Clinical Trial Uji Klinik: Abraham Simatupang

Clinical Trial
Uji Klinik
Abraham Simatupang
Dept. of Pharmacology & Therapeutics
Faculty of Medicine Universitas Kristen Indonesia
Profile
Abraham Simatupang
[email protected]
Clinical Pharmacologist
Faculty of Medicine - UKI
oMD FK UKI (1986)
oMKes. FK UGM (1993)
oDr.med. University of Bonn, (1996)
Director Acad. of Physiotherapy (2009 Director of Task Force for HIV & AIDS (20072009)
Head of Dept. of Pharmacology (2004i
n
a
y
Director of Research Center (1998-2004)
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nd
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k
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Panitia Penilaian Obat Jadi FK UI (2000an
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National Committee Ind. Drug Regulatory

(2000 -
What is Clinical
Trial?
A properly planned and
executed clinical trial is a
powerful experimental
technique for assessing
the effectiveness of an
intervention
Alexander Flemming
Types of Clinical Trials

Open trial
Non-randomized controlled trial
Randomized
controlled
trial: are
An experiment
in which subjects
randomly allocated into groups,
usually called study and control
groups, to receive or not to receive
an experimental preventive or
therapeutic procedure, maneuver, or
intervention. The results are
assessed by rigorous comparison of
rates of disease, death, recovery, or
other appropriate outcome in the
study and control groups,
Core Components of Clinical Trials

Involve human subjects
Move forward in time
Most have a comparison CONTROL
group
Must have method to measure
intervention
Focus on unknowns: effect of
medication
Must be done before medication is part
of standard of care
Conducted early NY/VI
in the
development of
AETC
Other important things

Ethical issues: Research proposal
should pass IRB or Institutional
Ethical Committee (IEC)
Informed consent
Data management & security
Statistical analysis
Sponsor finding, sponsor reporting
Publication planning
Blinding:
The basics design of RCTOne/doubl
Screenin
g,
Inclusion
&
exclusion
criteria
Sampling
Populatio
n
Study
population
e-blind
Grou
pA
Grou
pA
Interventions & measurements

Grou
pB
Grou
pB
Grou
pn
Grou
pn
Random
allocation
Cross-over design
Placebo
Placebo
Grou
pA
Study
population
Wash-out
Grou
pB
Interventions & measurements

Grou
pB
New drug
Wash-out
Grou
pA
New drug
Advantages of RCT
Allows rigorous evaluation of a single
variable (e.g. effect & AEs of drug treatment
vs placebo)
Prospective design
Uses hypotheticodeductive reasoning (seeks
to falsify, rather than to confirm, its own
hypothesis) null hypothesis
Potentially eradicate biases by comparing
two otherwise identical groups
Allows for meta analysis
Disadvantages of RCT
Expensive and time consuming
Many RCTs are either never done, are
performed on too few patients, or are
undertaken for too short a period.
Most are funded by large research
bodies dictate the research agenda
SURROGATE endpoints are often
used in preference to CLINICAL
outcome measures
Scientific Aspects of Clinical Trial
Phases of Clinical Trial

Phase I : First in man safety
Phase II : First in patient dose,
dosage form
Phase III : Efficacy, ADRs

Post marketing surveillance or
Phase IV : Evaluation in the real clinical
setting
Objectives
Phase I
1. To assess a safe & tolerated dose

2. To see if pharmacokinetics differ much from
animal to man
3. To see if kinetics show proper absorption,
bioavailability
4. To detect effects unrelated to the expected action
5. To detect any predictable toxicity
Inclusion criteria
. Healthy volunteers : Uniformity of subjects: age,
sex, nutritional status [Informed consent a must]
. Exception: Patients only for toxic drugs Eg
AntiHIV, Anticancer
Exclusion criteria
. Women of child bearing age, children,
Phase I (contd)
Methods:
First in Man : Small number of healthy
volunteers
First in a small group of 20 to 25
Start with a dose of about 1/10 to 1/5 tolerated
animal dose
Slowly increase the dose to find a safe tolerated
dose
If safe in a larger group of up to about 50 75
No blinding
Performed by clinical pharmacologists
Centre has emergency care & facility for
kinetics study
Performed in a single centre
Takes 3 6 months [ 70% success rate]
Phase II
First in patient [ different from healthy volunteer]
Early phase [20 200 patients with relevant
disease]
Therapeutic benefits & ADRs evaluated
Establish a dose range to be used in late phase
Single blind [Only patient knows] comparison with
standard drug
Late phase [ 50 500]

Double blind
Compared with a placebo or standard drug
Outcomes
Assesses efficacy against a defined therapeutic
endpoint
Detailed P.kinetic & P.dynamic data
Establishes a dose & a dosage form for future trials
Takes 6 months to 2 years [ 35% success rate]
Phase III
Large scale, Randomised, Controlled trials

Target population: 250 1000 patients
Performed by Clinicians in the hospital
Minimises errors of phases I and II
Methods
Multicentric Ensures geographic & ethnic
variations
Diff patient subgroups Eg pediatric, geriatric, renal
impaired
Randomised allocation of test drug /placebo /
standard drug
Double blinded:
Cross over design
Vigilant recording of all adverse drug reactions
Rigorous statistical evaluation of all clinical data
Takes a long time: up to 5 years [25% success]
Cross over design

GroupWeek 1 Week2 Week3
I
Standard Placebo Test
II
Placebo Test Standard
III
Test Standard Placebo
* A wash out period of a week
between two weeks of therapy
Phase IV or Post marketing

Surveillance
No fixed duration / patient
population
Starts immediately after marketing
Report all ADRs
Helps to detect
rare ADRs
Drug interactions
Also new uses for drugs [Sometimes
called Phase V]
The drug story
Pre-clinical
studies
Clinical
studies (I-III)
Registratio
n
Not-approved
Marketi
ng &
Selling
PMS (Phase
IV)
withdrawal
How to read medical articles
CONSORT
(Consolidation for Reporting Trials)
Paper section &
topic
Item
Description
TITLE & ABSTRACT
How participants were allocated to

intervention (e.g. random
allocation), ranoomised or
randomly assigned
INTRODUCTION
Background
Scientific background and

explanation of rationale
METHODS
Participants
Eligibility criteria for participants and

the settings and locations where the
data were collected
Interventions
Precise details of the interventions

intended for each group and how and
when they were actually
administered
Objectives
Specific objectives and hypotheses
Outcomes
Clearly defined primary and

secondary outcome measures and,
CONSORT (continued)
Paper section &
topic
Item
Description
Sample size
How sample size was determined

and, when applicable, explanation of
interim analyses and stopping rules
Randomization
Sequence generation
Method use to generate the random

allocation sequence , including
details of any restriction (e.g.
blocking, stratification)
Randomization
Allocation
concealment
Method used to implement the

random allocation sequence (e.g.
numbered containers or central
telephone), clarifying whether the
sequence was concealed until
interventions were assigned
Randomization
Implementation
10
Who generated the allocation

sequences, who enrolled
participants, and who assigned
participants to the groups
Blinding (masking)
11
Whether or not participants, those

administering the intervention, and
CONSORT (continued)
Paper section &
topic
Statistical methods
Item
Description
12
Statistical methods used to compare

groups for primary outcomes;
Methods for additional analyses,
such as subgroup analyses and
adjusted analyses
Participant flow
13
Flow of participants through each

stage (a diagram is strongly
recommended). Specifically, for each
group report the numbers of
participants randomly assigned,
receiving intended treatment,
completing the study protocol, and
analysed for the primary outcome.
Describe protocol deviations from
study as planned, together with
reasons.
Recruitment
14
Dates defining the periods of
RESULTS
CONSORT (continued)
Paper section &
topic
Item
Description
Numbers analysed
16
Number of participants
(denominator) in each group
included in each analysis and
whether the analysis was by
intention to treat. State the results
in absolute numbers when feasible
(e.g. 10/20, not 50%)
Outcomes and
estimations
17
For each primary and secondary

outcome, a summary of results for
each group, and the estimated effect
size and its precision (e.g. 95%
confidence interval)
Ancillary analyses
18
Address multiplicity by reporting any

other analyses performed, including
sub group analyses and adjusted
analyses, indicating those prespecified and those exploratory
Adverse events
19
All important adverse events or side
CONSORT (continued)
Paper section &
topic
Item
Description
DISCUSSION
Interpretation
20
Interpretation of the results, taking

into account study hypotheses,
sources of potential bias or
imprecision and the dangers
associated with multiplicity of
analyses and outcomes.
Generalizability
21
Generalizability (external validity) of

the trial findings
Overall evidence
22
General interpretation of the results

in the context of current evidence
e A, Sabin C. Medical statistics at a glance. 2012. Wiley-Blackwell, West Sussex,
Sy power in
The pyramid of
ste
Evidence Basema
Medicine (EBM)
tic
rev
ie
w/
me
ta
an
aly
sis
Cohort studies
RCTs
Case series
Case reports
Editorials & Opinions
Lab studies & Animal research
Level of Evidence
Level I: Evidence obtained from at least one properly
designed randomized controlled trial.
Level II-1: Evidence obtained from well-designed controlled
trials without randomization.
Level II-2: Evidence obtained from well-designed cohort or
case-control analytic studies, preferably from more than one
center or research group.
Level II-3: Evidence obtained from multiple time series with
or without the intervention. Dramatic results in uncontrolled
trials might also be regarded as this type of evidence.
Level III: Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.

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Clinical Trial

National Committee Ind. Drug Regulatory

Types of Clinical Trials

Core Components of Clinical Trials

Other important things

Interventions & measurements

Interventions & measurements

Scientific Aspects of Clinical Trial

Phases of Clinical Trial

Phase III : Efficacy, ADRs

1. To assess a safe & tolerated dose

Late phase [ 50 500]

Takes 6 months to 2 years [ 35% success rate]

Large scale, Randomised, Controlled trials

Takes a long time: up to 5 years [25% success]

Cross over design

Phase IV or Post marketing

The drug story

How to read medical articles

TITLE & ABSTRACT

How participants were allocated to

Scientific background and

Eligibility criteria for participants and

Precise details of the interventions

Specific objectives and hypotheses

Clearly defined primary and

How sample size was determined

Method use to generate the random

Method used to implement the

Who generated the allocation

Whether or not participants, those

Statistical methods used to compare

Flow of participants through each

Dates defining the periods of

For each primary and secondary

Address multiplicity by reporting any

All important adverse events or side

Interpretation of the results, taking

Generalizability (external validity) of

General interpretation of the results

e A, Sabin C. Medical statistics at a glance. 2012. Wiley-Blackwell, West Sussex,

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