Phase II/III Design: Case Study Case study: Seamless Phase II/III Design for Registration Program Jeff Maca, Ph.D. Senior Associate Director Novartis Pharmaceuticals

Phase II/III Design: Case Study

Case study: Seamless Phase II/III Design for Registration Program

Jeff Maca, Ph.D.Senior Associate DirectorNovartis Pharmaceuticals

2 | Seamless Case Study / KOL Series | June 12, 2009

Outline – Adaptive Seamless Case Study

Motivation/definitions

Adaptive seamless designs considerations

Case study example

• Simulation details

Conclusions


Motivation

An adaptive trial can plan at the design stage to correct for incorrect assumptions

Adaptive trials can merge what might be considered two separate trials into one trial

Improve efficiency in clinical development Careful planning is necessity

Adaptive Designs: Using accumulating data to decide on how to modify aspects of the trial design, during the conduct of the trial and without violating the integrity of the trial


Adaptive Seamless designs

Primary objective – combine “dose selection” and “confirmation” into one trial

Although dose is most common phase IIb objective, other choices could be made, e.g. population

After dose selection, change usually to new enrollments (patients could be re-randomized, and analyzed separately)

Patients on terminated treatment groups can be followed

All data from the chosen group and comparator is used in the final analysis. Appropriate statistical methods must be used



Statistical methodology for Adaptive Seamless Designs must account for potential biases and statistical issues

Selection bias (multiplicity) Multiple looks at the data (interim analysis) Combination of data from independent stages

• Closed testing procedure (data from stages are separated) and Bonferroni type adjustment (data is pooled across stages) are two possible methods



With the added flexibility of seamless designs, comes added complexity.

Careful consideration should be given to the feasibility for a seamless design for the project.

Not all projects can use seamless development

Even if two programs can use seamless development, one might be better suited than the other

Many characteristics add or subtract to the feasibility



Enrollment vs. Endpoint

The length of time needed to make a decision relative to the time of enrollment must be small

• Otherwise enrollment must be paused

Endpoint must be well known and accepted

• If the goal of Phase II is to determine the endpoint for registration, seamless development would be difficult

If surrogate marker will be used for dose selection, it must be accepted, validated and well understood



Clinical Development Time

There will usually be two pivotal trials for registration

Entire program must be completed in shorter timelines, not just the adaptive trial



Logistical considerations

Helpful if final product is available for adaptive trial (otherwise bioequivalence study is needed)

Decision process, and personnel must be carefully planned and pre-specified


Phase II/III Adaptive Design – Case Study

Case Study Introduction

Indication is a chronic disease

Adaptive seamless design (ASD) to select final dose to support registration of new formulation

Study will provide pivotal confirmation of efficacy, safety and tolerability of selected dose

Two adaptive studies are running concurrently, one in mono-therapy, one in add-on therapy



Case Study Introduction

Bias towards selecting the lower dose, unless

• Low dose would not have high likelihood of success

• High dose had considerably better efficacy

Selection probabilities and overall power derived via extensive simulation study

Studies are planned to have interim analysis occurring at the same time

• Dose selection simultaneous for both studies


High Dose

Low Dose

Placebo

Selected Dose

Active control

Dose Ranging24 weeks

Screening Interim Analysis

Efficacy and Safety52 weeks

STAGE 2 (phase III)STAGE 1 (phase IIb)

Ongoing treatment

Phase II/III adaptive design : Study 1

Final Analysis

IndependentDose

Selection


High Dose

Low Dose

Placebo

Active control

Selected Dose

Selected Dose

Active control

Dose Ranging24 weeks

Screening Interim Analysis

Efficacy and Safety52 weeks

STAGE 2 (phase III)STAGE 1 (phase IIb)

Ongoing treatment

Phase II/III adaptive design : Study 2

Final Analysis

IndependentDose

Selection



Studies are divided into three periods

Period 1 (Dose selection)

Intermediate period (during dose selection)

Period 2 (long term safety and efficacy)



Period 1

Patients randomized equally to high dose, low dose and control (s)

All patients complete 24 weeks of treatment which is the time to primary endpoint

Roughly 100 and 150 patients in the two studies will be randomized

Data from both studies will be used in selection



Intermediate Period

Patients randomized to non-placebo treatments will stay on treatment until dose selection is complete

Patients on placebo will be switched to active treatment (if completed 24 weeks)

Recruitment continues through this period



Period 2

Patients randomized to non selected dose(s) are switched to selected dose

Placebo patients are switched to active treatment

Patient randomized to selected dose or active control


Phase II/III adaptive design: Case study

Primary endpoint• Continuous variable – measured after 24 weeks

• Dose selected on a 12 week measurement (early readout)

• Comparison with placebo for superiority

Secondary endpoints• Comparison of safety and efficacy over 24 weeks

• Long term safety measured over 52 weeks



Objective of interim analysis

To investigate two doses of new treatment versus placebo and active controls with respect to primary endpoint after 12 weeks of treatment (early read-out)

Independent external DMC will select dose to continue into period 2

DMC would see analysis from both studies, and make same selection of dose for both studies

Interim analyses must be timed to occur at the same time (harder to do in practice than on paper)


Phase II/III adaptive design: Simulations

Sample sizes for stage 1 and 2 based on extensive simulation work• Stage 1 sample size chosen to ensure the “optimal”

dose was chosen with high probability

• Various dose responses were investigated

Stage 2 sample size sufficient to satisfy primary and secondary objectives of the study



Decision rule has tendency towards picking lower dose

In general, the low dose is selected unless high dose has “much” higher efficacy outcome, or low dose does not have “much” chance to succeed.

Different thresholds were investigated to make this determination of “much”



Output from simulation

Selection probabilities for each of the two treatment doses

Power conditional on the dose selected

Overall power that the selected doses would be confirmed



Statistical methodology A multiplicity correction will be used for the

final analysis to account for the two treatments • Dunnett step-down methodology will be used• Data not split by period with separate p-values

(inverse normal/closed testing methodology), although would have similar power

Procedure will control family-wise type I error rate for the primary endpoint



DMC guidelines Numerical values given (not inferential)

Thresholds are pre-defined (results from simulations ), for implementation by DMC

Trials will not be stopped for efficacy at interim analysis

Trials currently ongoing, with dose selection analysis upcoming shortly


Conclusions

Adaptive seamless designs have an ability to improve the development process by reducing timelines for approval

Extra planning is necessary to implement an adaptive seamless design protocol

Simulations can be used to determine decision rules, and operating characteristics of such a design

This case study successfully used simulations to plan and execute two simultaneous adaptive seamless designs which incorporate dose selection

Documents

Phase II/III Design: Case Study Case study: Seamless Phase II/III Design for Registration Program Jeff Maca, Ph.D. Senior Associate Director Novartis Pharmaceuticals