RCT Design Fundamentals

01/10/2011
Experimental Design
RCT (Randomized Controlled Clinical
Trial)
Iwan Dwiprahasto
CE&BU FK UGM/RSUP Dr. Sardjito
Quantitative Method
Research Design
Observational Experimental
study study
Quasi
Descriptive Analytic RCT Experiment
al
Case report,
outcome exposure both
case series,
Case Cohort Cross

control study sectional
study study
Iwan Dwiprahasto-CE&BU
1
01/10/2011
Quantitative Method
Research Design
Analytical studies Descriptive
Observational Experimental Case Case

studies studies report series
Cros Case - Quasi

Cohort RCT
sectional ontrol experiment
HIERARKHI METODOLOGI PENELITIAN
Systematic
review/MA
RCT
Quasi Experimental
Cohort/Case Control
Cross
challenge
sectional/Case
the process
Series
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01/10/2011
Kategori Evidence
Ia evidence dari meta analisis pada RCT
Ib evidence dari minimal 1 RCT
evidence dgn kelompok kontrol, tanpa

IIA randomisasi
IIb evidence dari suatu quasi experimental
evidence dari non-

III experimental/descriptive study
evidence dari laporan Expert

IV Committee/pendapat ahli
Why run an experiment?
We typically have a
to determine cause particular cause in mind,
and effect and want to know if it has
relationships an effect on an outcome,
and if so, to what degree.
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PRINCIPLES OF RESEARCH DESIGN
Three important principles of

research design.
Principle of Principle of Principle of

Replication randomization Local Control
PRINCIPLE OF RANDOMIZATION
Subject
Treatment A Treatment B
- Similar chance
- No right to choose
R= randomization
- Neutral
- To prevent Iwan
biasDwiprahasto-CE&BU
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01/10/2011
PRINCIPLE OF LOCAL CONTROL
All variables are closely controlled
Patients factor Disease factor

Age Severity
Sex Stages
Comorbidity
exposure
posure outcome
ACE--inhibitor
ACE Lowering
SBP
Treatment factor Other factors
Dose Compliance
Frequency Diet
Other drugs Life style Iwan Dwiprahasto-CE&BU
Definitions
Experimental group (EG) Control group (CG)
The group that is exposed A group not exposed to

to some sort of a change or changes or manipulations
manipulation in the IV
that serves as a baseline
comparison to the
experimental group
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01/10/2011
RCT (randomized controlled clinical trial)
Randomized Randomisasi
Inclusion
Controlled Prosedur
Outcome
Intervensi
Clinical Trial
vs. control group
RCT
Investigator Clinical manouvre Participants
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RCT
Quantitative Comparative Control Experiment
Measuring outcome Comparing 2 or more All variables are

quantitatively intervention Closely controlled
TUJUAN UJI KLINIK
Uji
klinik
obat pasien populasi
Efficacy Safety Quality
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01/10/2011
RCTs according to the aspects of the interventions

they evaluate
Explanatory and pragmatic trials
Efficacy and effectiveness trials
Phase I, II, and III trials
RCTs according to the aspects of the interventions they evaluate
inclusion criteria sangat ketat
Explanatory highly homogeneous study groups

trial
Mis. Hanya pasien usia 40 50 tahun
Mis. tahun,,
tanpa penyakit penyerta
Memasukkan subyek dengan

karakteristik yang heterogen
pragmatic Sesuai dengan pasien yang ditemui di

trials ruang praktek
Menggunakan kontrol aktif (mis
antihypertensive vs. b-blocker), flexible
regimens Iwan Dwiprahasto-CE&BU
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01/10/2011
RCTs according to the aspects of the interventions they evaluate
Efficacy trials effectiveness trials
Ideal setting Real setting
Semua variabel yang

berpengaruh thd
outcome dikendalikan
e.g.
Keparahan penyakit
Ketaatan minum obat,
Setelah/sebelum makan Iwan Dwiprahasto-CE&BU
TAHAP-TAHAP UJI KLINIK
sukarelawan sehat
efek samping & toleransi
Fase I hubungan dosis-
dosis-efek
farmakokinetika
uncontrolled
Fase II subyek terbatas
kemungkinan efek tx
controlled trial
Fase III efek terapi definitif
pms
Fase IV efek samping yg jarang
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01/10/2011
Phases of Clinical Trials
Phase I: Small sample [20-

[20-80]
Phase II: larger group [100-

[100-300]
Phase III: 1,000--3,000

1,000
Done after rx/

rx/tx has been
Phase IV:
marketed
Summary of Phases I-
I-III
% Drugs
# Subs. Length Purpose Successfully
Tested
Phase I 20 100 Several Mainly Safety 70%
months
Phase II Up to Several Short term 33%
several months--
months safety; mainly
100 2 yrs. effectiveness
Phase 100s 1-4 yrs. Safety, dosage 25-
25-30%
III several & effectiveness
1000
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DESIGN
(RCT-parallel design) (RCT cross-

cross-over design)
(RCT factorial design)
RCT--parallel design
RCT
Patient
treatment A O
U
T
C
eligible Random O
M
E
Treatment B
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RCT cross-
cross-over design
Patient
washed
out
eligible
O O
Treatment A U Treatment B U
T T
Random C C
O O
M M
Treatment B E Treatment A E
RCT--factorial design
RCT
Patient
O
tx A U
T
eligible Random Tx B C
O
M
tx A + tx B E
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Prospective, randomized, open, blinded-endpoint

evaluation (PROBE)
Pengukuran endpoint bersifat obyektif
misal
kadar gula kadar Kadar asam
Kadar CD20
darah, kholesterol urat
Review of Steps for RCT Design
1. Select sample from population
2. Measure baseline variables
3. Randomize
4. Apply interventions & placebo
5. Follow-up cohorts
6. Measure outcomes
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01/10/2011
1. Select sample from population
Inclusion Criteria Exclusion Criteria
1. Appropriate to the study 1. Exclude patients with

question conditions that will
2. Generalizable compete with the outcomes
3. Consider the outcome of (e.g. likely early death from
interest cancer)
4. Allow adequate recruitment 2. Contradictions to
(study patients you have interventions
access to) 3. Difficult to comply
Example of eligibility criteria

RCT: azithromycin vs clarithromycin for adult with mild to
moderate CAP
Male and female outpatients
Clinically diagnosed as CAP
Chest--X-ray: pulmonary infiltrate or consolidation

Chest
Showing at least three of the following symptom/sign:

nonproductive cough,
new onset of purulent sputum (productive cough), or
change in the character of their sputum;
sputum culture positive for gram-
gram-positive diplococci
diplococci;;
body temperature of 38 7C or more at least twice within a 24 h
period; and/or
elevated leukocyte count (10x10 9 /l). Iwan Dwiprahasto-CE&BU
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01/10/2011
Example of exclusion criteria

Terminal illness
Setiap kondisi yang dapat mengganggu visit
Pasien dengan kondisi berikut
Likely to affect gastrointestinal absorption of
antimicrobial activity
significant hepatic disease with a serum
transaminase level more than three times the upper
limit of the normal range [serum glutamic
oxalacetic transaminase (SGOT) 0.020.90 mM/s/;
serum glutamic pryruvic transaminase (SGPT) 0.15
0.95 mM/s/l].
hypersensitive to azithromycin, clarithromycin, or
other macrolide
cyclosporine, theophylline, astemizole, terfenadine,
or antacids
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Inclusion criteria Exclusion criteria

presence of typical stable acute myocardial infarction (3
months);
effort angina,
unstable angina;
positive stress test (either Any increase in CK-MB, troponin I,
ECG, nuclear scan, or or myoglobin above upper
stress echocardiogram), normal limit at the time of
indication for coronary randomization;
angioplasty. any increase in liver enzymes
(AST/ALT);
Left ventricular ejection fraction
30%; renal failure with creatinine
> 3 mg/dL;
history of liver or muscle disease;
or previous treatment with statins.
Patients undergoing current
therapy with statins
2. Measure baseline variables
Define potential important variables
Compare between study groups
Account for differences in study

design or analysis of results
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RCT helicobacter pylori

eradication in NSAID user
Measurement
Measurable Objective Accurate Consistent
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3. Randomize RANDOMISATION
Objective measures
Equal chance for treatment or control
group
Both groups are balanced
To prevent bias
metode
Simple Random Random

randomisation permuted block permuted block
within strata
RANDOMISATION
Simple randomisation
2 treatment groups:
(0-4= A; 5-9=B)
3 treatment groups:
(1-3= A; 4-6= B; 7-9 = C)
4 treatment groups
(1-2= A; 3-4= B; 5-6= C; 7-9=D)
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RANDOM LISTS
128 131 133 142 144 145

154 160 162 164 167 181
184 188 191 202 203 205
216 229 235 237 238 240
261 264 272 273 277 278
280 281 282 283 289 290
291 295 300 312 318 321
323 325 327 331 335 338
342 349 359 360 366 369
372 373 375 384 385 397
404 405 414 424 431 436
438 446 447 448 458 462
469 478 491 498 502 511
516 518 520 521 530 535
RANDOMISASI
Random permuted blocks

2 treatment groups:
AB for 0-4; BA for 5-9
3 treatment groups:
ABC= 1; ACB= 2; BAC= 3
BCA= 4; CAB= 5; CBA= 6
2 treatment group with block of 4 patient
AABB= 1; ABAB= 2; ABBA= 3
BBAA= 4; BABA= 5; BAAB= 6
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01/10/2011
Allocation Scheme
1. Masked to patients, MDs, others

2. Cannot predict future assignments
3. Allocation order is reproducible
4. Allocation methods documented
5. Allocation method has known mathematical
properties
6. Process provides a clear audit trail
7. Departures from allocation can be detected
4. Apply interventions & placebo
Treatment & Control group
Treatment Control
Drug formulation standard drug (DOC)

therapeutic class placebo
dosage non fatal outcome/ disease
drug administration,
frequency
duration of treatment
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01/10/2011
5. Follow-up cohorts
Requirements: Test and Control Groups

Distinguishable.
Medically justifiable
Ethical base for each treatment
Compatible with health care needs
Either treatment acceptable
Reasonable doubt about efficacy
Benefits outweigh risks
Similar to real-world use
RCT helicobacter pylori eradication in NSAID user
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01/10/2011
Intention-to-Treat
The full potential of a RCT to eliminate the

influence of baseline confounding variables is
only realized when the results are analyzed
according to random group assignments.
BLINDING
Single blind Double blind Triple blind
Patient Patient Patient

doctor/rater Doctor/rater
Statistician
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01/10/2011
BLINDING
Aims:
To prevent bias
To prevent prediction effect
Objective measures
Reducing risk of overwhelming
examination
Outcome Measures
Easy to diagnose and observe
Free of measurement or
ascertainment errors
Can be observed independent of

treatment assignment
Clinically relevant
Chosen before the start of data

collection
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01/10/2011
MEASURING RESPONSE
e.g: cytostatics
Survival time: early treatment vs. dead

tumor response: reduction of tumor size
Duration of treatment vs. treatment
response
Patients improvement
Toxicity
Randomised controlled trial of Helicobacter pylori eradication in patients on

non-steroidal anti-inflammatory drugs: HELP NSAIDs study
Lancet1998; 352: 101621
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01/10/2011
Severity of Illness
1. Difficult to measure
2. Disease specific vs. general
3. Use validated instruments
4. Applicability to study population
5. Acknowledge limitations
KOMPONEN UJI KLINIK
1. Seleksi/pemilihan subyek
2. Rancangan
3. Perlakuan & pembanding
4. Randomisasi
5. Besar sampel
6. Blinding
7. Penilaian respons
8. Analisis data
9. Protokol uji klinik
10. Etika uji klinik
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Seleksi/pemilihan subyek
1. Hospital based / community based

2. Diagnosis ? Kriteria
3. Kondisi yang tidak memungkinkan
diikutsertakannya pasien
Inclusion criteria
Jenis kelamin, umur, kriteria khusus
Kriteria penyakit
riwayat penyakit
diagnosis
cara menegakkan diagnosis
alat untuk menegakkan diagnosis
siapa yang melakukan pemeriksaan
Informed consent
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01/10/2011
Example of eligibility criteria

RCT: azithromycin vs clarithromycin for adult with mild to
moderate CAP
Male and female outpatients

Clinically diagnosed as CAP
Chest-X-ray: pulmonary infiltrate or consolidation
Showing at least three of the following symptom/sign:
nonproductive cough,
new onset of purulent sputum (productive cough), or
change in the character of their sputum;
sputum culture positive for gram-positive diplococci;
body temperature of 38 7C or more at least twice within a 24 h
period; and/or
elevated leukocyte count (10x10 9 /l).
Exclusion criteria
Kontraindikasi terapi
Kehamilan
Hipersensitivitas
Mencetuskan kondisi emergency
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Contoh exclusion criteria

Penyakit terminal
Pasien dengan keadaan berikut:
1. Mengganggu absorpsi antimikroba pada
sistema gastrointestinal
2. Penyakit hepar dengan kenaikan kadar serum
transaminase 3 kali lebih tinggi dari nilai
ambang atasnya SGOT: 0.020.90 mM/s/;
SGPT: 0.150.95 mM/s/l].
3. Hypersensitiv terhadap azithromycin,
clarithromycin, atau jenis macrolide lainnya,
4. Dalam terapi dengan cyclosporine,
theophylline, astemizole, terfenadine, or
antacids
Treatment & Control group
Treatment Control
Drug formulation standard drug (DOC)

therapeutic class placebo
dosage non fatal outcome/ disease
drug administration,
frequency
duration of treatment
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Treatment schedule
Formulasi obat
Cara pemberian
Dosis
Frekuensi pemberian
Lamanya terapi
Efek samping
samping,, modifikasi dosis
Supervisi
RANDOMISATION
Objective measures
Equal chance for treatment or control group
Both groups are balanced
To prevent bias
metode
Simple Random Random

randomisation permuted block permuted block
within strata
29
01/10/2011
RANDOMISATION
Simple randomisation
2 treatment groups:
(0-4= A; 5-9=B)
3 treatment groups:
(1-3= A; 4-6= B; 7-9 = C)
4 treatment groups
(1-2= A; 3-4= B; 5-6= C; 7-9=D)
RANDOMISASI
Random permuted blocks

2 treatment groups:
AB for 0-4; BA for 5-9
3 treatment groups:
ABC= 1; ACB= 2; BAC= 3
BCA= 4; CAB= 5; CBA= 6
2 treatment group with block of 4 patient
AABB= 1; ABAB= 2; ABBA= 3
BBAA= 4; BABA= 5; BAAB= 6
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01/10/2011
RANDOMISASI
Random permuted blocks within strata
Stratified
Several criterias
Example:
Age < 50 year + 1-3 nodules
Age > 50 year + 1-3 nodules
Age < 50 year + > 4 nodules
Age > 50 year + > 4 nodules
BLINDING
Single blind Double blind Triple blind
Patient Patient Patient

doctor/examiner Doctor/examiner
Statistician
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BLINDING
Aims:
To prevent bias
To prevent prediction effect
Objective measures
Reducing risk of overwhelming examination
MEASUREMENT
Measurable
Objective
Accurate
Consistent
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MEASURING RESPONSE
Baseline Before treatment

assessment
Main criteria main indication
Additional criteria e.g. adverse event
Monitoring patient compliance
MEASURING RESPONSE
e.g: cytostatics
Survival time: early treatment vs. dead

tumor response: reduction of tumor size
Duration of treatment vs. treatment
response
Patients improvement
Toxicity
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01/10/2011
Kriteria utama pengukuran outcome
Easy to diagnose
Objective measures
Reducing risk of incorrect measurement
Could be independently observed
Clinically relevance
Determined and agreed upon before
research conduct
ANALYSIS
Qualitative
yes/no
cured/not cured
alive/dead
Quantitative
mean, SD, X- square, t-test
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PROTOKOL UJI KLINIK

Treatment procedure
Design
background Randomisation
objective sample size
patients criteria analysis
procedure informed consent
measuring response record form
design administration
The Quality Assurance Cycle
Patient/Client Prep
Sample Collection
Personnel competency
Reportin Test Evaluations
g Data and Lab
Management
Safety
Customer
Service Sample Receipt
and Accessioning
Record
Keeping
Quality Control Sample Transport
Testing
35

RCT Design Fundamentals

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RCT Design Fundamentals

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01/10/2011

Case Cohort Cross

Analytical studies Descriptive

Observational Experimental Case Case

Cros Case - Quasi

HIERARKHI METODOLOGI PENELITIAN

Ia evidence dari meta analisis pada RCT

Ib evidence dari minimal 1 RCT

evidence dgn kelompok kontrol, tanpa

IIb evidence dari suatu quasi experimental

evidence dari non-

evidence dari laporan Expert

Why run an experiment?

PRINCIPLES OF RESEARCH DESIGN

Three important principles of

Principle of Principle of Principle of

PRINCIPLE OF LOCAL CONTROL

All variables are closely controlled

Patients factor Disease factor

Experimental group (EG) Control group (CG)

The group that is exposed A group not exposed to

RCT (randomized controlled clinical trial)

Investigator Clinical manouvre Participants

Quantitative Comparative Control Experiment

Measuring outcome Comparing 2 or more All variables are

TUJUAN UJI KLINIK

obat pasien populasi

Efficacy Safety Quality

RCTs according to the aspects of the interventions

Explanatory and pragmatic trials

Efficacy and effectiveness trials

Phase I, II, and III trials

RCTs according to the aspects of the interventions they evaluate

inclusion criteria sangat ketat

Explanatory highly homogeneous study groups

Memasukkan subyek dengan

pragmatic Sesuai dengan pasien yang ditemui di

RCTs according to the aspects of the interventions they evaluate

Efficacy trials effectiveness trials

Ideal setting Real setting

Semua variabel yang

TAHAP-TAHAP UJI KLINIK

Phases of Clinical Trials

Phase I: Small sample [20-

Phase II: larger group [100-

Phase III: 1,000--3,000

Done after rx/

(RCT-parallel design) (RCT cross-

(RCT factorial design)

Prospective, randomized, open, blinded-endpoint

Pengukuran endpoint bersifat obyektif

Review of Steps for RCT Design

1. Select sample from population

2. Measure baseline variables

4. Apply interventions & placebo

1. Select sample from population

Inclusion Criteria Exclusion Criteria

1. Appropriate to the study 1. Exclude patients with

Example of eligibility criteria

Clinically diagnosed as CAP

Chest--X-ray: pulmonary infiltrate or consolidation

Showing at least three of the following symptom/sign:

Example of exclusion criteria

Survival time: early treatment vs. dead

Survival time: early treatment vs. dead