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 Then, the NCI recommendation was exposed by mass

media  the politicians did voting recommended
mammography screening for young women population!
 Many cases that politician pressure scientists to change
their recommendation
Dr. Arnold
Relman
“Most scientific information is of a
probable nature, and we are only (the former
talking about probability, not Editor of NEJM)
certainty. What we are concluding is
the best opinion at the moment, and
things may be updated in the future”

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 Contradictory results on epidemiology study is

common
 Biasand confounding factors
 Systematic error
 additional factors
 etc

Types of Bias and Confounder

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 Selection bias
 Misal: meneliti hubungan merokok dengan kanker paru  cenderung
memilih subyek yang perokok
 Measurement bias
 Misal: meneliti hubungan obesitas dengan CVD risks  mengukur berat
badan dengan timbangan yang berbeda - beda
 Information bias
 Misal: Meneliti hubungan merokok dengan kanker paru  ketika menggali
data dari subyek penderita kanker, dilakukan secara mendalam
 Recall bias
 Misal: Meneliti hubungan asupan makanan ibu hamil dengan BB bayi 
meminta subyek menyampaikan menu makanan selama kehamilan
 Confounder
 Misal: Meneliti hubungan hipertensi dengan kejadian stroke  subyek juga
menderita hiperkolesterol

Minimizing bias
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 Restriction / exclusion criteria

 Randomization
 Matching
 Stratification

p-value
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 The degree of probability and improbability of a

certain results in an experiment
 p-value = 0.05 an experiment were repeated
100 times, the same answer = 95 times; 5 times =
a different answer
 p-value less than 0.05  statistically significant

Sample size
68
 Alpha / type I error  “The probability of concluding

there is a different, when in fact one does not exist”
 Conventionally, alpha is set as 0.05
 Beta / type II error  “The probability of concluding
there is NO different, when in fact one DOES exist”
(kemungkinan untuk tidak mendeteksi perbedaan
yang sungguh ada) 
 Power: 1- Beta  “The probability of detecting a
difference if one really exists).
 Conventionally, Beta is set as 0.1 or 0.2

Example of sample size calculation

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 Peneliti ingin membandingkan 2 jenis obat, A dan

B. Berdasarkan penelusuran pustaka,
diperkirakan bahwa persentase kesembuhan
setelah pemberian obat A adalah 95% dan obat B
adalah 90%. Ditentukan alpha = 0,05 dan Beta =
0,1 ; f(α,β) = 10,5.
 n (per- kelompok) = [{P1 x (100 – P1) + P2 x (100-

P2)} / {P1-P2} 2 ] x f(α,β)

Types of Data
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 Nominal
 Ordinal
 Interval
 Ratio
Normality data
 Normal  parametric test
 Non – normal  Non-parametric test

Statistical analysis
Two groups Chi Square

Independent
sample
Three or more Contingency
Nominal
Non
independent Two McNemar’s test
(paired)

Two Mann Whitney,

Wilcoxon
Independent
Three or more Kruskal Wallis
Ordinal
Two Wilcoxon
Paired
Three or more Friedman’s

Two t-test
Independent
Three or more ANOVA
Continuous/
interval-
ratio Two Paired t-test
paired
ANOVA for
Three or more repeated
measures

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TERIMA KASIH

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Universitas Sanata Dharma

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

 Why is John Snow called “The father of

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

High resolution maps: http://www.ph.ucla.edu/epi/snow/highressnowmap.html

Source of water Total number of Number of cholera

Southwark & 40,046 1263

Other 256,423 1422

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Istilah – istilah dalam Epidemiologi

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

study (after the John Snow study) 27

 Framingham Heart Study (FHS)  Risks of heart

Integrating academic excellence and humanistic values

Desain studi Epidemiologi

 Studi intervensi (eksperimental)

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Tugas Kelompok (20%)

 Buat kelompok dengan anggota 5-6 orang

Integrating academic excellence and humanistic values

 Prevalensi suatu penyakit dalam populasi yang

Integrating academic excellence and humanistic values

 Contoh: pada study Doll and Hill

 Observation 7 years: per-year  which physicians

Integrating academic excellence and humanistic values

Efek + (A) Efek – (B) Efek + (C) Efek – (D)

Integrating academic excellence and humanistic values

Relative Risk (RR)

 Insidensi penyakit dalam populasi yang terkait

Integrating academic excellence and humanistic values

Integrating academic excellence and humanistic values

Example of case-control study (1)

 Reye’s syndrome case  children recovered

Integrating academic excellence and humanistic values

Odds Ratio (OR)

Integrating academic excellence and humanistic values

Reye’s syndrome for health policy 40

 From the results of the Reye’s syndrome case-

Integrating academic excellence and humanistic values

Example of case-control study (2)

 Study on breast cancer in 1980s  exploration

Integrating academic excellence and humanistic values

Contraceptive use Breast cancer cases Controls OR

Integrating academic excellence and humanistic values

Experimental / intervention study