Clinical Study: Design and Methods

Hail M. Al-Abdely, MD Consultant, Infectious Diseases King Faisal Specialist Hospital & Research Centre
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Definitions of Research
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 of critical investigation.
(The Concise Oxford Dictionary)
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Where to Start?

A good clinical study starts with

a good question based on good hypothesis that is based on good and comprehensive review of the available evidence from pre-clinical and clinical data

Type of design depends on the question to be answered

Formulating a Research Question

Focused and specific

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

Cross-sectional study control

What are the risk factors for hepatitis B infection? Prospective cohort or caseIs interferon a useful therapy for hepatitis B infection? Therapeutic clinical trial Is vancomycin better than ceftazidime against gram negative organisms? Is smoking associated with lung cancer?

Supported by available data

Not a replication of already established evidence

Ethical Answerable

Methods, resources .etc

Objectives

Specific aims

Clear and detailed

Primary

End point(s)

The main answer to the research question Answer other related questions

Secondary

Study Design

Your question

Describe Analyze Retrospective Prospective Acceptance of research

Your resources

Community

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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Levels of Evidence
Hierarchy of Strength of Evidence for Treatment Decisions
Level I: Level I (A): Level I (B): Level II (A): Level II (B): Level III: Level IV: N of 1 randomized trial (double-blinded, cross-over) Systematic reviews of randomized trials Single randomized trial Systematic review of observational studies addressing patient-important outcome Single observational study addressing important outcome Physiologic studies Unsystematic clinical observations (case-reports, anecdotal)

JAMA 2000; 284(10):1290-96

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Observational study Clinical trial

observational study

describe as occurring in nature

exposed

outcome
allocate randomly non exposed

Clinical Trial

Ethics!

Important issues in Study Design

Validity: Truth

External Validity:

Can the study be generalized to the population Results will not be due to chance, bias or confounding factors

Internal Validity:

Symmetry Principle: Groups are similar

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Important issues in Study Design

Confounding: distortion of the effect of one risk factor by the presence of another Bias: Any effect from design, execution, & interpretation that shifts or influences results

Confounding bias: failure to account for the effect of one or more variables that are not distributed equally Measurement bias: measurement methods differ between groups Sampling (selection) bias: design and execution errors in sampling

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Introduction
Why 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. hospitals But: - 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 same point in time n

exposed ? diseased ? past present future

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Cross - Sectional Study (2)

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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Cross - Sectional Study (3)

Can study several exposure factors and outcomes simultaneously 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 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 Any siblings who smoke: Y vs. N Mother smokes: Yes vs. No Have no mother vs No OR 36.5 18.4 7.5 2.1 2.8 1.9 3.5 95% CI 9.3 142.8 5.5 61.8 2.2 26.0 0.6 7.9 1.8 4.3 1.3 2.9 0.8 15.0
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Cohort Studies

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Cohort studies

Follow-up studies; subjects selected on presence or absence of exposure & absence of disease at one point in time. Disease is then assessed for all subjects at another point in time. Typically prospective but can be retrospective, depending on temporal relationship between study initiation & occurrence of disease.

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Cohort Study (1)

Individuals selected by exposure status and future occurrence of disease measured

n
yes no

n
disease ? yes Exposed disease ? no disease ? disease ?

Exposed

past

present

future
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Cohort studies (2)

More clearly established temporal sequence between 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

with outcome Exposed Cohort with outcome Unexposed without outcome without outcome

Onset of study

Time
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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Case-Control Study (2)

Diseased and non-diseased individuals are selected first Then past exposure status is retrieved
n

exposed ? exposed ?
past

yes disease no present

future
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Case-Control Study (3)

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

Exposed Unexposed Exposed Controls Unexposed Data collection
Direction of inquiry

Cases

Time

Q: What happened?
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Case-Control study (4)

Study subjects selected on basis of whether they have (case) or do not have (control) a disease Useful for disease with long latency period Efficient in terms of time & costs Particularly suited for rare diseases Examines multiple exposures to a single disease
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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 unless attributable risk is high

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Case Selection
Define source population Cases
incident/prevalent diagnostic criteria (sensitivity + specificity)

Controls
selected from same population as cases select independent of exposure status

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Control Selection
Random selection from source population Hospital based controls:
convenient selection controls from variety of diagnostic groups other than case diagnosis avoid selection of diagnoses related to particular risk factors limit number of diagnoses in individuals
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Summary of Observational Studies

Characteristic Cross Sectional Case Control Cohort

Sampling

Time Causality Frequency measure Risk parameter

Random sample: Purposive sample: population diseased/nondiseased One point Retrospective Statistical Screening for association many risk factors Prevalence None Prevalence (risk) Odds ratio ratio, odds ratio

Purposive sample: Exposed/nonexposed Prospective Testing one (or few) risk factors Incidence Relative risk, odds ratio
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Clinical Trials

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Clinical Trials Drug Development

Basic Research

Novel Compounds

In-Vitro Screening
Isolated cells & tissues

In-Vivo Screening

In Animals

Drug Licensing & Release

Clinical Trials I - III In Humans

Safety Testing

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Clinical trials in drug development

(Any alternatives) In-Vitro Tests Can Show Whether:
A compound has the desired effect on isolated cells or tissues
There are adverse effects on those tissues

In-Vitro Tests Cannot Show 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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Clinical trials in drug development

(Any alternatives)

Animal Tests Can:

Suggest which drugs are likely to be effective in humans Indicate which drugs may not be harmful in humans

Animal Tests Cannot:

Predict with absolute certainty what will happen in humans

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Clinical trial vs. Cross-sectional

Clinical trial:

Cross Sectional Study:

Individuals selected by entry condition Control over exposure Exposure groups fully comparable Outcome measured after allocating individuals to exposure Therefore: causal association likely

Individuals selected randomly Exposure observed as occurring in nature (groups not identical) Exposure AND outcome measured 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 On patients to confirm the effectiveness of the drug Large groups of patients for statistical confirmation of effect and incidence of side-effects Post marketing studies. Fine tuning and new rare findings from a very large population
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Phase II - Does it help the Patient?

Phase III - Is it any better?

Phase IV - Does it work in the community?

Clinical Trial: Study Design

Uncontrolled Controlled
Before/after (cross-over) Historical Concurrent, not randomized Randomized

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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 Truly dramatic response
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Advantages of Randomized Control Clinical Trial

1.

Randomization "tends" to produce comparable groups Assure causal relationship Randomization produces valid statistical tests

2.

3.

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Disadvantages of Randomized Control Clinical Trial

1. 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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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

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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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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, outcome assessment) Intervention assignment procedure Data collection sheet Informed consent
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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

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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 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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Methods outlines (3)

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

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Lipid lowering drugs after myocardial infarction

Mortality

clofibrate
placebo
Overall Clofibrate 18.2%

18.2%
19.4%
Clofibrate Adherence 80 15.0% < 80% 24.6%

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Methods outlines (4)

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 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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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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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 the particular hypothesis to be tested with consideration of current 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
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