Efficient Designs for Phase II Efficient Designs for Phase II and Phase IIIand Phase III Trials Trials

Jim PaulJim Paul

CRUK Clinical Trials Unit GlasgowCRUK Clinical Trials Unit Glasgow

EfficientEfficient

Maximising the probability of getting Maximising the probability of getting the the rightright answer as quickly as answer as quickly as possiblepossible

Very easy to get the Very easy to get the wrongwrong “answer” “answer”

Finding effective treatmentsFinding effective treatments Dismissing ineffectiveDismissing ineffective

Miss effective treatments at phase II, Miss effective treatments at phase II, because of poor study designbecause of poor study design

Wasting resource on phase III studies Wasting resource on phase III studies of ineffective regimensof ineffective regimens

Getting it wrong:-Getting it wrong:-

Found 43 phase III studies fulfilling this Found 43 phase III studies fulfilling this criteria (1998-2003)criteria (1998-2003)

Comparison of Outcome in Phase II Comparison of Outcome in Phase II Studies and Subsequent Randomized Studies and Subsequent Randomized Control Studies Using Identical Control Studies Using Identical Chemotherapeutic RegimensChemotherapeutic Regimens Zia et al JCO Zia et al JCO 20052005

Only Only 28%28% of subsequent phase III studies of subsequent phase III studies were positivewere positive

Mean size of phase II :- 52 Mean size of phase II :- 52 patientspatients Some evidence that bigger phase Some evidence that bigger phase

II studies gave better predictions of II studies gave better predictions of phase III successphase III success

96% single arm phase II96% single arm phase II

Efficient design for Efficient design for phase II trialsphase II trials

Phase II is the foundation on which Phase II is the foundation on which we build – needs to be soundwe build – needs to be sound

Reliably quantify/indicate the risk of Reliably quantify/indicate the risk of success/failure in a subsequent phase III success/failure in a subsequent phase III study study

Best way to do this is to Best way to do this is to randomiserandomise between the experimental and control between the experimental and control arms in the phase II settingarms in the phase II setting

Randomisation in Phase II Randomisation in Phase II studiesstudies

•Van Glabbeke M, Steward W, Armand JP. Non-randomised phase II trials of drug combinations: often meaningless, sometimes misleading. Are there alternative strategies? EJC (2002)

•Recommended changes to oncology clinical trial design: Revolution or evolution?, Ratain et al EJC, Jan 2008

“We strongly recommend that randomised comparative phase II trials become a standard approach in oncology, especially for the development of drug combinations”

•Optimising the design of phase II oncology trials: The importance of randomisation. Mark Ratain and Dan Sargent EJC (2009)

“…fundamental need for randomisation in phase II oncology trials….ideally with blinding and dose ranging.”

• Single arm studies prone to selection bias (clinician selection/patient preference) – therefore comparisons with historical benchmarks are intrinsically an unreliable basis for decision making

•Major problems in studies where the new drug is combined with active standard treatment and the additional benefit is likely to be “modest” and could easily be lost in study bias or in the imprecision of the estimated historical effect

Need for randomisation: - Need for randomisation: -

• No real allowance for imprecision in the historical estimate of response used as the basis for single arm phase II design

Randomised Phase II Trial Randomised Phase II Trial Design in Ovarian CancerDesign in Ovarian Cancer

Role of randomisationRole of randomisation

• What size of benefit can be expected from new agents in ovarian cancer?

•Introduction of taxanes into first line (GOG111/OV10) – 25% reduction in hazard for pfs

• Addition of taxane in relapse (ICON4) – 25% reduction in hazard for pfs

• 25% reduction in hazard (HR=.75) corresponds to an absolute increase in pfs of only approximately 10% at a given time-point (e.g. 50% to 60% or 20% to 30%)

Randomised Phase II Trial Randomised Phase II Trial DesignDesign

Screening designScreening design (Rubinstein (Rubinstein J Clin Oncol 23:7199-7206 (2005))

• Use a permissive 1-sided significance level (10% or 20%) to decide whether there is sufficient activity to go to phase III

• Set realistic bar for efficacy

Randomised Phase II Trial Randomised Phase II Trial DesignDesign

Any way to reduce these numbers?Any way to reduce these numbers?

Early stopping for futility in a Early stopping for futility in a randomised phase II:-randomised phase II:-

Sin-Ho Jung Statist. Med. 2008; 27:568–583

Three outcome design:-Three outcome design:- A Three Outcome Design for A Three Outcome Design for Randomised Comparative phase II Randomised Comparative phase II Clinical Trials.Clinical Trials. Hong and Wang. Hong and Wang. Statistics in Medicine (2006)Statistics in Medicine (2006)

Randomised Phase II Trial Randomised Phase II Trial DesignDesign Three outcome designThree outcome design

Statistically significant at 10%:- Statistically significant at 10%:- Clear indication from study data to Clear indication from study data to proceed to phase IIIproceed to phase IIINot statistically significant at 20%:-Not statistically significant at 20%:- Clear indication from study data Clear indication from study data NOT NOT to to proceed to phase IIIproceed to phase III

Three possible outcomes Three possible outcomes e.g.:-e.g.:-

Statistically significant at 20%, but not 10%:-Statistically significant at 20%, but not 10%:-Uncertain outcome – decision based on Uncertain outcome – decision based on

other information (changes in relevant biomarkers, other information (changes in relevant biomarkers, clinical judgement)clinical judgement)

Randomised Phase II Trial Randomised Phase II Trial DesignDesign Three outcome designThree outcome design

Allows the sample size requirements for screening designs to be lowered Allows the sample size requirements for screening designs to be lowered ((20–30% less than that of the corresponding two-outcome screening design)

The price paid is the introduction The price paid is the introduction of an area of uncertaintyof an area of uncertainty

Avoids the “discomfort” of a Avoids the “discomfort” of a go/no-go decision resting go/no-go decision resting potentially on a single responsepotentially on a single response

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Ha

zard

ra

tioE

stim

ate

d H

R f

rom

p

hase

II

Est

imate

d H

R f

rom

p

hase

II

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Haz

ard

rati o

(f r

om p

h ase

I I)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0Probability of success in phase III

A Better Estimate of Success at Phase III

Weighted average probability of success over range of plausible estimates of HR from phase II

(Christy Chuang-Stein Sample size and the probability of a successful trial (Christy Chuang-Stein Sample size and the probability of a successful trial Pharmaceut. Statist. 2006; 5: 305–309)Pharmaceut. Statist. 2006; 5: 305–309)

Moving from Phase II to Phase Moving from Phase II to Phase IIIIII

For fixed phase III sample size estimated For fixed phase III sample size estimated probability of success depends on –probability of success depends on –

Estimated phase II hazard ratio (bigger Estimated phase II hazard ratio (bigger difference -> bigger probability of success)difference -> bigger probability of success)

Precision of estimate (higher precision of Precision of estimate (higher precision of estimate -> higher probability of successestimate -> higher probability of success))

Use these probabilities to prioritise your Use these probabilities to prioritise your phase III effortphase III effort

Seamless Phase II/III Trial Seamless Phase II/III Trial DesignDesign

- To make efficient use of the patients involved in phase II - desirable to incorporate their information into subsequent phase III – seamless phase II/III

Reliable randomised Phase II Reliable randomised Phase II designs tend to be relatively largedesigns tend to be relatively large

- To make efficient use of control patients involved - incorporate multiple experimental arms – not all of which will go on to phase III stage

Seamless Phase II/III Trial DesignSeamless Phase II/III Trial Design- Multi-Arm/Multi-Stage (MAMS) - Multi-Arm/Multi-Stage (MAMS)

Designs –Designs –Parmar et a JNCI 2008Parmar et a JNCI 2008 GOG182 -ICON 5 prime example (4 GOG182 -ICON 5 prime example (4

experimental arms/ 2 stages)experimental arms/ 2 stages)

- Used intermediate phase II outcome (pfs) to decide whether to continue experimental arms to phase III

Phase III bitPhase II bit

Seamless Phase II/III Trial DesignSeamless Phase II/III Trial Design- Multi-Arm/Multi-Stage (MAMS) - Multi-Arm/Multi-Stage (MAMS)

Design –Design – MRC STAMPEDE study in prostate cancerMRC STAMPEDE study in prostate cancer(1 control, 5 experimental arms – randomisation ratio (1 control, 5 experimental arms – randomisation ratio

(2:1:1:1:1:1)(2:1:1:1:1:1)

Phase II bit

Phase III bit

Seamless Phase II/III Trial DesignSeamless Phase II/III Trial Design- Multi-Arm/Multi-Stage (MAMS) - Multi-Arm/Multi-Stage (MAMS)

Design –Design – AdvantagesAdvantages

-Rapid and reliable way to assess a large number of promising new combinations simultaneously – ICON5 (3.5 years to assess 4 new treatments)

DisadvantagesDisadvantages

-Time consuming and complex to set up

-Potentially very large studies requiring large inter-group collaboration

Seamless Phase II/III Trial Seamless Phase II/III Trial DesignDesign

- Sequential Bayesian Phase - Sequential Bayesian Phase II/III -II/III -Inoue, LYT; Thall, PF; Berry, DA BIOMETRICS (2002 )Inoue, LYT; Thall, PF; Berry, DA BIOMETRICS (2002 )

- Randomised design

- Decision to switch from phase II to phase III can take place at several times during a defined phase II period if there is enough favourable data- Uses the impact of experimental treatment on the phase II end-point (6 months pfs) to predict impact of experimental treatment on phase III end-point (survival)

6 months pfs

SurvivalExperimental treatment Observed

Predicted

- Two arms only – experimental and contol

Seamless Phase II/III Trial Seamless Phase II/III Trial DesignDesign

- Sequential Bayesian Phase - Sequential Bayesian Phase II/III -II/III -Inoue, LYT; Thall, PF; Berry, DA BIOMETRICS (2002 )Inoue, LYT; Thall, PF; Berry, DA BIOMETRICS (2002 )

- Not tried in practice

- Sample size may be much smaller than “conventional” sequential or multi-stage designs

- Issues of using phase II end-point information in reaching definitive phase III conclusions

-Smaller sample size due to use of phase II end-point to predict effect of new treatment on actual outcome (OS)