25/5/2009 dr. salwa tayel 1. 25/5/2009 dr. salwa tayel2 associate professor family and community...

25/5/200925/5/2009 Dr. Salwa TayelDr. Salwa Tayel 11


Associate Professor Associate Professor Family and Community Medicine DepartmentFamily and Community Medicine Department

King Saud UniversityKing Saud University

ByBy


Learning ObjectivesLearning Objectives

To understand: To understand:

• What are experimental studies?What are experimental studies?

• The value of clinical trialsThe value of clinical trials

• The basic methodology of RCTsThe basic methodology of RCTs

• Advantages and disadvantages of RCTsAdvantages and disadvantages of RCTs


A. A. ExperimentalExperimental - study factor is - study factor is

manipulated by the investigatormanipulated by the investigator

B. B. ObservationalObservational – no manipulation of – no manipulation of

study factor by the investigatorstudy factor by the investigator Descriptive Descriptive

AnalyticAnalytic


Intervention studies are similar in approach Intervention studies are similar in approach

to cohort studies except that the investigator to cohort studies except that the investigator

directly control exposure.directly control exposure.

Similar to laboratory experiments except Similar to laboratory experiments except

living populationsliving populations are the subjects are the subjects

TThey are the ultimate step in testing causal hey are the ultimate step in testing causal

hypotheses.hypotheses.


New treatments - pharmaceutical agents,

devices, surgical procedures - are being

developed every day.

Before an intervention becomes standard

practice, assessment of its efficacy and safety in

comparison to standard therapy should be

undertaken.

Back ground


WHAT ARE CLINICAL TRIALS?WHAT ARE CLINICAL TRIALS?WHAT ARE CLINICAL TRIALS?WHAT ARE CLINICAL TRIALS?

Clinical trialsClinical trials (Experimental studies)) are research are research

activities that involve the administration of a activities that involve the administration of a

therapeutic or a preventive regimen to humans to therapeutic or a preventive regimen to humans to

evaluate its safety and efficacy.evaluate its safety and efficacy.

Experimental studies are the best epidemiological Experimental studies are the best epidemiological

study design to prove causation.study design to prove causation.


Types of Experimental studies:Types of Experimental studies:

1. Preventive trials1. Preventive trials

These evaluate whether a preventive agent These evaluate whether a preventive agent

(e.g. Vaccine) or procedure reduces the risk (e.g. Vaccine) or procedure reduces the risk

of development of a particular disease. of development of a particular disease.

We compare incidence rate among exposed and We compare incidence rate among exposed and

non-exposed.non-exposed.


2. Therapeutic trials:2. Therapeutic trials:

Carried out among patients with a Carried out among patients with a

particular disease, to determine the particular disease, to determine the

ability of an agent or procedure to ability of an agent or procedure to

diminish symptoms, prevent diminish symptoms, prevent

recurrence, or decrease risk of death recurrence, or decrease risk of death

from that disease.from that disease.


Values of Clinical trialsValues of Clinical trials

Clinical trials are useful for evaluating:Clinical trials are useful for evaluating:

New drugs or other treatments for disease.New drugs or other treatments for disease.

New medical/health care technology.New medical/health care technology.

New methods of prevention.New methods of prevention.

New programs for screening and diagnosis.New programs for screening and diagnosis.

New methods of providing health care.New methods of providing health care.

New health care policies.New health care policies.


Pre-clinicalPre-clinical trials in animal and lab. trials in animal and lab.

Testing drugsTesting drugs in humanin human

Phases of testing new agent Phases of testing new agent


Pre-clinical Pre-clinical trialstrials Before clinical trials of any medication in Before clinical trials of any medication in

human subjects are undertaken, human subjects are undertaken,

considerable research in experimental considerable research in experimental

animalsanimals is essential. is essential.

It includes pharmacological and toxicological It includes pharmacological and toxicological

studies. studies.

Aims:Aims:

• to establish that the new agent is effective to establish that the new agent is effective

and may be suitable for human use.and may be suitable for human use.

• to estimate roughly the dose to be used in to estimate roughly the dose to be used in

man.man.


Clinical trials of new agents in human pass through 4 Clinical trials of new agents in human pass through 4

phasesphases

Phase I: Phase I: Aims:Aims:

• to find a safe tolerated dose in manto find a safe tolerated dose in man

• to test effects on body functions under close to test effects on body functions under close

supervision.supervision.

It is carried out onIt is carried out on (20 to 25) (20 to 25) of healthy volunteers of healthy volunteers

• They receive small doses of new drugs They receive small doses of new drugs

• This phase is of short duration (one or two months) This phase is of short duration (one or two months)

• It is performed by clinical pharmacologists.It is performed by clinical pharmacologists.

Testing drugs in humanTesting drugs in human


Phase II:Phase II:

It is carried out on 20 – 200 patients with relevant disease

It lasts longer than Phase I trials (6 months to 2 years)

The purpose of Phase II is:

to assess therapeutic benefits & adverse reactions of the drug

To establish a dose range and to investigate its side effects.


Phase IIIPhase III (The classical phase)(The classical phase) Large scale, Randomised, Controlled Trials (RCTs)Large scale, Randomised, Controlled Trials (RCTs) Target population: 250 – 1000 Target population: 250 – 1000 patientspatients

Performed by Clinicians in mPerformed by Clinicians in multi-centric hospitals.hospitals.

The The purposepurpose of this phase is to: of this phase is to:

• assess the assess the efficacyefficacy and safety. and safety.

• reduce the side effects & improve the quality of life. reduce the side effects & improve the quality of life.

Results from Phase III trials are used to evaluate Results from Phase III trials are used to evaluate whether a new product or device should be whether a new product or device should be licensedlicensed for general public use.for general public use.


Phase IV:Phase IV: ((Post marketing Surveillance)Post marketing Surveillance)

It is a trial in normal field conditions when the drug is It is a trial in normal field conditions when the drug is

already available by prescription in the market. already available by prescription in the market.

The The purposepurpose of the Phase IV trial is to assess: of the Phase IV trial is to assess:

• EffectivenessEffectiveness under actual field conditionsunder actual field conditions

• Safety& acceptabilitySafety& acceptability

• Long-term side effects. Long-term side effects.

• Rare adverse reactions and Rare adverse reactions and

• Drug interactionsDrug interactions


1.1. The first step is to identify the The first step is to identify the reference populationreference population

(the target population).(the target population).

The reference population The reference population is the population to which is the population to which

generalizations of the results of the experiment apply.generalizations of the results of the experiment apply.

2.2. Second, Selection of a Second, Selection of a study populationstudy population after defining after defining

inclusion/exclusion criteria. inclusion/exclusion criteria.

• The inclusion criteria identify the target group or subgroup The inclusion criteria identify the target group or subgroup

that will enter the studythat will enter the study

• The exclusion criteria are chosen to minimize potential The exclusion criteria are chosen to minimize potential

dangers (e.g. elderly patients, pregnant women, children)dangers (e.g. elderly patients, pregnant women, children)

Design of Randomized Clinical Trials (RCTs):Design of Randomized Clinical Trials (RCTs):


3.3. Getting ‘Getting ‘informed consentinformed consent’ from the participants ’ from the participants before they are subjected to experiments.before they are subjected to experiments.

4.4. Random allocationRandom allocation of subjects to the experiment of subjects to the experiment and control groups,and control groups,

5.5. Follow upFollow up for a specified period of time under strict for a specified period of time under strict conditionsconditions

6.6. The The outcomeoutcome of the experiment is carefully of the experiment is carefully measuredmeasured. .

The outcome may be a cure, recurrence of the The outcome may be a cure, recurrence of the disease, survival, relief of pain, or reduction disease, survival, relief of pain, or reduction in blood pressure, etc. in blood pressure, etc.

7.7. The outcome measures are The outcome measures are comparedcompared between the between the groups using appropriate statistical methods.groups using appropriate statistical methods.


Design of a Randomized Design of a Randomized Controlled Clinical trialControlled Clinical trial

Design of a Randomized Design of a Randomized Controlled Clinical trialControlled Clinical trial

With outcomeWith outcome

Without Without outcomeoutcome

With outcomeWith outcome

Without Without outcomeoutcome

Treatment groupTreatment group(New therapy)(New therapy)

Control groupControl group(Standard therapy)(Standard therapy)

ParticipantParticipant

(consenters)(consenters)

Randomization

Follow Follow upup


Random allocationRandom allocation Random allocation is the method of Random allocation is the method of

assigning patients to treatment groups.assigning patients to treatment groups.

Each subject has an equal chance of being Each subject has an equal chance of being

assigned to any group in the studyassigned to any group in the study

All groups in a study are similar in all All groups in a study are similar in all

characteristicscharacteristics

It avoids It avoids selection biasselection bias on the part of the on the part of the

investigator or the patient.investigator or the patient.


Value of RandomizationValue of Randomization

Successful randomization tends to create Successful randomization tends to create

comparison groups that are similar in comparison groups that are similar in

terms of both known and unknown terms of both known and unknown

factors that may be related to outcomefactors that may be related to outcome

(e.g. (e.g. gender, age group, disease stage, or gender, age group, disease stage, or

other prognostic factor)other prognostic factor)..


It is a method of concealing (hiding) knowledge of It is a method of concealing (hiding) knowledge of treatment assignment to reduce treatment assignment to reduce biasbias in measuring in measuring outcome. outcome.

A A Single masked studySingle masked study – subjects are unaware of – subjects are unaware of whether they are in the experimental or control whether they are in the experimental or control groupgroup study. study.

A A Double masked studyDouble masked study – the subject and the – the subject and the observer are unaware of the subject’s group observer are unaware of the subject’s group allocation.allocation.

AA Triple masked studyTriple masked study – the subject, observer and – the subject, observer and data analyst are unaware of the subject’s group data analyst are unaware of the subject’s group allocation.allocation.

Masking or "blindingMasking or "blinding""


Masking is achieved by ensuring that all treatments Masking is achieved by ensuring that all treatments

appear appear identical (form & shape of drugs)identical (form & shape of drugs)..

A A placeboplacebo is used for the comparison group if the is used for the comparison group if the

objective is to evaluate a new drug in comparison objective is to evaluate a new drug in comparison

with no treatment.with no treatment.

A A placeboplacebo is an inactive agent made to seem is an inactive agent made to seem

identical to the active agent in terms of appearance identical to the active agent in terms of appearance

and mode of administration.and mode of administration.

Methods of BlindingMethods of Blinding


Relative RiskRelative Risk

GroupGroup outcomeoutcome TotalTotal

PositivePositive NegativeNegative

InterventionIntervention aa bb a +ba +b

ControlControl cc dd c +dc +d


Measures of effect size

Relative risk (RR)

Is the ratio of the incidence of a given outcome in experimental group compared to that in the control group

( a/(a + b)) / (c /( c + d))

25/5/2009Dr. Salwa Tayel28

RR=(18/64) / (29/65) = 0.281/0.446 =0.63

Intervention

Outcome

Total

Death survival

Intervention A 18 46 64

Intervention B 29 36 65


More scientifically valid (More scientifically valid (timetime relation is relation is

clearly established).clearly established).

Advantages of RCTSAdvantages of RCTSAdvantages of RCTSAdvantages of RCTS

Unbiased allocation of subjects through Unbiased allocation of subjects through

randomizationrandomization. (No Selection Bias). (No Selection Bias)

Unbiased assessment of outcomes Unbiased assessment of outcomes

through through blindingblinding. (No measurement bias). (No measurement bias)


Disadvantages of RCTS Disadvantages of RCTS Disadvantages of RCTS Disadvantages of RCTS

Require large sample size.Require large sample size.

Time consuming and expensive.Time consuming and expensive.

Non-compliance to treatment Non-compliance to treatment assignmentassignment

Attrition (Losses to follow-up) may affect Attrition (Losses to follow-up) may affect validity of results.validity of results.

Ethical issues may arise.Ethical issues may arise.


Are exposure and disease linked?Are exposure and disease linked?

Exposure Disease


Descriptive Studies

Case-control Studies

Cohort Studies

Develop hypothesis

Investigate it’sassociation to

outcomes

Define it’s risk with exposures

Clinical trialsTest link

experimentally

Incr

easi

ng

Kn

owle

dge

of

Dis

ease

/Exp

osu

reKnowledge of Exposure/DiseaseKnowledge of Exposure/Disease


In summary, there is a hierarchy of studies In summary, there is a hierarchy of studies

from ones that open up a question to ones from ones that open up a question to ones

that may be the definitive answer or very that may be the definitive answer or very

close to thatclose to that. .

With increasing certaintyWith increasing certainty comes increasing comes increasing

complexity and attention to detail complexity and attention to detail ((and and

increasing expense, time, and cooperationincreasing expense, time, and cooperation). ).


ThanThank youk you

Bibliotheca Alexandrina

The EndThe End

Website http://faculty.ksu.edu.sa/73234/[email protected]

25/5/2009 dr. salwa tayel 1. 25/5/2009 dr. salwa tayel2 associate professor family and community...

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