What is a Clinical TrialWhat is a Clinical Trial(alpha version)(alpha version)

John M. Harris Jr., MDJohn M. Harris Jr., MD

PresidentPresident

Medical Directions, Inc.Medical Directions, Inc.

Learning ObjectivesLearning Objectives

The US Government’s definition of The US Government’s definition of a clinical triala clinical trial

Important terms that describe Important terms that describe clinical trialsclinical trials

The four phases of clinical trialsThe four phases of clinical trialsControls in clinical trialsControls in clinical trialsRandomization in clinical trialsRandomization in clinical trialsBlinding in clinical trialsBlinding in clinical trials

The US Government’s The US Government’s Definition of a Clinical TrialDefinition of a Clinical Trial

US Government’s DefinitionUS Government’s Definition

Practical definition of the term, “clinical Practical definition of the term, “clinical trial” that clarifies the difference trial” that clarifies the difference between clinical trials and other types of between clinical trials and other types of human researchhuman research

If a research project is funded If a research project is funded oror regulated by the US government, then it regulated by the US government, then it must also meet a number of legal and must also meet a number of legal and regulatory requirements that do not regulatory requirements that do not apply to other types of researchapply to other types of research

US Government’s DefinitionUS Government’s Definition It is a It is a prospectiveprospective study study It is in humans It is in humans It is designed to answer questions about It is designed to answer questions about

an intervention an intervention – a biomedical intervention a biomedical intervention – a behavioral interventiona behavioral intervention

A prospective biomedical or behavioral A prospective biomedical or behavioral research study of human subjects, that is research study of human subjects, that is designed to answer specific questions designed to answer specific questions about biomedical or behavioral about biomedical or behavioral interventions.interventions.

What is NOT a Clinical Trial?What is NOT a Clinical Trial?

A study that seeks to understand A study that seeks to understand how a disease affects people is how a disease affects people is notnot a a clinical trial unless participants are clinical trial unless participants are deliberately given either the disease deliberately given either the disease or a treatment for it.or a treatment for it.

Drug abuse research projects that Drug abuse research projects that are not clinical trialsare not clinical trials

Primate (monkey) testing of a new HIV therapy Primate (monkey) testing of a new HIV therapy intended for humansintended for humans

Ethnographic research to understand information Ethnographic research to understand information gathering patterns of injecting drug usersgathering patterns of injecting drug users

A program evaluation of a government initiative A program evaluation of a government initiative to reduce cocaine use by unwed mothers to reduce cocaine use by unwed mothers

A descriptive (epidemiologic) study of drug abuse A descriptive (epidemiologic) study of drug abuse patterns among persons receiving naltrexone for patterns among persons receiving naltrexone for alcohol dependencyalcohol dependency

Examples of activities that areExamples of activities that areclinical trialsclinical trials

Suppose you supervise four drug abuse Suppose you supervise four drug abuse clinics clinics – female patients may not be attending drug female patients may not be attending drug

abuse program due to child care problemsabuse program due to child care problems– provide supervised child care and a hot meal in provide supervised child care and a hot meal in

two clinics for 6 months two clinics for 6 months – Is this a clinical trial?Is this a clinical trial?

Yes - Yes - prospectivelyprospectively testing an testing an interventionintervention (food and child care) in (food and child care) in humanshumans. .

What What dodo you have to worry about? you have to worry about?

Ethical issuesEthical issues

Scientific issuesScientific issues

Successful management of ethical Successful management of ethical and scientific issues, in addition to and scientific issues, in addition to any local regulatory requirementsany local regulatory requirements

Important Terms That Important Terms That Describe Clinical TrialsDescribe Clinical Trials

Four Major Features toFour Major Features toClinical TrialsClinical Trials

The stage of the study intervention (study The stage of the study intervention (study phase)phase)

Whether the trial is a controlled studyWhether the trial is a controlled study

Whether participants are randomizedWhether participants are randomized

Whether participants are unaware of (or Whether participants are unaware of (or “blinded” to) treatments and results“blinded” to) treatments and results

Key terms to describe the four Key terms to describe the four basic features of a clinical trial basic features of a clinical trial

FEATURE TERMS USED

Study StagePhase I

(New intervention)

Phase II (Intervention is

promising)

Phase III(Real world evaluation )

Phase IV (Intervention is

in use)

Controls Uncontrolled Placebo Active Control(s)

Randomization Non-randomized Randomized

Blinding UnblindedSingle-blind

Double-blind Triple(+)-blind

The Four Phases of The Four Phases of Clinical TrialsClinical Trials

The Four Phases of The Four Phases of Clinical TrialsClinical Trials

Phase IPhase I – The intervention is new and is being – The intervention is new and is being tested in a small group of people for safetytested in a small group of people for safety

Phase IIPhase II – The intervention looks promising and – The intervention looks promising and is being evaluated in a larger group of people for is being evaluated in a larger group of people for safety and efficacysafety and efficacy

Phase IIIPhase III – The intervention appears safe and – The intervention appears safe and effective and is being evaluated in a real-world effective and is being evaluated in a real-world studystudy

Phase IVPhase IV – The intervention is now in use and is – The intervention is now in use and is being monitored for safetybeing monitored for safety

How clinical trials can be How clinical trials can be interpretedinterpreted

The US NIH The US NIH definitions of a clinical trial used for humadefinitions of a clinical trial used for human subjects researchn subjects research give estimates of the number of people give estimates of the number of people involved and specifically state that all involved and specifically state that all phase III trials require comparison studies phase III trials require comparison studies

The US NIH The US NIH definitions of a clinical trial used to registedefinitions of a clinical trial used to register clinical trialsr clinical trials do not mention the number of persons do not mention the number of persons involved in the different phases but note involved in the different phases but note that phase II studies involve comparisons that phase II studies involve comparisons (controls), while phase III studies may not(controls), while phase III studies may not

Controls in Clinical Controls in Clinical TrialsTrials

What is a clinical control?What is a clinical control?

What has been done in the past?What has been done in the past? Current treatments (standard Current treatments (standard

treatment)?treatment)? A similar-looking but ineffective A similar-looking but ineffective

treatment (placebo)?treatment (placebo)?

Whenever an intervention is Whenever an intervention is compared to something else, the compared to something else, the alternative is called a “control”.alternative is called a “control”.

Placebo ControlsPlacebo Controls Designed to duplicate the experience of the Designed to duplicate the experience of the

intervention without providing the active intervention without providing the active componentcomponent

Recognizes that many health outcomes are Recognizes that many health outcomes are dependent on the patient’s willingness to dependent on the patient’s willingness to participate and the patient’s and physician’s participate and the patient’s and physician’s perception of benefitperception of benefit

Can provide clear improvement in symptoms (the Can provide clear improvement in symptoms (the “placebo effect”)“placebo effect”)

Can more accurately determine the extent to Can more accurately determine the extent to which the intervention alone affects treatmentwhich the intervention alone affects treatment

InterventionsInterventions

The control contains an active The control contains an active component and is, therefore, an component and is, therefore, an active controlactive control

Active controls are frequently done in Active controls are frequently done in phase III trials where the intent is to phase III trials where the intent is to understand the benefits of a new understand the benefits of a new treatment in a real-world settingtreatment in a real-world setting

Randomization in Randomization in Clinical TrialsClinical Trials

Why is randomization necessaryWhy is randomization necessary

How does the researcher decide who gets How does the researcher decide who gets which treatment?which treatment?– every person will get the new treatmentevery person will get the new treatment– some persons may be willing to accept the new some persons may be willing to accept the new

treatment while others are not. treatment while others are not.

Whenever there is a good possibility that Whenever there is a good possibility that the control group and the intervention the control group and the intervention group are not identical, there is also a group are not identical, there is also a good possibility that the results will differ good possibility that the results will differ because of some factor totally unrelated to because of some factor totally unrelated to the treatment.the treatment.

What is Randomization?What is Randomization? Randomization -the assigning of persons Randomization -the assigning of persons

to the control group or the intervention to the control group or the intervention groups based on chance.groups based on chance.

An essential feature of good clinical trial An essential feature of good clinical trial design whenever there are one or more design whenever there are one or more control groups. control groups.

The process of randomization must be The process of randomization must be totally unrelated to the variables of totally unrelated to the variables of interest. interest.

Common randomization schemesCommon randomization schemes

Complete randomizationComplete randomization

Block randomization Block randomization

Urn randomization Urn randomization

Stratified randomizationStratified randomization

Cluster randomizationCluster randomization

Complete randomizationComplete randomization Individuals are assigned to control and Individuals are assigned to control and

intervention groups based on a random intervention groups based on a random event that is proportional to the size of the event that is proportional to the size of the groupsgroups

The event could be a coin toss for two The event could be a coin toss for two groups of equal size or a more complex groups of equal size or a more complex computer generated algorithmcomputer generated algorithm

Resulting group sizes may not be equal (or Resulting group sizes may not be equal (or in the desired ratio) because the process is in the desired ratio) because the process is truly randomtruly random

Block randomizationBlock randomization Also known as permuted block randomizationAlso known as permuted block randomization Ensures that the number of subjects assigned to Ensures that the number of subjects assigned to

treatment and control groups is balanced treatment and control groups is balanced Individuals are placed into small groups (blocks) Individuals are placed into small groups (blocks)

and then randomly assigned to control and and then randomly assigned to control and intervention groups.intervention groups.– Example:Example:

Two groups (A & B) and block size is fourTwo groups (A & B) and block size is four Two persons are randomly assigned to group ATwo persons are randomly assigned to group A Remaining two in that block are assigned to group BRemaining two in that block are assigned to group B

Creates the potential for bias because the Creates the potential for bias because the assignment of certain block members is assignment of certain block members is determined by the assignment of others.determined by the assignment of others.

Urn randomizationUrn randomization

Form of “adaptive randomization” whose Form of “adaptive randomization” whose intent is to balance the number of intent is to balance the number of individuals in each group without individuals in each group without specifying that an individual must be specifying that an individual must be assigned to a specific groupassigned to a specific group

The chances that an individual will be The chances that an individual will be assigned to a treatment or control group assigned to a treatment or control group are allowed to vary based on prior are allowed to vary based on prior assignmentsassignments

Stratified randomizationStratified randomization

Used to guarantee that there is a balance Used to guarantee that there is a balance of certain characteristics in treatment and of certain characteristics in treatment and control groupscontrol groups

Individuals are separated into subgroups Individuals are separated into subgroups (strata) based on a predetermined feature (strata) based on a predetermined feature

Randomly assigned to control and Randomly assigned to control and intervention groups using one of the intervention groups using one of the methods mention in previous slidesmethods mention in previous slides

Cluster randomizationCluster randomization Created in an attempt to deal with issues of Created in an attempt to deal with issues of

contamination within subgroupscontamination within subgroups

Individuals are placed in subgroupsIndividuals are placed in subgroups

The entire subgroup (cluster) is randomly The entire subgroup (cluster) is randomly assigned to be part of a control or intervention assigned to be part of a control or intervention groupgroup

Increasingly popular but requires an adequate Increasingly popular but requires an adequate number of clusters and careful designnumber of clusters and careful design

Blinding in Clinical Blinding in Clinical TrialsTrials

The purpose of blindingThe purpose of blinding

Many clinical trials lack well-defined, Many clinical trials lack well-defined, objective endpointsobjective endpoints

Such measures are subject to intentional Such measures are subject to intentional manipulation and unintentional bias manipulation and unintentional bias

Researchers may seek to disguise whether Researchers may seek to disguise whether the subjects are receiving the intervention the subjects are receiving the intervention or the control treatmentor the control treatment

What is Blinding?What is Blinding?

The term “blinding” is used to The term “blinding” is used to describe the techniques used to describe the techniques used to disguise treatments, and sometimes disguise treatments, and sometimes outcomesoutcomes

Different types of blindingDifferent types of blinding– Unblinded or Open LabelUnblinded or Open Label– Single blindSingle blind– Double blind Double blind – Triple blindTriple blind

SummarySummary US Government’s Definition of a Clinical Trial as a US Government’s Definition of a Clinical Trial as a

prospective study, that deals with human subjects prospective study, that deals with human subjects and designed to answer questions about an and designed to answer questions about an interventionintervention

There are important features and terms that help There are important features and terms that help describe clinical trialsdescribe clinical trials

The four phases of clinical trials help define the The four phases of clinical trials help define the intent of the research project than its scientific intent of the research project than its scientific detailsdetails

Controls, randomization, and blinding are tools used Controls, randomization, and blinding are tools used in in clinical trials to reduce data manipulation and in in clinical trials to reduce data manipulation and biasbias