Presented by: Rather waseem yousuf

Clinical TrialsA clinical trial : prospectively planned

experiment for the purpose of evaluating potentially beneficial therapies or treatments

In general, these studies are conducted under as many controlled conditions as possible so that they provide definitive answers to pre-determined, well-defined questions

Why Clinical Trials?1. Most definitive method to determine

whether a treatment is effective.

Other designs have more potential biases

One cannot determine in an uncontrolled setting whether an intervention has made a difference in the outcome.

Why Clinical Trials?2. Help determine incidence of side effects and

complications.

3. Theory not always best path

TYPES3 ways of classificationResearchers behavior Clinical observational study Interventional study

Purpose based Prevention trials Screening trials Diagnostic trials Treatment trials Supportive care trials

TYPES

Weather trial design allow changes based on data accumulated

Fixed trialAdaptive clinical trial

Miscellaneous typesField trialsCommunity trials

Phases of Clinical TrialPhases of Clinical Trial

Phase 0Phase 0Also called Human Micro-dosing studies.

Gathers preliminary data Pharmacodynamics and Pharmacokinetics.

Gives no data on safety or efficacy.

Small number of subjects (10-15).

Phase IPhase IFirst stage of testing in human subjects (20-100).

Designed to assess the safety, tolerability, PK and PD of drug.

Dose ranging – Dose escalation.

Phase IIPhase IITherapeutic Exploratory Trial. (20-300 Subjects).

Efficacy in patients (primary objective)

Safety issues (secondary objective)

Optimum dose finding

Phase IIIPhase III

Therapeutic confirmatory trials. (300-3000 subjects).

To establish efficacy of the drug against existing therapy in larger number of patients, method of usage etc.,.

Phase IVPhase IVPost Marketing Studies (PMS).

Involves safety surveillance.

Determine behavior of drug in real life situations.

Evaluate action of drug in a situation of missed dosage or over dosage.

CLINICAL TRIAL PROTOCOLDefines and manages trialRequired by the regulatory organizationsPrepared by panel of expertsProvides background about the trialSpecifies trial objectivesDescribes trial design Ensures that trial procedures are consistently

carried out

COMPONENTS

1. General information Title of trial Names and adresses of investigators and

sponsors Identity of trial site

2. Justification and objectives Reason for execution of trial Primary hypothesis to be tested Primary end point

COMPONENTS3. Design Response variables (nature of response variable , scoring system) Efficacy (magnitude of difference to be detected between treatment and

control groups)4. Duration Date of beginning Date of end Duration of disease under study Duration of treatment Drug withdrawal period Decision rules for terminating a trial

COMPONENTS5. Experimental population

Population in which trial is conducted Should be representative of target population

Experimental unit (smallest independent unit to which treatment is randomly

allocated) Composition (e.g. Age , sex , breed) Inclusion/exclusion criteria Selection of controls (to allow discrimination of patient

outcomes caused by other factors , fair comparisons)

COMPONENTS Sample size determination

• Level of significance• Power

Owners informed consent6.Therapeutic or prophylactic procedure Dosage Product formulation and identification Placebo/standard treatment formulation and identification Method of administration Operators safety

Bias and VariabilityThe clinical trial is considered to be the “gold standard” in

clinical research

Clinical trials provide the ability to reduce bias and variability that can obscure the true effects of treatment

Bias affects accuracy

Variability affects precision

Bias: any influence which acts to make the observed results non-representative of the true effect of therapy

Examples:

healthier patients given treatment A, sicker patients given treatment B

treatment A is “new and exciting” so both the physician and the patient expect better results on A

Variability: high variability makes it more difficult to discern treatment differences

Some sources of variabilityMeasurement

instrument Observer

Biologic within individuals between individuals

Fundamental principle in comparing treatment groups:Groups must be alike in all important aspects and only

differ in the treatment each group receives

In practical terms, “comparable treatment groups” means “alike on the average”

Why is this important?If there is a group imbalance for an important factor

then an observed treatment difference may be due to the imbalance rather than the effect of treatment

Example:Drug X versus placebo for osteoporosisAge is a risk factor for osteoporosisOlder subjects are enrolled in Drug X groupTreatment group comparison will be biased due to

imbalance on age

How can we ensure comparability of treatment groups?We can not ensure comparability but randomization helps

to balance all factors between treatment groups

If randomization “works” then groups will be similar in all aspects except for the treatment received

RandomizationAllocation of treatments to participants is carried out

using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned

Simplest Case: each patient has the same chance of receiving any of the treatments under study

Randomization

Simple Randomization

Think of tossing a coin each time a subject is eligible to be randomized HEADS: Treatment A TAILS: Treatment B

Approximately ½ will be assigned to treatments A and B

Problem with Simple Randomization:May result in substantial imbalance in either

an important baseline factor and/orthe number of subjects assigned to each group

Solution: Use blocking and/or stratified randomization

Block RandomizationArranging experimental units in groups that are

similar to one another

Typically , blocking factor is source of variability that is not of primary interest to the experimenter

The Randomized Block Design Divides the group of experimental units into n

homogeneous groups of size t These homogeneous groups are called blocks The treatments are then randomly assigned to the

experimental units in each block - one treatment to a unit in each block

Stratification ExampleTo ensure balance on an important baseline factor,

create strata and set up separate randomization schedules within each stratum

Example: if we want prevent an imbalance on age in an osteoporosis study, first create the strata “< 75 years” and “ 75 years”

then randomize within each stratum separatelyBlocking should be also be used within each stratum

Stratification

BlindingMasking the identity of the assigned interventions

Main goal: avoid potential bias caused by conscious or subconscious factors

Single blind: patient is blinded

Double blind: patient and assessing investigator are blinded

Triple blind: committee monitoring response variables (e.g.

statistician) is also blinded

How to Blind

To “blind” patients, can use a placebo

Examples

pill of same size, color, shape as treatment

sham surgery

sham device such as sham acupuncture

General Study DesignsParallel group designs Type of clinical design which compares two

treatments (A and B) so that one group receives only A while

other group receives only B

R A N D

A

B

C

control

Cross-Over DesignsSubjects are randomized to sequences of treatments

(A then B or B then A)

Uses the patient as his/her own control

Often a “wash-out” period (time between treatment periods) is used to avoid a “carry over” effect (the effect of treatment in the first period affecting outcomes in the second period)

Can have a cross-over design with more than 2 periods

General Study DesignsCross-Over Designs

R A N D

A

B

B

A

WASH-OUT

Cross-Over Designs

Advantage: treatment comparison is only subject to within-subject variability not between-subject variability

reduced sample sizes

Disadvantages:strict assumption about carry-over effectsinappropriate for certain acute diseases (where a

condition may be cured during the first period)drop outs before second period

General study designsSequential trials It is one whose conduct at any stage depends

on the results so far obtained

Two treatments are compared , experimental units enter the trial in pairs

Results are analyzed sequentially according to the outcome in the pairs

Sequential Design

Continue to randomize subjects until H0 is either rejected or “accepted”

A large statistical literature for classical sequential designs

Developed for industrial setting

General study designsAdvantages:1.Early detection of beneficial treatment effects

2. Require fewer experimental units

3. Significance tests can be conducted repeatedly on accumulating data

General study designsDisadvantages:

1.Difficult to plan

2.Unsuited to the trial in which treatment response times are long

Losses to “follow-up”It refers to subjects who at one point in time

were actively participating in a clinical trial ,but have become lost at the point of follow-up in trial

Reasons:• Withdrawal from the trial without informing

investigator• Moved away from the trial site• Became ill and unable to communicate

Compliance Success of a trial depends on participants acting

in accordance with the instructions of the trial designers; that is, complying with treatment

Reasons for poor compliance 1.Unclear instructions2.Forgetfulness3.Inconvenience of participation4.Disappointment with results5.Side effects

Terminating a trial It may be necessary to terminate a trial

prematurely if there are serious adverse side effects in the treatment group, and such a decision rule should be written into the trial’s protocol