Clinical Trials Design Dr Ritu Budania JR 2 Department of Pharmacology GMC Nagpur

Overview•Introduction

• Clinical Trial Designs

•Challenges

•Application in different phases of trial

•Summary

Clinical Research

All scientific approaches to evaluate medical disease in terms

Prevention Diagnosis Treatment

Humans

Clinical research design

No intervention Intervention

Observational Experimental

Comparison group

NoYes

Analytical study (case control,

cohort)

Descriptive study

Random allocation

Yes No

Randomized controlled trial

Non-Randomised

Types of Clinical trials

Treatment trials

Prevention trials

Quality of life trials

Diagnostic trials

Drug development

Clinical Trial Designs

Designs

Parallel Cross over Factorial Randomized withdrawal approach Adaptive Superiority Non-inferiority

Parallel

• Subjects are randomised to one of two or more arms

• Each arm being allocated a different treatment

• Most commonly used design

Eligibilty assessed

Consent

Control

Test drug

Randomised

Controls in Clinical Trials

1. Placebo

2.No-treatment

3.Active

4. Dose Response

5. External Controls

5 mg

1. Placebo Control• Placebo- inert substance – looks exactly

like test drug but contains no drug

• In trials testing efficacy

• Double blinded

Advantages of Placebo control

• Minimizes bias

• Ability to demonstrate efficacy

When to use placebo?1.In disease in which no prior drug has been

established as - standard therapy2. Minimal risk, short term study3.Add-on design

Disadvantages of Placebo Control: 1.Ethical Issues - Lack of treatment -Serious harm( such as

death or irreversible morbidity) -Declaration of Helsinki – use of standard

treatment as control -Used where minimal risk

2.Patient and physician concerns:-Patients may not enroll-Withdraw

2. No treatment control

• Subjects are randomly assigned to test treatment or to no treatment

• Subjects, investigators are not blind to treatment

• Bias

3.Active control Standard treatment exists

phase III study designs compare “new drug” to standard or compare standard to combination therapy that

involves the standard + “new drug”

• 4.Dose response control• 5.External control

Comparability ?Baseline characteristics?No randomization, blindingBias

Uncontrolled trials

• No controls• When-- Determine pharmacokinetic properties of a

new drug (phase 1 trial)• Limitation- Bias , as no randomization, less

validity than RCT

Run-In Design

• Non-compliance

Run-In Design

Screen & Consent

Placebo Run-In Period

RANDOMIZECompliance Unsatisfactory

Dropped

B

A complianceSatisfactory c

2.Cross over

• Each patient gets both drugs• the order in which the patient gets each drug is randomized• Each patient serves as his own control• Avoids between participant variation in estimating

intervention effect • Requires a small sample size • Assumptions: –The effects of intervention during first period does not carry

over into second period. –Internal and external factors are constant over time

A A

B B

A followed by BB followed by A

ABABAB

ABABBABA

Cross over design with switch-back

C.O. design with double switch-back

Run in

Wash out period

Prerequisites for crossover design

• Disease – chronic (asthma, osteoarthritis) stable

• Effects of drug should develop fully within treatment period (not for Hit and run type drugs)

• Washout periods -sufficiently long for complete reversibility of drug effect

• Wash out period- five half lives of drug

Crossover designs- problems

1.Carryover effect 2.Period effect- patients vary from 1 period to another3.Not useful for acute disease4.Difficulties in assigning adverse events which occur in later

treatment periods to appropriate treatment 5.generally not used in vaccine trials because immune

system is permanently affected (or at least affected for a long time)

Use of cross over design:

• Bioequivalence studies• Phase I

Parallel Crossover

Groups assigned different treatments

Each patient receives both treatments

Shorter duration Longer

Sample size- large Smaller

No carryover effect Carryover effect

Acute cases Not in acute, Chronic,stable

Latin Square Design

A B C

B C A C A B

I II III

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Subjects

Period

Greco-Latin Squares

Effect of treatment & effect of another factor (eg. ancillary Treatment, diet etc)  

A B C B C A C A B

I II III

1

2

3

Subjects

Intensive Design: Comparing 2 Tts.(A & B) each subject receives same Tt. several times.

Period I II III IV V VI

Treatment A B B A A B

- For short period of Rx/single dose- For testing efficacy of new compound

3.Factorial design

- two or more interventions- Allows study of interactive effects

2×2 factorial design

B only Neither A nor B

A onlyBoth A and B

Advantages-Two drugs studied at same time-Discover interactions-Test FDC

Disadvantages1.Complexity of trial design2. Complexity of statistical analysis

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Incomplete Factorial DesignEg. depression; if unethical to

do nothing

• A – Desipramine• B – Congnitive therapy• C – Combination of A & B

3 n eligible

A no, B yes

A yes, B no

A yes, B yes

4.Randomized withdrawal approach

Third, the design is particularly useful in determining how long a therapy should be continued (e.g., post-infarction treatments with a beta-blocker

Group 1 Group II

Pt Sex Age IQ Pt Sex Age IQ 1. m 25 95 4 m 25 95 2. f 35 100 5 f 35 100 3. m 45 105 6 m 45 105

5. Matched pairs - Pts. With same characteristics - Expected to respond similarly

Group characteristics

2 males 1 female 2 males 1 female Average age 35 yrs. 35 yrs.Average IQ 100 100 Pt 1. matches with Pt 4

2. 5״ ״ ״

3. 6״ ״ ״ Advantage- Less Variability 

  

Group -I Group-II

Clinical trial design innovations

• Adaptive Design- allows adaptations or modifications to trial

design after its initiation without undermining validity and integrity of trial

1.Maximum Information Design

• interim analyses until the target or maximum information level reached.

• Whenever the pre-specified target information level is reached, the patient recruitment is stopped.

2.N-Adjustable Design

3. Group sequential design

prematurely terminating trial based on the results of interim analyses

• Early-efficacy stopping• Early futility stopping

(4) Drop-Losers Design

- allows dropping of treatment arm(s) during study based on interim analysis results

-trial starts with several treatment groups; at each stage, interim analyses are performed

- losers (inferior groups) are dropped based on prespecified criteria.

-best arm(s) will be retained. -used in a phase-II/III combined trial

5.Adaptive Randomization Design

• Response-adaptive randomization (RAR) -allocation probability is based on response of previous patients.

• The purpose is to provide the patients with a better chance of being assigned to the better/best treatment

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Superiority Trials

Show that new treatment is better than control or standard (maybe a placebo)

• Examples:Placebo-controlled efficacy trials

Active controlled

Non-Inferiority Trials

-Show that new treatmentIs not worse that the standard by more than

some margin-Active control equivalence trial -Placebo not used-Better tolerated, less dosing

X is non inferior

Placebo Active ControlDELTA

Multicentric trials

1. Large sample size needed- in less time2. Availability of eligible patients is a constraint3. Role of Racial/ Ethnic factors to be studied

• Strict protocol compliance by Investigators at all centres

• Central monitoring committee• Phase III trials

Challenges in Design:

Control of bias (Randomization, Blinding )

Bias

Prejudice Deviation from truth Selection/Allocation bias Observer bias

Good study design - minimizing all possible sources of bias

Randomization

-Assigns patients to treatment arms by chance-Eliminates selection bias

Pseudo randomization

Randomization methods

1. Simple randomization

2. Block Randomization

3. Stratified Randomization ( age, gender, stage, severity)

Tossing coin Dice

Random number table Computer generated

Randomized controlled trials

• Gold standard• Minimize bias• Costly, time consuming

Allocation Concealment

• Preventing next assignment in clinical trial from being known

• procedure for protecting randomization process so that treatment to be allocated is not known before the patient is entered into the study

Methods of Allocation concealement

• Sequentially numbered, opaque, sealed envelopes,

• Pharmacy-controlled allocations • Coded identical containers or kits • Central randomisation systems

Blinding

• ensuring that neither patients, healthcare providers, nor researchers know to which group specific patients are assigned

Reasons for blinding-Patients on active treatment - adhere Placebo- do not adhere - Observer’s bias- Principal investigator-more vigorously examine active group

Blinding types

• Open label• Single blind• Double blind• Triple blind • PROBE (Prospective Randomized Open with

Blinded End point Assessment)

No standard definitionShould be specified who is blinded and how

Double dummy technique

Randomise

Placebo

Placebo

Blinding not possible when

• Surgery with non–surgical treatment• Types of dialysis [hemodialysis versus

peritoneal dialysis]

Application of various designs in phases of clinical trial

Phase I (Human Pharmacology)Aims:

– To find safe dose range – Pharmacokinetics of drug– Drug food interaction– First in man study

Sample:• Healthy volunteers • Drug -too toxic (cancer, HIV): patients Sample size- 20-50

Phase I contd

Design Open label Non-randomized Dose escalation Uncontrolled

Randomized 2 way crossover study of one dose level of drug under fasting and fed conditions

6004/11/2023

Phase II (Therapeutic exploratory) IIa IIb

II a- Proof of conceptSample – PatientsSample size- 40-100 subjectsPlacebo control preferrednot- multi centered

Phase II b- Dose range finding• To find optimal dose response range• 300-400 patients• Placebo/ active control• Multicentric

Phase III

Confirmatory trials- confirm drug is safe and effective• Sample- 1000-3000 patients• Active controlled• Randomized• Double blinded• Parallel• Non-inferiority• Multicentric

Phase IV

Post- marketing surveillance• Detect long term ,rare side effects• Pharmacoeconomics• New indication

UncontrolledObservationalNew drug status-

4 years

Bioequivalence studies

• For generic drug submission• ANDA- Abbreviated new drug application• RLD- Reference listed drug• Parallel-Group Design •Even number of subjects in two groups •Each receive a different formulation

Single dose,two way crossover

fasting

Single dose,two way crossover

fed

Single dose parallel fasting

Multiple dose, crossover fasting

Microdosing (Phase 0)

• Candidate drugs fail- suboptimal human pharmacokinetics

• FDA- 100 mcg drug or < 1/100 th of pharmacological dose

determined from animal models• LCMS

Hierarchy of EvidenceRCT

Open label,Cohort studies

Case control studies

Case series

Case reports

SummarySuccess of clinical trial- appropriate clinical

design, control group

RCT – gold standard

Blinding, randomization- minimize bias

References

1.ICH E8 ,9,10 Guidelines : General consideration for clinical trials, Current Step 4 version, 1997

2. Lawrence J. Appel. Primer on the Design, Conduct, and Interpretation of Clinical Trials. Clin J Am Soc Nephrol 1: 1360–1367, 2006

3.Shein-Chung Chow and Mark Chang. Adaptive design methods in clinical trials – a review .Orphanet Journal of Rare Diseases 2008, 3:11

4.Kenneth F Schulz, David A Grimes. Blinding in randomised trials: hiding who got what. THE LANCET 2002 ,359:2

5.New Movement in Drug Development Technology – Micro-dosing and its challenges, QUARTERL REVIEW No.40 / July 2011

6.Thereasa A , Clinical pharmacology ; Goodman and Gilmans, Pharmacological basis of therapeutics; 12;1731-50; 2010.

7.HL Sharma and KK Sharma, Clinical pharmacology , Principles of Pharmacology;2;871-91;2010