Adaptive Study Designs

Dr. Anirudha Potey

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Background

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Defining adaptive study design

Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics

‘a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study ’

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without undermining the validity and integrity of

the trial

Is Adaptive Study Design a Modern Phenomenon?

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Not Adaptive Study Design

Revisions based on the data

• Obtained external of the current trial

• After unblinding data and not pre-planned

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Types of adaptations

• Prospective

• Concurrent

• Retrospective

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Types of adaptations

Trial procedures

Eligibility criteria

Study dose – therapy regimen

Duration of treatment

Study endpoints

Lab testing procedures

Diagnostic procedures

Concomitant treatments used

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Types of adaptations

Trial procedures

Planned schedule of the patient evaluations

evaluations for the data collection (eg.

number of the intermediate time points,

timing of the last patient observation and

duration of the patient study participation)

Criteria for evaluation and assessment of

clinical responses

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Types of adaptations

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Statistical procedure

Randomization

Study design

Study hypothesis

Sample size

Data monitoring

Interim analysis

Statistical analysis plan/

Well understood Adaptive Study Designs

• Adaptation of Study Eligibility Criteria Based

• Adaptations to Maintain Study Power

• Adaptations based on the interim results of an outcome unrelated to efficacy

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Well understood Adaptive Study Designs

• Adaptations Using Group Sequential Methods and unblinded Analyses

• Adaptations based on the Data Analysis Plan

• Adaptation for the primary endpoint

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Types of Adaptive Study Designs• Adaptive Randomization Design

• Sample size re-estimation design

• Drop the loser design

• Adaptive dose finding design

• Biomarker adaptive design

• Adaptive treatment switching design

• Group sequential design

• Hypothesis adaptive design

• Adaptive seamless phase II/III trial design

• Multiple adaptive design12

Allocation

rule

Sampling

rule

Stopping

rule

Decision

rule

Fifth rule

Adaptive Randomization

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Group Sequential Design

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Group Sequential Design

• Early Termination

• Stopping rules

• Utility rules

• Futility rules

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Sample size re-estimation

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Drop the loser

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Adaptive Dose finding design

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Biomarker adaptive design

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Adaptive treatment switching design

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Hypothesis adaptive design

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Adaptive seamless phase II/III design

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Multiple adaptive designs

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Advantages over Conventional Study Designs• Same information more efficiently

• More success

• Improved understanding of treatment effect

• CSD – inaccurate estimates or assumptions

• Decrease cost and time by discontinuing a group

• Adjust sample to avoid an undesired powered study

• Assessment of more choices within same time frame

• No protocol amendment24

Comparing Adaptive and Conventional study designsFeatures Conventional

trial

Adaptive design

Design More rigid Flexible

Treatment arms Max. 2 – 3 Many

simultaneously

Hypothesis Test the

hypothesis

under

consideration

Fit data into

hypothesis

Modifications Not allowed

without protocol

amendments

Pre-specified

allowed25

Comparing Adaptive and Conventional study designs

Features Conventional

trial

Adaptive design

Phases Phases I – II are

well defined

Can be seamless

phase 2/3

Statistical

analysis

Frequentist

approach

Complicated

Bayesian

approach

Organization Much simple Complicated

Interim analysis Not routine Routinely and

frequently

Regulatory view Well endorsed speculative26

Concerns associated with Adaptive study designs

• Increased type I error

• Difficult interpretation of results

• More planning and lead time

• Develop into a completely different trial

• Incorporation of a totally different population

• Bayesian statistics

• Computer based simulations

• Challenge to CROs and EC27

Concerns associated with Adaptive study designs

• Lack of definition by regulatory authorities

• Bayesian approach is compulsion – non

standard

• Damage to integrity

• Magnify bias with increase in sample size

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Procedural issues

• Rapid electronic collection of data

• Efficient interaction b/w investigator and

sponsor

• Financial investments

• Computer based simulations with

infrastructure and software

• CRO & EC lack experience of monitoring

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Regulatory perspective

• Acceptable level of adaptation?

• Regulatory standards for review and approval

process of clinical data?

• A completely new clinical trial post

modification?

• Increased interaction b/w FDA and sponsors

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Ethics

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Writing adaptive protocols

• Description of adaptive features

• Defining limits of adaptations

• Description of control mechanism

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Keep in mind the adaptive process

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Conclusion

• Many advantages

• Infant stage – many areas are controversial

• Not an ad hoc measure for poor planning

• Strong promise for the future

• More guidelines and better understanding

• Complexities limit use

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