Randomized Controlled Trials (RCT). Definition of levels of evidence and grading of recommendation...

Randomized Controlled Trials Randomized Controlled Trials (RCT)(RCT)

Definition of levels of evidence and grading Definition of levels of evidence and grading of recommendationof recommendation

LevelLevel Type of evidence available fromType of evidence available from GradeGrade

I aI a Meta-analysis of RCTsMeta-analysis of RCTsAA

I bI b At least one RCTAt least one RCT

I I aI I a At least one well-designed controlled study without At least one well-designed controlled study without

randomizationrandomization

BBI I bI I b At least one other type of well-designed quasi-At least one other type of well-designed quasi-

experimental studyexperimental study

IIIIII Well-designed non-experimental descriptive Well-designed non-experimental descriptive

studiesstudies

IVIV Expert committee reports or opinions and/or clinical Expert committee reports or opinions and/or clinical

experience of respected authoritiesexperience of respected authoritiesCC

EXPERIMENTALEXPERIMENTAL Exposure manipulated by InvestigatorExposure manipulated by Investigator

DescriptiveDescriptiveAnalyticAnalytic

Exposure NOT manipulated by InvestigatorExposure NOT manipulated by InvestigatorOBSERVATIONALOBSERVATIONAL

• Cohort

• Case-control

• Case-series• Cross-sectional• Ecological

• Clinical trials

Study DesignsStudy Designs

The results of any epidemiological study may reflect the true effect of an exposure on the development of disease

It is also possible that the findings may have an alternative explanation !

Three possibilities ??

AssociationAssociation

• Chance

• Bias

• Confounding

Three possibilitiesThree possibilities

• Selection bias

• Information bias

• Confounding bias

Bias in epidemiological studiesBias in epidemiological studies

Bias is systematicsystematic error (or non-random error) that

introduces distortion in estimates/results of studyintroduces distortion in estimates/results of study

Randomized Controlled Trials (RCT)Randomized Controlled Trials (RCT)Randomized Controlled Trials (RCT)Randomized Controlled Trials (RCT)

• The methodologic standard of excellence for scientific The methodologic standard of excellence for scientific

experimentsexperiments

• ‘ ‘RCT has probably contributed more than any single RCT has probably contributed more than any single

scientific discovery to the improvement in medical care’ scientific discovery to the improvement in medical care’

( Lancet, 1987)( Lancet, 1987)

• The methodologic standard of excellence for scientific The methodologic standard of excellence for scientific

experimentsexperiments

• ‘ ‘RCT has probably contributed more than any single RCT has probably contributed more than any single

scientific discovery to the improvement in medical care’ scientific discovery to the improvement in medical care’

( Lancet, 1987)( Lancet, 1987)

• One of the main scientific advances in methods of

clinical research in the 20th century

• RCT is considered as the Gold standard for

demonstrating therapeutic efficacy for a

pharmaceutical agent

• Efficacy is not transferable from one goal to another

( e.g. Lowering of blood glucose and

prevention of vascular complications)

Randomized Controlled TrialsRandomized Controlled Trials

RCTRCTRCTRCT

A clinical trial is a planned experiment designed to A clinical trial is a planned experiment designed to

assess the efficacy of a treatment in humans by assess the efficacy of a treatment in humans by

comparing the outcomescomparing the outcomes in a group of in a group of patientspatients treated treated

with a test with a test treatmenttreatment with those observed in a with those observed in a

comparable group of patients receiving a control comparable group of patients receiving a control

treatment where patients in both groups are enrolled, treatment where patients in both groups are enrolled,

treated and followed over the same period.treated and followed over the same period.

Curtis L Meinert: Clinical Trials, Oxford Univ Press, 1986Curtis L Meinert: Clinical Trials, Oxford Univ Press, 1986

A clinical trial is a planned experiment designed to A clinical trial is a planned experiment designed to

assess the efficacy of a treatment in humans by assess the efficacy of a treatment in humans by

comparing the outcomescomparing the outcomes in a group of in a group of patientspatients treated treated

with a test with a test treatmenttreatment with those observed in a with those observed in a

comparable group of patients receiving a control comparable group of patients receiving a control

treatment where patients in both groups are enrolled, treatment where patients in both groups are enrolled,

treated and followed over the same period.treated and followed over the same period.

Curtis L Meinert: Clinical Trials, Oxford Univ Press, 1986Curtis L Meinert: Clinical Trials, Oxford Univ Press, 1986

“ “ A scientific research activity undertaken to define A scientific research activity undertaken to define

prospectively the effect and value of prophylactic / diagnostic prospectively the effect and value of prophylactic / diagnostic

/ therapeutic agents, devices, regimens, procedures etc. / therapeutic agents, devices, regimens, procedures etc.

applied to human subjects.applied to human subjects.

It is essential that the study be prospective and that It is essential that the study be prospective and that

intervention of some sort occur”intervention of some sort occur”

“ “ A scientific research activity undertaken to define A scientific research activity undertaken to define

prospectively the effect and value of prophylactic / diagnostic prospectively the effect and value of prophylactic / diagnostic

/ therapeutic agents, devices, regimens, procedures etc. / therapeutic agents, devices, regimens, procedures etc.

applied to human subjects.applied to human subjects.

It is essential that the study be prospective and that It is essential that the study be prospective and that

intervention of some sort occur”intervention of some sort occur”

NIH (1980)NIH (1980)

RCTRCTRCTRCT

RCT ParadigmRCT Paradigm

Population of InterestPopulation of Interest

Child Child <<5 year presenting at 5 year presenting at hospital with severe malariahospital with severe malaria

RandomizeRandomize

TxTx PlaceboPlacebo

Outcome AssessmentOutcome AssessmentDeath within 7 daysDeath within 7 days

Randomized (controlled) clinical trials Randomized (controlled) clinical trials are described often as Phase III clinical are described often as Phase III clinical trialstrials

Randomized (controlled) clinical trials Randomized (controlled) clinical trials are described often as Phase III clinical are described often as Phase III clinical trialstrials

•Phase I Clinical Trial is usually carried out in ‘normal’ Phase I Clinical Trial is usually carried out in ‘normal’

•human volunteers to examine clinical pharmacology of human volunteers to examine clinical pharmacology of

a new drug. This phase is concerned with a new drug. This phase is concerned with SafetySafety of the of the

drug in humans, and studiesdrug in humans, and studies

• - Drug metabolism, Bio-availability- Drug metabolism, Bio-availability

• - Dose ranging and Multiple Doses - Dose ranging and Multiple Doses

•Phase I Clinical Trial is usually carried out in ‘normal’ Phase I Clinical Trial is usually carried out in ‘normal’

•human volunteers to examine clinical pharmacology of human volunteers to examine clinical pharmacology of

a new drug. This phase is concerned with a new drug. This phase is concerned with SafetySafety of the of the

drug in humans, and studiesdrug in humans, and studies

• - Drug metabolism, Bio-availability- Drug metabolism, Bio-availability

• - Dose ranging and Multiple Doses - Dose ranging and Multiple Doses

Phase IPhase I • Clinical pharmacology & toxicity

• Human volunteers

• Hospital study

Phase IIPhase II • Initial clinical investigation for treatment effects

• Patients

• Hospital study

Phase IIIPhase III • Full-scale evaluation • Patients • Hospital study

Phase IVPhase IV • Post-marketing surveillance

Phases of trialPhases of trial

Phase I Clinical TrialsPhase I Clinical TrialsPhase I Clinical TrialsPhase I Clinical Trials

• Usually carried out in ‘normal’ Human volunteers to Usually carried out in ‘normal’ Human volunteers to

examine clinical pharmacology of a new drugexamine clinical pharmacology of a new drug

• Concerned with Concerned with SafetySafety of the drug in humans, and of the drug in humans, and

studies Drug metabolism, Bio-availability, Dose studies Drug metabolism, Bio-availability, Dose

ranging and Multiple Doses ranging and Multiple Doses

• Usually carried out in ‘normal’ Human volunteers to Usually carried out in ‘normal’ Human volunteers to

examine clinical pharmacology of a new drugexamine clinical pharmacology of a new drug

• Concerned with Concerned with SafetySafety of the drug in humans, and of the drug in humans, and

studies Drug metabolism, Bio-availability, Dose studies Drug metabolism, Bio-availability, Dose

ranging and Multiple Doses ranging and Multiple Doses

Phase II Clinical TrialsPhase II Clinical TrialsPhase II Clinical TrialsPhase II Clinical Trials

It evaluatesIt evaluates

• Effectiveness of a drug based on Clinical EndpointsEffectiveness of a drug based on Clinical Endpoints

• Dosing Ranges and Doses for Phase III trialDosing Ranges and Doses for Phase III trial

• Common Short-term Side Effects and Risks associated Common Short-term Side Effects and Risks associated

with the drugwith the drug

It evaluatesIt evaluates

• Effectiveness of a drug based on Clinical EndpointsEffectiveness of a drug based on Clinical Endpoints

• Dosing Ranges and Doses for Phase III trialDosing Ranges and Doses for Phase III trial

• Common Short-term Side Effects and Risks associated Common Short-term Side Effects and Risks associated

with the drugwith the drug

• The final stage in testing a new treatment in humansThe final stage in testing a new treatment in humans

• Is primarily concerned with assessment of efficacy Is primarily concerned with assessment of efficacy

and safety studied under controlled conditionsand safety studied under controlled conditions

Phase III Clinical TrialsPhase III Clinical TrialsPhase III Clinical TrialsPhase III Clinical Trials

Phase IV trialsPhase IV trialsPhase IV trialsPhase IV trials

• Post-marketing trials assess incidence of Post-marketing trials assess incidence of

adverse reactions and effect on morbidity adverse reactions and effect on morbidity

and mortality in the populationand mortality in the population

• Post-marketing trials assess incidence of Post-marketing trials assess incidence of

adverse reactions and effect on morbidity adverse reactions and effect on morbidity

and mortality in the populationand mortality in the population

Classification of RCTClassification of RCTClassification of RCTClassification of RCT

Based onBased on ClassificationClassification

Type of interventionType of intervention Therapeutic; PreventiveTherapeutic; Preventive

Unit of randomizationUnit of randomization Individual ;CommunityIndividual ;Community

DesignDesign Parallel; Cross-over; FactorialParallel; Cross-over; Factorial

Sample SizeSample Size Fixed; SequentialFixed; Sequential

RandomizationRandomization Fixed; Adaptive (Number, Baseline, Fixed; Adaptive (Number, Baseline,

Outcome); BlockingOutcome); Blocking

MaskingMasking Single, Double, Triple,…Single, Double, Triple,…

Assures ComparabilityAssures ComparabilityAssures ComparabilityAssures Comparability

• In observational studies, statistical In observational studies, statistical

methods allow investigators to control methods allow investigators to control

for confounding factorsfor confounding factors

• Must be measuredMust be measured

• In observational studies, statistical In observational studies, statistical

methods allow investigators to control methods allow investigators to control

for confounding factorsfor confounding factors

• Must be measuredMust be measured

Randomized Trials Require Randomized Trials Require Methodological RigorMethodological Rigor

Randomized Trials Require Randomized Trials Require Methodological RigorMethodological Rigor

• Improperly conducted RCTs yield biased resultsImproperly conducted RCTs yield biased results

• Researchers must devote assiduous attention Researchers must devote assiduous attention

to design and conduct of RCTsto design and conduct of RCTs

• Only properly conducted RCTs will fulfill their Only properly conducted RCTs will fulfill their

promise of minimizing biaspromise of minimizing bias

• Improperly conducted RCTs yield biased resultsImproperly conducted RCTs yield biased results

• Researchers must devote assiduous attention Researchers must devote assiduous attention

to design and conduct of RCTsto design and conduct of RCTs

• Only properly conducted RCTs will fulfill their Only properly conducted RCTs will fulfill their

promise of minimizing biaspromise of minimizing bias

Advantages of Randomized TrialsAdvantages of Randomized TrialsAdvantages of Randomized TrialsAdvantages of Randomized Trials

• First and foremost, the only effective method First and foremost, the only effective method

known to control selection biasknown to control selection bias

• Controls confounding bias without adjustmentControls confounding bias without adjustment

• Facilitates effective blinding in some trialsFacilitates effective blinding in some trials

• Theoretically attractive -many statistical Theoretically attractive -many statistical

methods assume random assignmentmethods assume random assignment

• Maintains advantages of cohort studiesMaintains advantages of cohort studies

• First and foremost, the only effective method First and foremost, the only effective method

known to control selection biasknown to control selection bias

• Controls confounding bias without adjustmentControls confounding bias without adjustment

• Facilitates effective blinding in some trialsFacilitates effective blinding in some trials

• Theoretically attractive -many statistical Theoretically attractive -many statistical

methods assume random assignmentmethods assume random assignment

• Maintains advantages of cohort studiesMaintains advantages of cohort studies

Disadvantages of Randomized TrialsDisadvantages of Randomized Trials Disadvantages of Randomized TrialsDisadvantages of Randomized Trials

• May be complex and expensiveMay be complex and expensive

• Prohibitively difficult and expensive with low Prohibitively difficult and expensive with low incidence outcomesincidence outcomes

• May lack representativeness - volunteers may May lack representativeness - volunteers may differ from population of interestdiffer from population of interest

• Ethical challenges of experimental researchEthical challenges of experimental research

• Sometimes impossible or impractical to Sometimes impossible or impractical to conductconduct

• May be complex and expensiveMay be complex and expensive

• Prohibitively difficult and expensive with low Prohibitively difficult and expensive with low incidence outcomesincidence outcomes

• May lack representativeness - volunteers may May lack representativeness - volunteers may differ from population of interestdiffer from population of interest

• Ethical challenges of experimental researchEthical challenges of experimental research

• Sometimes impossible or impractical to Sometimes impossible or impractical to conductconduct

Study outcome measuresStudy outcome measures

• Quantitative

• Qualitative

• Primary

• Secondary

Study outcome measures (contd.)Study outcome measures (contd.)

• Multiple outcomes

• Intermediate endpoints

• Misclassification

• We deal mostly with Phase III trials

• Comparative or Controlled trials

• Variations are kept under control

• Groups differ only with respect to “treatment”

• Integration of statistical ideas and methodology

• Elimination of bias at Design and Analysis Stages

• Define purpose of the trial

(General – Specific objectives)

• Design the trial

(Written protocol, Work instructions etc.,)

• Conduct the trial (Good organization)

• Interim analyses (Stopping rules)

• Analyse the data

(Descriptive statistics, Test the hypothesis)

• Draw conclusions

• Publish results

Steps in RCTsSteps in RCTs

Interventions amenable to Interventions amenable to be studied using clinical be studied using clinical

trialstrials

Interventions amenable to Interventions amenable to be studied using clinical be studied using clinical

trialstrials• Life styleLife style

• DietDiet

• DrugsDrugs

• Operational factorsOperational factors

• Surgical proceduresSurgical procedures

• RehabilitationRehabilitation

• Life styleLife style

• DietDiet

• DrugsDrugs

• Operational factorsOperational factors

• Surgical proceduresSurgical procedures

• RehabilitationRehabilitation

Specific issuesSpecific issues

• Sample selection

• Sample size

• Control groups

• Uncertainty principle:Definite indications

and contraindications

• Randomization

• Blind assessment

• Length of follow-up

Specific issues (cont)Specific issues (cont)Specific issues (cont)Specific issues (cont)

• True effect may not be True effect may not be ascertained for many yearsascertained for many years

• Study power is dependent Study power is dependent on number of events on number of events observed during the studyobserved during the study

• Random allocationRandom allocation

• True effect may not be True effect may not be ascertained for many yearsascertained for many years

• Study power is dependent Study power is dependent on number of events on number of events observed during the studyobserved during the study

• Random allocationRandom allocation

Good Clinical Practices (GCP)Good Clinical Practices (GCP)Good Clinical Practices (GCP)Good Clinical Practices (GCP)

GCP are international ethical and GCP are international ethical and scientific standards scientific standards

setting the setting the minimumminimum requirements requirements

for the development,conduct, for the development,conduct, performance, performance,

monitoring, auditing, recording, monitoring, auditing, recording, analysis and analysis and

reporting of clinical trials that reporting of clinical trials that involve the involve the

participation of human subjectsparticipation of human subjects

GCP are international ethical and GCP are international ethical and scientific standards scientific standards

setting the setting the minimumminimum requirements requirements

for the development,conduct, for the development,conduct, performance, performance,

monitoring, auditing, recording, monitoring, auditing, recording, analysis and analysis and

reporting of clinical trials that reporting of clinical trials that involve the involve the

participation of human subjectsparticipation of human subjects

GCP standards are established by:GCP standards are established by:GCP standards are established by:GCP standards are established by:

• International Conference on HarmonizationInternational Conference on Harmonization

• US Food and Drug AdministrationUS Food and Drug Administration

• Guidelines for Clinical Trials on Pharmaceutical Guidelines for Clinical Trials on Pharmaceutical

Products in India,Central Drugs Standards Products in India,Central Drugs Standards

Control Organization, DGHS, Ministry of Health Control Organization, DGHS, Ministry of Health

and Family Welfare, Govt. of India, 2001and Family Welfare, Govt. of India, 2001

• International Conference on HarmonizationInternational Conference on Harmonization

• US Food and Drug AdministrationUS Food and Drug Administration

• Guidelines for Clinical Trials on Pharmaceutical Guidelines for Clinical Trials on Pharmaceutical

Products in India,Central Drugs Standards Products in India,Central Drugs Standards

Control Organization, DGHS, Ministry of Health Control Organization, DGHS, Ministry of Health

and Family Welfare, Govt. of India, 2001and Family Welfare, Govt. of India, 2001

GCP SynopsisGCP SynopsisGCP SynopsisGCP Synopsis

• Regulations for informed consentRegulations for informed consent

• Regulations for Institutional Ethics Regulations for Institutional Ethics CommitteesCommittees

• Defining the responsibilities of the Defining the responsibilities of the sponsor and investigatorsponsor and investigator

• Control of investigational productControl of investigational product

• Required elements of the investigator’s Required elements of the investigator’s brochurebrochure

• Essential documentsEssential documents

• Regulations for informed consentRegulations for informed consent

• Regulations for Institutional Ethics Regulations for Institutional Ethics CommitteesCommittees

• Defining the responsibilities of the Defining the responsibilities of the sponsor and investigatorsponsor and investigator

• Control of investigational productControl of investigational product

• Required elements of the investigator’s Required elements of the investigator’s brochurebrochure

• Essential documentsEssential documents

Patients, Treatment and Comparison (or Patients, Treatment and Comparison (or Evaluation) are the three key words in Evaluation) are the three key words in the above definitionsthe above definitions

Patients, Treatment and Comparison (or Patients, Treatment and Comparison (or Evaluation) are the three key words in Evaluation) are the three key words in the above definitionsthe above definitions•Patient has to be representative of a targeted Patient has to be representative of a targeted population under study. The results must be population under study. The results must be generalisable to the study population. Healthy generalisable to the study population. Healthy individuals are the experimental units in individuals are the experimental units in prophylactic studiesprophylactic studies

•Treatment may be a Placebo or a Drug or a Treatment may be a Placebo or a Drug or a Compound (low dose aspirin + Beta carotene) or a Compound (low dose aspirin + Beta carotene) or a Diet, or a Surgical Procedure, a Medical Device, a Diet, or a Surgical Procedure, a Medical Device, a Diagnostic test , or even no Treatment:Diagnostic test , or even no Treatment:

•Patient has to be representative of a targeted Patient has to be representative of a targeted population under study. The results must be population under study. The results must be generalisable to the study population. Healthy generalisable to the study population. Healthy individuals are the experimental units in individuals are the experimental units in prophylactic studiesprophylactic studies

•Treatment may be a Placebo or a Drug or a Treatment may be a Placebo or a Drug or a Compound (low dose aspirin + Beta carotene) or a Compound (low dose aspirin + Beta carotene) or a Diet, or a Surgical Procedure, a Medical Device, a Diet, or a Surgical Procedure, a Medical Device, a Diagnostic test , or even no Treatment:Diagnostic test , or even no Treatment:

Patients, Treatment and Comparison (or Patients, Treatment and Comparison (or Evaluation) are the three key words in Evaluation) are the three key words in the above definitions (contd.)the above definitions (contd.)

Patients, Treatment and Comparison (or Patients, Treatment and Comparison (or Evaluation) are the three key words in Evaluation) are the three key words in the above definitions (contd.)the above definitions (contd.)

• e.g.– Radio Therapy + Surgery for Breast Cancere.g.– Radio Therapy + Surgery for Breast Cancer

• – – Antiarrythmic agent + defibrillatorAntiarrythmic agent + defibrillator

• – – MRI with or without a contrast imaging MRI with or without a contrast imaging agentagent

•Evaluation: Efficacy; safety (adverse Evaluation: Efficacy; safety (adverse experience). Recent years have seen evaluation experience). Recent years have seen evaluation encompass encompass Assessment of Quality of Life, Cost- Assessment of Quality of Life, Cost-effectiveness and Cost- Benefiteffectiveness and Cost- Benefit

• e.g.– Radio Therapy + Surgery for Breast Cancere.g.– Radio Therapy + Surgery for Breast Cancer

• – – Antiarrythmic agent + defibrillatorAntiarrythmic agent + defibrillator

• – – MRI with or without a contrast imaging MRI with or without a contrast imaging agentagent

•Evaluation: Efficacy; safety (adverse Evaluation: Efficacy; safety (adverse experience). Recent years have seen evaluation experience). Recent years have seen evaluation encompass encompass Assessment of Quality of Life, Cost- Assessment of Quality of Life, Cost-effectiveness and Cost- Benefiteffectiveness and Cost- Benefit

Designing a Controlled Clinical Designing a Controlled Clinical Trial (RCT)Trial (RCT)

Designing a Controlled Clinical Designing a Controlled Clinical Trial (RCT)Trial (RCT)

1.1. Starting point for a Controlled Clinical Trial is a clear Starting point for a Controlled Clinical Trial is a clear

statement of the Research Question. It is advisable statement of the Research Question. It is advisable

to have a single Primary Research Question to have a single Primary Research Question

addressed in the trial. There may be Secondary addressed in the trial. There may be Secondary

questions also. The trial will be planned to answer questions also. The trial will be planned to answer

the Primary Question with adequate Power.the Primary Question with adequate Power.

1.1. Starting point for a Controlled Clinical Trial is a clear Starting point for a Controlled Clinical Trial is a clear

statement of the Research Question. It is advisable statement of the Research Question. It is advisable

to have a single Primary Research Question to have a single Primary Research Question

addressed in the trial. There may be Secondary addressed in the trial. There may be Secondary

questions also. The trial will be planned to answer questions also. The trial will be planned to answer

the Primary Question with adequate Power.the Primary Question with adequate Power.

Designing a RCTDesigning a RCTDesigning a RCTDesigning a RCT

22.. The Primary Research Question will determine the The Primary Research Question will determine the

Study Objective (s) and will help us to set up Study Objective (s) and will help us to set up

appropriate hypotheses for evaluationappropriate hypotheses for evaluation• e.g Sample Statement of Objectives:e.g Sample Statement of Objectives:• Evaluate the efficacy of several lipid-influencing drugs in the long-term Evaluate the efficacy of several lipid-influencing drugs in the long-term

therapy of CHD in men ages 30 through 64 with evidence of previous therapy of CHD in men ages 30 through 64 with evidence of previous myocardial infarctionmyocardial infarction

• State type of patients, class of treatments; But ambiguous on outcomeState type of patients, class of treatments; But ambiguous on outcome

3.3. The next step would be to prepare a well-organised The next step would be to prepare a well-organised

written protocol of the clinical trialwritten protocol of the clinical trial

22.. The Primary Research Question will determine the The Primary Research Question will determine the

Study Objective (s) and will help us to set up Study Objective (s) and will help us to set up

appropriate hypotheses for evaluationappropriate hypotheses for evaluation• e.g Sample Statement of Objectives:e.g Sample Statement of Objectives:• Evaluate the efficacy of several lipid-influencing drugs in the long-term Evaluate the efficacy of several lipid-influencing drugs in the long-term

therapy of CHD in men ages 30 through 64 with evidence of previous therapy of CHD in men ages 30 through 64 with evidence of previous myocardial infarctionmyocardial infarction

• State type of patients, class of treatments; But ambiguous on outcomeState type of patients, class of treatments; But ambiguous on outcome

3.3. The next step would be to prepare a well-organised The next step would be to prepare a well-organised

written protocol of the clinical trialwritten protocol of the clinical trial

Contents of Protocol for Clinical TrialsContents of Protocol for Clinical TrialsContents of Protocol for Clinical TrialsContents of Protocol for Clinical Trials

1.1. Study BackgroundStudy Background

2.2. Statement of objectivesStatement of objectives

3.3. Primary objectivePrimary objective – with a Concise and Precise – with a Concise and Precise statement of pre-specified hypotheses based on statement of pre-specified hypotheses based on clinical responses for evaluation of the drug. clinical responses for evaluation of the drug. (Patients to be studied, treatment, and outcome )(Patients to be studied, treatment, and outcome )

4.4. Secondary objective (s)Secondary objective (s)

• (Sometimes sub-group analyses may be stated)(Sometimes sub-group analyses may be stated)

1.1. Study BackgroundStudy Background

2.2. Statement of objectivesStatement of objectives

3.3. Primary objectivePrimary objective – with a Concise and Precise – with a Concise and Precise statement of pre-specified hypotheses based on statement of pre-specified hypotheses based on clinical responses for evaluation of the drug. clinical responses for evaluation of the drug. (Patients to be studied, treatment, and outcome )(Patients to be studied, treatment, and outcome )

4.4. Secondary objective (s)Secondary objective (s)

• (Sometimes sub-group analyses may be stated)(Sometimes sub-group analyses may be stated)

• 3. Study plan3. Study plan

- Study design - Study design

- Should permit valid Statistical Inference- Should permit valid Statistical Inference

- Describe Patient and Control groups with rationale for - Describe Patient and Control groups with rationale for choicechoice

- Single centre or Multi-centric study- Single centre or Multi-centric study

- Patient Inclusion and Exclusion criteria- Patient Inclusion and Exclusion criteria

Unambiguous to define the targeted populationUnambiguous to define the targeted population

- Method of Randomisation & BlindingMethod of Randomisation & Blinding

- Study Subject withdrawal- Study Subject withdrawal

• 3. Study plan3. Study plan

- Study design - Study design

- Should permit valid Statistical Inference- Should permit valid Statistical Inference

- Describe Patient and Control groups with rationale for - Describe Patient and Control groups with rationale for choicechoice

- Single centre or Multi-centric study- Single centre or Multi-centric study

- Patient Inclusion and Exclusion criteria- Patient Inclusion and Exclusion criteria

Unambiguous to define the targeted populationUnambiguous to define the targeted population

- Method of Randomisation & BlindingMethod of Randomisation & Blinding

- Study Subject withdrawal- Study Subject withdrawal


• 4. Study Drugs4. Study Drugs

• Dose and Route of administration and DurationDose and Route of administration and Duration

• Method of Dispensing Method of Dispensing (Package and labeling included)(Package and labeling included)

• Method of AdministrationMethod of Administration

• Any Concomitant medications / proceduresAny Concomitant medications / procedures

• 4. Study Drugs4. Study Drugs

• Dose and Route of administration and DurationDose and Route of administration and Duration

• Method of Dispensing Method of Dispensing (Package and labeling included)(Package and labeling included)

• Method of AdministrationMethod of Administration

• Any Concomitant medications / proceduresAny Concomitant medications / procedures


• 5. Measurements and observations5. Measurements and observations• Response variable Response variable

– – Valid and Reliable measurement; Valid and Reliable measurement;

- measurement schedulemeasurement schedule

- Surrogate response variableSurrogate response variable

• Intermediate end point like CD Intermediate end point like CD 4 4 in AIDS or mortality in AIDS or mortality

in HIV +ve reduces period of follow up Impact on in HIV +ve reduces period of follow up Impact on sample size ( Continuous Vs Qualitative variable)sample size ( Continuous Vs Qualitative variable)

• Caution Caution Should truly reflect the Clinical outcome and Should truly reflect the Clinical outcome and be acceptable to study patientsbe acceptable to study patients

• Adverse effects of intervention may be incompletely Adverse effects of intervention may be incompletely evaluatedevaluated

• 5. Measurements and observations5. Measurements and observations• Response variable Response variable

– – Valid and Reliable measurement; Valid and Reliable measurement;

- measurement schedulemeasurement schedule

- Surrogate response variableSurrogate response variable

• Intermediate end point like CD Intermediate end point like CD 4 4 in AIDS or mortality in AIDS or mortality

in HIV +ve reduces period of follow up Impact on in HIV +ve reduces period of follow up Impact on sample size ( Continuous Vs Qualitative variable)sample size ( Continuous Vs Qualitative variable)

• Caution Caution Should truly reflect the Clinical outcome and Should truly reflect the Clinical outcome and be acceptable to study patientsbe acceptable to study patients

• Adverse effects of intervention may be incompletely Adverse effects of intervention may be incompletely evaluatedevaluated



• 6. Statistical methods6. Statistical methods

• Sample size; Handling Dropouts, Missing Data, Sample size; Handling Dropouts, Missing Data,

• Measurement of Covariates, Sub-group analyses Measurement of Covariates, Sub-group analyses planned planned

• Interim analysis (Termination), Analytical tools to Interim analysis (Termination), Analytical tools to be usedbe used

• 7.Adverse events (Side-effects…) Reporting7.Adverse events (Side-effects…) Reporting

• Clinical / laboratory supportedClinical / laboratory supported

• 8. Institutional Review / Ethics Committee approval8. Institutional Review / Ethics Committee approval

• 6. Statistical methods6. Statistical methods

• Sample size; Handling Dropouts, Missing Data, Sample size; Handling Dropouts, Missing Data,

• Measurement of Covariates, Sub-group analyses Measurement of Covariates, Sub-group analyses planned planned

• Interim analysis (Termination), Analytical tools to Interim analysis (Termination), Analytical tools to be usedbe used

• 7.Adverse events (Side-effects…) Reporting7.Adverse events (Side-effects…) Reporting

• Clinical / laboratory supportedClinical / laboratory supported

• 8. Institutional Review / Ethics Committee approval8. Institutional Review / Ethics Committee approval

Ethical issues in clinical trialsEthical issues in clinical trialsEthical issues in clinical trialsEthical issues in clinical trials

1.1. Ethics of Doing and not Doing a clinical trialEthics of Doing and not Doing a clinical trial

2.2. No harm to participantsNo harm to participants

3.3. Not missing opportunity to benefit societyNot missing opportunity to benefit society

4.4. If drug known to be better – no control groupIf drug known to be better – no control group

5.5. Alternative treatment as a controlAlternative treatment as a control (unrelated treatment (unrelated treatment also)also)

6.6. Efficacy of drug must be truly unknown Study Validity Efficacy of drug must be truly unknown Study Validity should be ensuredshould be ensured – – Sample size, Allocation, Blinding etc.Sample size, Allocation, Blinding etc.

1.1. Ethics of Doing and not Doing a clinical trialEthics of Doing and not Doing a clinical trial

2.2. No harm to participantsNo harm to participants

3.3. Not missing opportunity to benefit societyNot missing opportunity to benefit society

4.4. If drug known to be better – no control groupIf drug known to be better – no control group

5.5. Alternative treatment as a controlAlternative treatment as a control (unrelated treatment (unrelated treatment also)also)

6.6. Efficacy of drug must be truly unknown Study Validity Efficacy of drug must be truly unknown Study Validity should be ensuredshould be ensured – – Sample size, Allocation, Blinding etc.Sample size, Allocation, Blinding etc.

• 3. Informed consent 3. Informed consent Understand requirements for Understand requirements for

participation in trial. Must be clearly explained procedures participation in trial. Must be clearly explained procedures

to be performed.to be performed.

Should consent to receiving a placebo. Should be free to Should consent to receiving a placebo. Should be free to

refuse to participate or withdraw refuse to participate or withdraw

4. Stopping rule to be stated before start of trial4. Stopping rule to be stated before start of trial

- Clinical efficacy of test treatmentClinical efficacy of test treatment

- Toxicity of test treatmentToxicity of test treatment

- External ( independent ) experts to do thisExternal ( independent ) experts to do this

• 3. Informed consent 3. Informed consent Understand requirements for Understand requirements for

participation in trial. Must be clearly explained procedures participation in trial. Must be clearly explained procedures

to be performed.to be performed.

Should consent to receiving a placebo. Should be free to Should consent to receiving a placebo. Should be free to

refuse to participate or withdraw refuse to participate or withdraw

4. Stopping rule to be stated before start of trial4. Stopping rule to be stated before start of trial

- Clinical efficacy of test treatmentClinical efficacy of test treatment

- Toxicity of test treatmentToxicity of test treatment

- External ( independent ) experts to do thisExternal ( independent ) experts to do this

Ethical issues in clinical trialsEthical issues in clinical trialsEthical issues in clinical trialsEthical issues in clinical trials

Randomisation proceduresRandomisation proceduresRandomisation proceduresRandomisation procedures

• 1.Fixed numbers to treatment regimens1.Fixed numbers to treatment regimens

a) Simple randomisationa) Simple randomisation

b) Blocked randomisationb) Blocked randomisation

c) Stratified allocationc) Stratified allocation

2. Adaptive Randomisation2. Adaptive Randomisation

- to ensure desired allocation ratio- to ensure desired allocation ratio

• - to ensure comparability of baseline - to ensure comparability of baseline characteristicscharacteristics

• - outcome adaptive - outcome adaptive not desirable not desirable

• 1.Fixed numbers to treatment regimens1.Fixed numbers to treatment regimens

a) Simple randomisationa) Simple randomisation

b) Blocked randomisationb) Blocked randomisation

c) Stratified allocationc) Stratified allocation

2. Adaptive Randomisation2. Adaptive Randomisation

- to ensure desired allocation ratio- to ensure desired allocation ratio

• - to ensure comparability of baseline - to ensure comparability of baseline characteristicscharacteristics

• - outcome adaptive - outcome adaptive not desirable not desirable

Bias Bias Bias Bias

• Selection Selection Incomplete review; of literature also Incomplete review; of literature also

• ObservationObservation Exposure and outcome Exposure and outcome

• Statistical procedureStatistical procedure Analysis / Interpretation Analysis / Interpretation

• PublicationPublication

• Selection Selection Incomplete review; of literature also Incomplete review; of literature also

• ObservationObservation Exposure and outcome Exposure and outcome

• Statistical procedureStatistical procedure Analysis / Interpretation Analysis / Interpretation

• PublicationPublication

ConclusionsConclusionsConclusionsConclusions

• RCT is the standard but not the only approachRCT is the standard but not the only approach

• Rigorous scientific assessment – absolutely essentialRigorous scientific assessment – absolutely essential

• Involve researchers and practitioners in the concerned Involve researchers and practitioners in the concerned

system of medicine system of medicine

• Ethics and human rightsEthics and human rights

• RCT is the standard but not the only approachRCT is the standard but not the only approach

• Rigorous scientific assessment – absolutely essentialRigorous scientific assessment – absolutely essential

• Involve researchers and practitioners in the concerned Involve researchers and practitioners in the concerned

system of medicine system of medicine

• Ethics and human rightsEthics and human rights

Randomized Controlled Trials (RCT). Definition of levels of evidence and grading of recommendation...

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