Uji Klinis Protocol

8/13/2019 Uji Klinis Protocol

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CLINICAL

PROTOCOL

DEVELOPMENT


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Whats The Question?

What is the study hypothesis?


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Whats The Question?

Whats the outcome?

Whats the intervention?

When and for how long?

For whom?

How many participants are needed?

How can we optimize potentialbenefit (and what we learn) while

minimizing potential harm?


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Answering the Question

Response variable selection andmeasurement

Defining the intervention

Study design Eligibility criteria

Sample size estimate

Patient management procedures

Monitoring for safety and benefit

Data analysis approaches


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Response Variable Selection

Dose ranging

Biologic activity

Biomarker

Understand mechanism Surrogate outcome

Toxicity

Condition/vector/gene interaction

Feasibility for larger study

Clinical outcome


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Response Variable Criteria

Well defined

Stable

Reproducible

Unbiased

Ascertainable in all participants Adequately address study

hypothesis


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Defining the Intervention

Dose/dosing schedule

Vector

Route of delivery

Method of preparation


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Study Design

Uncontrolled

Controlled

Before/after

Historical

Concurrent, not randomized

Randomized


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Comparing Treatments

Fundamental principle Groups must be alike in all important aspects and only differ

in the intervention each group receives

In practical terms, comparable treatment groups means

alike on the average

Randomization Each participant has the same chance of receiving any of the

interventions under study

Allocation is carried out using a chance mechanism so that

neither the participant nor the investigator will know in

advance which will be assigned

Blinding

Avoidance of conscious or subconscious influence

Fair evaluation of outcomes


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Non-randomized Trials

May Be Appropriate

Early studies of new and untried therapies

Uncontrolled early phase studies where

the standard is relatively ineffective

Investigations which cannot be done

within the current climate of controversy(no clinical equipoise)

Truly dramatic response


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Advantages of Randomized

Control Clinical Trial

1. Randomization "tends" to produce

comparable groups

2. Randomization produces valid statistical

tests


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Disadvantages of

Randomized Control Clinical Trial1. Generalizable Results?

Participants studied may not represent

general study population.

2. Recruitment

Hard

3. Acceptability of Randomization Process

Some physicians will refuse

Some participants will refuse

4. Administrative Complexity


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Study Population

Subset of the general population determined

by the eligibility criteria

General population

Eligibility criteria

Study population

Enrollment

Study sample

Observed


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Eligibility Criteria

State in advance

Consider

Potential for effect of intervention

Ability to detect that effect

Safety

Ability for true informed consent


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Sample Size (1)

The study is an experiment in people

Need enough participants to answer

the question

Should not enroll more than needed

to answer the question

Sample size is an estimate, using

guidelines and assumptions


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Sample Size (2)

Approaches for early phase studies

Dose escalation schemes

Decision that intervention is unlikely tobe effective in x% of participants

Decision that intervention could be

effective in x% of participants Standard ways of estimating for

phase III


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Sample Size (3)

Assumptions depend on

Nature of condition

Desired precision of answer

Availability of alternative treatments

Knowledge of intervention being

studied Availability of participants


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Regular Follow-up

Routine Procedures (report forms)

Interviews

Examinations

Laboratory Tests

Adverse Event Detection/Reporting

Quality Assurance


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Contingency Plans

Patient management

Evaluation and reporting to all

relevant persons and groups

Data monitoring plans

Protocol amendment or study

termination


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Data Analysis (1)

Occurrence of event

Time to event

Mean level of response

Duration of response


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Data Analysis (2)

Intention-to-treat

Explanatory

Subgroups

Adjusted vs. Unadjusted


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Data Analysis (3)

Specify in advance

Primary

Secondary

Other

Statistical approach

Exploratory


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Summary

Protocol lays out who, what, why,

when, where, how

Safeguards participants

Safeguards study integrity

Midcourse changes are often

appropriate (even necessary)

Documents

Uji Klinis Protocol