Curriculum

Curriculum Vitae
Vitae
• Name: Joewono Soeroso, MD, MSc PhD, Internist-
Rheumatologist-Clinical Epidemiologist
• DOB : Purwokerto 1 July 1950
• Educations:
– MD: Diponegoro University 1977
– Internist: Airlangga Unversity 1986
– MSc (Clinical-Epidemiologi & Evidence Based
Medicine): College of Medicine Univ. of The
Philippines Manila 1995
– Rheumatologist: 1999
– HLA analysis: Fred Hutchinson Research Center,
Seattle 2002
– PhD: Airlangga Unversity 2004
– GB Airlangga Univ 2014
• Teaching Saff at FK Unair 1991- now
 CLINICAL TRIALS
HIGHLIGHTS
Joewono Soeroso
Faculty of Medicine-Airlangga University-Dr Soetomo Hospital
joewono.soeroso4@gmail.com
 Clinical Research

Biologic Early Diagnosis Diagnosis

End Points
Onset (Subclinical Disease)(Clinical Disease) • Cured
• Complications
* + Dx
• Disabled
Diagnostic Prognostic • Died
Risk Factor
Screening Test Factor
(Causation)
Clinical Trial: Diagnostic
Clinical Trial: Therapy Test
Primary Prevention
 Introduction
Randomized Clinical Trial (RCT)
• “or” randomized controlled trial
• Compares the effect, safety and value of an
intervention against a control
• Usually in human subjects
• True experimental study
• Randomisation is the important issue
• “Gold Standard” of clinical study
• Many ethical ptoblems in RCT: should
follows GCP
 Strength an Weakness of RCT
Strength
• Randomisation, inclusion, and exclusion may control
confoundings
• Confoundings can also be minimized through multivariate
analysis at the end of the study

Weakness
• Tight controls on the study process may unmeet to the
target population
• True efficacy may be different with the true effectiveness
in the target population (i.e in the community)
 15 hari

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Salep tetrasiklin
20 Pasien
ULKUS TANPA RANDOMISASI p= > 0.05
PEDIS
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Sembuh

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 15 hari

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Salep tetrasiklin
20 Pasien
ULKUS TANPA RANDOMISASI p= > 0.05
PEDIS
Salep Plasebo

Sembuh

Tidak Sembuh

DM & Tidak Sembuh

 15 hari

`
Salep tetrasiklin
20 Pasien
p= < 0.05
ULKUS RANDOMISATION
PEDIS
Salep Plasebo

Sembuh

Tidak Sembuh
DM & Tidak Sembuh
 Intervention Modalities
• The term ’Clinical’ refers to the setting of the
study, e.g inpatients or ambulatory patients at
hospital or private practice

• Drugs, vaccinces, environment or lifestyle

modification

• Physical, mechanical or chemical methods to

modify human tissues
 Outcomes of RCT
• Efficacy
Clinical cure/improvement, decreased complications,
decreased disease activities, decreased death rates, etc
• Safety
• Survival
• Costs (Cost effectiveness, utility, benefits)
• Can be used also for screening trials
Components of Clinical Trials

• Reviews of existing scientific data & to build on

that knowledge
• Test a certain hypothesis
• Study protocol must be built on sound & ethically
• Control for any potential biases
• Good document practice
IMPROVEMENT
16
TREATMENT
14 PLACEBO
HAWTHORNE
12 NATURAL HISTORY
10

Kesembuhan suatu penyakit adalah total dari penyembuhan

spontan, respons non spesifik dan efek terapi. Efek hawthorne yaitu
subyek merasa lebih baik karena adanya perhatian, perlakuan dari
peneliti10
 Summary of Phases I-IV
# Subjects Length Purpose Design % Drugs
Successfully
Tested
Phase I 20 – 100 Several Mainly Safety, RCT 70%
months
Phase II Up to 100s Months - Short safety; RCT 33%
2 yrs. dosage, efficacy
Phase III 100s – 1-4 yrs. Safety & RCT 25-80%
1000s efficacy

Phase IV 1000s Varied Safety, Observa varied

effectiveness tional
Ethical Norms of Clinical Trials
Sound study designs take into account:
• Randomization or sharing of risks
• Proper use of placebo
• Processes to monitor safety of rx/tx
• Competent investigators
• Informed consent
• Equitable selection of participants
• Compensation for study related injuries
NY/VI AETC
Treatment
Placebo
Hawthorne Effect
Natural History of the disease
The Impact of Studies
Other clinical trials have not been as
successful for a variety of reasons:
• Medications did not work as in laboratory
• Loss to Follow-Up of too many patients
• Harmful substance
• Unethical & poorly conducted study (Ex:
Tuskegee Study & recent Gene Replacement
Study)
 EBM Revisited
The Hierarchy of Study Designs
Stronger 1. Mega trial
2. Meta-analysis
3. Randomized Clinical Trial (RCT)
4. Cohort
5. Case-control
6. Cross-sectional
7. Case-series
8. Expert-Opinion
Weaker
 EBM Revisited
What are in the real world?

• Haynes (An Intern Med 1986; 309 :105) ; 800 research

articles in 4 famous journals  valid only 19%

• Reid (JAMA 1995; 274: 651 ) ; 1300 research

articles on accuracy of diagnostic tools from urine
dipstick to MRI and CT scan  valid only 6%
• Cohrane Collaboration (1996): out of 16,000 studies on tx of mild
hypertension valid only 22 studies
 EBM Revisited
Publication Bias

Is The New Antibiotic for Typhoid Fever effficacious?

Cured Not cured

 EBM Revisited
Publication Bias
Studies
1 2 3 4 5 6

Good results published Poor resultsnever published

Agency for Health Research Quality

(AHRQ)
Predicted though meta analysis by Funnel Plots
 48% medical research
were not published
Steps in Developing Protocol
Making a Research Question

– Literature studies regarding: the

intervention, research methods,
research development and
management etc
 Preparing RCT
Refreshment
Avoid bias
• Bias is a systematic error that leads to flawed
results
• Can be a consequence of study designs
 Preparing RCT
Refreshment
Type of Bias
• Sampling Bias
– Violation inclusion and exclusion citeria
– Misclassification of disease.
• Observation Bias
– Inaccurate measurements and observation
• Confounding Bias
 Valid – Not valid – Not valid –
and precise But Precise Not precise
 Study Participant Recruitment
• Identify eligible Participants should be told:
participants • May have side effects
• Explain study (adverse effects)
• Provide informed • Time commitment
consent • Benefits & risks
• Re-assess eligibility • May withdraw at any
• Assign to one group time
• Enrollment 100%
voluntary
 Taking Part in Research Studies:
Questions to Ask
• What is study about? • Is there an incentive?
• What are the goals? • How protected from harm?
• Study sponsor? • What is required: # study visit
• Participant input into & what occurs?
protocols? • What happens after study is
• Inclusion criteria? over?
• Benefits & risks • How results will be
disseminated?
 Steps in Developing Protocol
Making a Research Question

• P: population
• I: Intervention
• C: Comparator(s)
• O: Outcome(s)

Among adult population with RA (P), is tocilizumab

plus methhotrexate (I) more efficacious and safe
compared to methotrexate alone ( C) to reduce
disease activity (O)?
 Steps in Developing Protocol
Planning of Measurements and Observations

– Accuracy and precison

• Diagnostic criteria,
• imaging, laboratory exam
– Interobserver agreement
• Tools for data recording and monitoring
– Questionnaires, forms
– Must be validated first
Steps in Developing Protocol
Sampling
– Identification of target population
• Inclusion
– Pts with RA classified by ACR-EULAR 2010
– Age 16-60 yo
– Not pregnant etc
– Identification of target population
• Greographical,social
– Stay in East Java
– Occupation
Sensitivity 79%, spesificity 93%
04/16/2020
04/16/2020
04/16/2020
 The Concept of Population

External
External population
validity

Internal Target population

validity

statistical Actual population

inference

Sample

Kleinbaum, Kupper, Morgenstern 1982

 Sampling
Sample size of comparing two proportions
•  
 Designing
Step 1.Select subjects through inclusion and
exclusion criteria
Step 2. Random Allocation
Step 3. Assess base line data
Step 4. Follow up and monitoring.
Step 5. Assess outcomes
Step 6. Analysis
 
 The Statistical Analysis
• The outcomes of evidence o RCT based
must be:
– Cured or not cured
– Decrease of complications
– Decrease of death rate
– Increased of survival (Hazard Ratios)
Therefore the statistic supposed to be binomials
or proporton (Chi-square, Hazards’ ratio)

NY/VI AETC
The Design
 Proporsi    
Kematian NNT

Plasebo Obat RRR ARR 1/ARR = NNT

P X (P-X)

 0.22   0.08 64%  0.14 1/0.14 = 7

 Critical Appraisal for Therapy
as a Guide in Conducting RCT
Was the assignment really
randomized?
Were clinically important outcomes
assesses objectively?
Were their at least 80% follow up of
subjects
Was the treatment feasible to your
practice?
Were both statistical and clinical
significant considered? (RRR,
NNT,NNH, LHH) NY/VI AETC
Ethical Issues:
Protection of Human Subjects
• Rely on integrity of Investigator but outside groups also
have oversight
• Participants’ rights protected by Institutional Review
Boards [IRBs]

o An IRB is defined as: "any board, committee or other

group formally designated by an institution to review,
to approve the initiation of, and to conduct periodic
review of biomedical research involving human
subjects"
Human Subjects’ Protection
IRB responsible for such tasks:
• Review research to ensure that potential benefits
outweigh risks
• Develop and issue written procedures
• Review research for risk/benefit analysis & proper
protection of subjects
• Issue written notice of approval/disapproval to the
Investigator
• Review and respond to proposed protocol changes
submitted by the Investigator
Ethics of Clinical Trials:
Protection of Participants
3 ethical principles guide clinical research:
• Respect for Persons: Treatment of person as
autonomous
• Beneficence: Issue re: potential conflict between
good of society vs. individual
• Justice: Treatment of all fairly & all equally share
benefits & risks
Ethical Norms of Clinical Trials
Sound study designs take into account:
• Equitable selection of participants
• Informed consent
• Randomization or sharing of risks
• Proper use of placebo
• Processes to monitor safety of rx/tx
• Competent investigators
• Compensation for study related injuries
 Conclusions
• Clinical trials often yield important results that affect
health and well being
• The design must be robust in terms of validity as
well as precision
• Must follow guidelines & protocol
• Must ensure well-being of participant
• Clinical trials are susceptible to human error either
on part of investigator or patient
• Must follow GCP
THANK YOU
 Finding in
Phenomena
The universe
of interest
 RANDOMISASI
Angka Random
• Terapi A • 20127 50294
• = 01234 12909 25063
• Terapi B 62043 77661
57366 18250
• = 56789
09041 10109
06905 16518
NY/VI AETC
Perspect Clin Res. 2011 Apr-
Jun; 2(2): 59–63.
doi: 
10.4103/2229-3485.80368
PMCID: PMC3121265
Good documentation practice
in clinical research
Chitra Bargaje