methodologi clinical trial

7/22/2019 Methodologi Clinical Trial

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Clinical Study: Designand Methods

Hail M. Al-Abdely, MD

Consultant, Infectious Diseases

King Faisal Specialist Hospital & ResearchCentre


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Systematic investigation towards increasing the sum of

knowledge

(Chambers 20th Century Dictionary)

an endeavour to discover new or collate old facts etc.

by the scientific study of a subject or by a course ofcritical investigation.

(The Concise Oxford Dictionary)

Definitions of Research


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Where to Start?

A good clinical study starts with

a good questionbased ongood hypothesisthat is based ongood and comprehensive reviewof the available evidence

from pre-clinical and clinical data

Type of design depends on the question to beanswered


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Formulating a Research Question

Focused and specific What is the prevalence of Hepatitis B surface Antigen in Saudi Arabia?

Cross-sectional study

What are the risk factors for hepatitis B infection? Prospective cohort or case-control

Is interferon a useful therapy for hepatitis B infection? Therapeutic clinical trial Supported by available data

Is vancomycin better than ceftazidime against gram negative organisms?

Not a replication of already established evidence Is smoking associated with lung cancer?

Ethical Answerable

Methods, resources .etc


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Objectives

Specific aims

Clear and detailed

End point(s) Primary

The main answer to the research question

Secondary

Answer other related questions


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Study Design

Your question

Describe

Analyze

Your resources Retrospective

Prospective

Community Acceptance of research

Observational

Interventional


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Clinical Study Types

Observational Studies Cohort (Incidence, Longitudinal)

Case-Control Cross-Sectional (Prevalence)

Case Series

Case Report

Experimental Studies Uncontrolled Trials

Controlled Trials


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Level I: N of 1 randomized trial (double-blinded, cross-over)

Level I (A): Systematic reviews of randomized trials

Level I (B): Single randomized trialLevel II (A): Systematic review of observational studies addressing

patient-important outcome

Level II (B): Single observational study addressing important outcome

Level III: Physiologic studies

Level IV: Unsystematic clinical observations (case-reports, anecdotal)

Levels of Evidence

Hierarchy of Strength of Evidence for Treatment Decisions

JAMA 2000; 284(10):1290-96


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Observational study Clinical trial

exposed

non exposed

outcome

Clinical

Trial

observational

studydescribe as

occurring in nature

allocate

randomlyEthics!


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Important issues in Study Design

Validity: Truth

External Validity:

Can the study be generalized to the population

Internal Validity:

Results will not be due to chance, bias or confounding factors

Symmetry Principle: Groups are similar


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Confounding:distortion of the effect of one risk factor by the presence ofanother

Bias:Any effect from design, execution, & interpretation that shifts orinfluences results

Confounding bias:failure to account for the effect of one or morevariables that are not distributed equally

Measurement bias:measurement methods differ between groups

Sampling (selection) bias:design and execution errors insampling

Important issues in Study Design


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IntroductionWhy this study is needed ?

What is the purpose of this study?

Was purpose known before the study?

What has been done before and how does this

study differ?

inadequacies of earlier work or next step in an

overall research project

Does the location of the study have relevance?


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Why doing a study?

Alternative:

census: test every individual in the population

use available data, e.g. hospitalsBut:

- data availability

- data quality

- cost

- questions require specific type of data and

circumstances


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Types of observational studies

CROSS - SECTIONAL STUDY

COHORT STUDY

CASE CONTROL STUDY

CASE SERIES/CASE REPORTS


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Characteristics of observational studies

No control over study units

need to clearly describe study individuals

Can study risk factors that have serious consequences Study individuals in their natural environment (>>

extrapolation)

Possibility of confounding


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Aims of observational studies

Evaluate the effect of a suspected

risk factor (exposure) on an outcome

(e.g. disease)

define exposure and disease

Describe the impact of the risk factor

on the frequency of disease in a

population


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Cross - Sectional Study


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Cross - Sectional Study (1)

Exposure and disease measured once, i.e. at the samepoint in time

present futurepast

n

exposed ?

diseased ?


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Random sample from population

i.e. results reflect reference population

Estimates the frequencies of both exposure and

outcome in the population Measuring both exposure and outcome at one point

in time

Typically a survey


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Can study several exposure factors and outcomessimultaneously

Determines disease prevalence

Helpful in public health administration & planning Quick

Low cost (e.g. mail survey)

Limitation: Does not determine causal relationship

Not appropriate if either exposure or outcome is rare


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Cross-Sectional: Risk Factors for Smoking

Variable OR 95% CI

No. friends who smoke:

- all vs. none of them

- most vs. none of them-about half vs. none of them

-a few vs. none of them

36.5

18.47.5

2.1

9.3142.8

5.561.82.226.0

0.67.9

Any siblings who smoke: Y vs. N 2.8 1.84.3

Mother smokes:

Yes vs. No

Have no mother vs No

1.9

3.5

1.32.9

0.815.0


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Cohort Studies


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Cohort studies

Follow-up studies; subjects selected on presence orabsence of exposure & absence of disease at onepoint in time. Disease is then assessed for allsubjects

at another point in time.

Typically prospective but can be retrospective,depending on temporal relationship between studyinitiation & occurrence of disease.


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Cohort Study (1)

Individuals selected by exposure status and futureoccurrence of disease measured

present futurepast

n

Exposed yesno

disease ?disease ?

n

Exposed yesno

disease ?disease ?


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Cohort studies (2)

More clearly established temporal sequencebetween exposure & disease

Allows direct measurement of incidence

Examines multiple effects of a single exposure(nurses health study, OC and breast, ovarioan

cancers)


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Cohort studies (3)

Limitations:

time consuming and expensive

loss to follow-up & unavailability of data potential confounding factors

inefficient for rare diseases


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Prospective Cohort Study

without

outcome

Cohort

with outcome

with outcome

without

outcome

Exposed

Unexposed

TimeOnset

of study Direction of inquiry

Q: What will happen?


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Prospective Cohort Study

Appropriate for frequent disease

Can examine only few risk factors

Usually expensive

RR = relative risk = incidence rate ratio

AR = incidence difference


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Case-Control Studies


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Case-Control Study (1)

Retrospective Can use hospital or health register data

First identify cases

Then identify suitable controls Hardest part: who is suitable ??

Then inquire or retrieve previous exposure

By interview By databases (e.g. hospital, health insurance)


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Diseased and non-diseased individuals are selectedfirst

Then past exposure status is retrieved

present futurepast

n

yes

nodisease

exposed ?

exposed ?


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Good for rare disease (e.g. cancer)

Can study many risk factors at the same time

Usually low cost Confounding likely

OR (not RR !!)


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Case-Control Study Design

Cases

Controls

Exposed

Unexposed

Exposed

Unexposed

TimeDatacollection

Direction of inquiry

Q: What happened?


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Study subjects selected on basis of whetherthey have (case) or do not have (control) adisease

Useful for disease with long latency period Efficient in terms of time & costs

Particularly suited for rare diseases

Examines multiple exposures to a singledisease

Case-Control study (4)


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Case-control study (5)

Limitations:

(1) susceptible to bias (particularly selection &recall)

(2) difficulties in selection of controls

(3) ascertainment of disease & exposure status

(4) inefficient for rare exposures unlessattributable risk is high


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Case Selection

Define source population

Cases

incident/prevalentdiagnostic criteria (sensitivity + specificity)

Controls

selected from same population as casesselect independent of exposure status


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Control Selection

Random selection from source population

Hospital based controls:

convenient selectioncontrols from variety of diagnostic groups other

than case diagnosis

avoid selection of diagnoses related toparticular risk factors

limit number of diagnoses in individuals


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Characteristic Cross -

Sectional

Case Control Cohort

Sampling Random sample:

population

Purposive sample:

diseased/non-diseased

Purposive sample:

Exposed/non-exposed

Time One point Retrospective Prospective

Causality Statistical

association

Screening for

many risk factors

Testing one (or

few) risk factors

Frequencymeasure Prevalence None Incidence

Risk

parameter

Prevalence (risk)ratio, odds ratio

Odds ratio Relative risk, oddsratio

Summary of Observational Studies


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Clinical Trials


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Clinical Trials Drug Development

Basic

ResearchNovel

Compounds

SafetyTesting

Drug

Licensing

& Release

In-Vitro

ScreeningIsolated cells

& tissues

In-Vivo

ScreeningInAnimals

ClinicalTrials I - III

In Humans


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Clinical trials in drug development(Any alternatives)

In-Vitro Tests CanShow Whether:

A compound has the desired effect on isolated cells ortissues

There are adverse effects on those tissues

In-Vitro Tests CannotShow Whether:

The desired effect will occur in a complete living system

There will be any adverse effects in a complete living system


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Animal Tests Can:

Suggest which drugs are likely to be effective inhumans

Indicate which drugs may not be harmful in humans

Animal Tests Cannot:

Predict with absolute certainty what will happen in

humans

Clinical trials in drug development(Any alternatives)


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Clinical trial vs. Cross-sectional

Clinical trial: Individuals selected by

entry condition

Control over exposure

Exposure groups fullycomparable

Outcome measured afterallocating individuals to

exposure Therefore: causal

association likely

Cross Sectional Study: Individuals selected

randomly

Exposure observed as

occurring in nature (groupsnot identical)

Exposure AND outcomemeasured at one point in

time No causal interpretation


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Clinical Trials-Phases Phase I - Does it hurt the Patient?

Usually in normal volunteers, small groups for safety testing

Phase II - Does it help the Patient? On patients to confirm the effectiveness of the drug

Phase III - Is it any better? Large groups of patients for statistical confirmation of effect

and incidence of side-effects

Phase IV - Does it work in the community? Post marketing studies. Fine tuning and new rare findings from a

very large population


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Clinical Trial: Study Design

Uncontrolled

Controlled

Before/after (cross-over)

Historical

Concurrent, not randomized

Randomized


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Non-randomized TrialsMay Be Appropriate

Early studies of new and untried therapies

Uncontrolled early phase studies where thestandard is relatively ineffective

Investigations which cannot be done within the

current climate of controversy

Truly dramatic response


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Advantages of Randomized

Control Clinical Trial

1. Randomization "tends" to produce comparable groups

2. Assure causal relationship

3. Randomization produces valid statistical tests

Di d f


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Disadvantages of

Randomized Control Clinical Trial

1. Generalizable Results?

Participants studied may not represent generalstudy population.

2. Recruitment

Hard

3. Acceptability of Randomization Process

Some physicians will refuse Some participants will refuse

4. Administrative Complexity


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Clinical Protocol (1)

Background/Justification--Where we are in the field

--What the study will add that is important

Objectives--Primary hypothesis

--Secondary hypotheses

--Other

Study Population


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Study Population

Subset of the general population determined by the

eligibility criteria

General population

Eligibility criteria

Study population

Enrollment

Study sampleObserved


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Clinical Protocol (2)

Study Design and Methods

Type of study, comparison

Inclusion and exclusion criteria

Description of intervention (what, how) Concomitant therapy

Examination procedures (baseline, follow-up, outcomeassessment)

Intervention assignment procedure Data collection sheet

Informed consent

Eli ibilit C it i


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Eligibility Criteria(inclusion & exclusion)

State in advance

Consider

Potential for effect of intervention

Ability to detect that effect

Safety

Ability for informed consent

M h d O li (1)


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Method Outlines (1)

The independent (predictor) and dependent (outcome)variables in the study should be clearly identified, defined,and Measured?

How to choose subjects?

Random or not

Are they going to be representative of the population?

Random selection is not random assignment

Types of Blinding (Masking) Single, Double, Triple.

Control group? How is it chosen?

How are patients followed up? Who are the dropouts? How is the data quality insured? Reliability?

Consider independent review of data? Compliance?


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Methods outlines (2)

Reference any unusual methods?

Statistical methods specified in sufficient

details

Is there a statement about sample size issues or

statistical power?

? multicenter study. Quality assurance

measures should be employed to obtain

consistency across sites?


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Comparing Treatments Fundamental principle

Groups must be alike in all important aspects and only differ in theintervention 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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Monitoring and Management

--Data and safety monitoring

--Adverse event assessment, reporting

--Contingency procedures

--Withdrawal criteria



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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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Compliance/adherence

Pill counts and computers

Diaries

Biological tests

Lipid lowering drugs after myocardial


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Lipid lowering drugs after myocardial

infarction

Mortality

clofibrate 18.2%

placebo 19.4%

ClofibrateAdherence

80 < 80%

18.2% 15.0% 24.6%

Overall

Clofibrate


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Statistics

--Sample size

--Stopping guidelines

--Analysis plans

Participant protection issues



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Sample Size

The study is an experiment in people

Need enough participants to answer thequestion

Should not enroll more than needed to answerthe question

Sample size is an estimate, using guidelines andassumptions


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Contingency Plans

Patient management

Evaluation and reporting to all relevant personsand groups

Data monitoring plans

Protocol amendment or study termination


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Human Subjects Protection

Institutional Review Board

Informed consent

Different levels of risk

Confidentiality as well as risk of new tx

Patient can refuse to participate w/o effect

Path to exit study known Compensation


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Summary

Selection of design should be made on the basis of theparticular hypothesis to be tested with consideration ofcurrent state of knowledge

Consider available resources when deciding on a study

design A clear and organized study design leads to successful

results Observational studies are especially valuable in

epidemiology Clinical trials carry the highest level of evidence and

should be pursued whenever feasible

methodologi clinical trial

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