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Statistical and Practical Aspects of a Non-Stop Drug Development Strategy

Karen L. Kesler and Ronald W. Helms

Rho, Inc.

Contact: kkesler@RhoWorld.com

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Introduction

• Approval Process—Phase I, II, & III

• Phase II designed to: – Discover best treatment regimen: route, dose, timing, etc.– Profile Safety– Develop information needed to design Phase III trials

• Phase III designed to show efficacy

• Time from patent to approval >12 years and growing

How can we use new statistical methods to shorten overall development time?

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NonStop Concept

• Design a Phase II study with enough arms to cover all plausible regimens, plus placebo– K possible doses K+1 arms

• Conduct a sequence of frequent interim analyses (using group sequential methods).

• At each interim analysis, potentially prune treatment arms, except control.

• Ultimately, at some interim analysis, the treatment arms are reduced to one active treatment regimen and the placebo.

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NonStop Overview

• Specify frequent interim analyses whose primary objective is to prune (kill) treatment arms as quickly as possible.– For either safety or futility.– The placebo arm is never pruned.

• The project’s primary objective is to get to Phase III ASAP.

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NonStop Overview

Sco

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Number of subjects per treatment group

Boundary for pruning

Boundary for stopping for efficacy

Treatment pruned: safety Administrative

Boundary

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NonStop Overview

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• NonStop development is literally non-stop: virtually all the “wasted” time is eliminated:– Between sequential Phase II studies, and – Between the last Phase II and first Phase III study.

• Recall our Phase II goals:– Profile safety.– Choose the most appropriate outcome.– Choose the most efficacious dose or regimen.– Eliminate ineffective compounds quickly.

What makes it work?

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Issues

• How many treatment arms to start with? Which doses/regimens to use?

• How to select the most appropriate outcome?

• What are the challenges associated with this type of design?– Centralized randomization– Quick data capture and management

• Who gets to see the interim analysis results?

• Will regulatory agencies (like FDA) accept this design?

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How many treatment arms?

• Clinical Decision– Depends on how much is known about the

compound.

• Dose Response– Need to cover enough of the dose response curve.

• Safety– Do not want to endanger the subjects.

• Balance

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How many treatment arms?An Example

• Untested compound, but some literature on the class of compound.

• Suggests highest safe dose is 750 mg/kg.

• Investigators interested in 500 mg/kg also.

• Recommend adding 250 mg/kg to get dose-response curve.

• Decision: Four arms (Pbo, low, med, high).

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How many treatment arms?An Example

• Known compound, interested in combination therapy for resistant strain.

• Current standard of care is 75mg/kg/day.

• Want to investigate high doses, possibly up to 125 mg/kg/day.

• Above 125 not feasible due to cost constraints

• Decision: Start with 75 and 100, develop safety profile of higher dose and add 125 if determined to be safe.

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How to select a primary outcome

• Some etiologies do not have clearly defined associated outcomes.– Multiple scales– Length of follow up– Choices of statistical model

• Typical considerations are– Cost– Accuracy– Power (continuous vs. categorical)– Clinical Relevance (surrogate vs. “hard” endpoint)

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How to select a primary outcome

• With NonStop design in Phase II, we analyze all of the outcomes at each interim.– Allows for complete picture

• Do the various measures agree?

– Can monitor for variability in the outcome• Is the outcome consistent over time?

– Gives a good idea of collection issues• Can we collect this accurately?

• Only works for outcomes with a short follow up time.

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How to select a primary outcomeAn Example

• Infection rate– Rate of infection w/in 30 days– Time to first infection– Rate of infection per person-day– Varying definitions of infection

• Declare Primary for sample size calculations

• Compare interpretations of each type of outcome

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Other Key Logistics

• Statistical/Clinical Communication

• Constant Team Coordination

• Centralized Randomization

• Efficient Data Management

• Planning, Planning, Planning. . .

Let’s examine some of these in detail . . .

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Centralized Randomization

• Maintains balance over many treatment arms (and any important strata)

• Allows for instantaneous curtailment of a pruned treatment arm

• Preserves masking at the site when treatment arms are pruned

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Quick Data Capture and Management

• Need as up-to-date information as possible to make decisions

• Need to enter and query data as quickly as possible

• Monitoring issues:– Using monitored vs. unmonitored data– Timing

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Regulatory Issues: Maintaining the Mask

Who gets to see the results of the Phase II interim analyses?

• This is a controversial issue, both for NonStop and traditional strategies.

• In this case, the results of interim analyses can be held as closely as one wishes.

• In a traditional strategy, the results of each Phase II study – the analog of this study’s interim results - are disseminated widely.

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Regulatory Issues: Maintaining the Mask

• Who is allowed to see the interim results?– Definitely “No”:

• Site Personnel

• Anyone making a determination on patient care

• Anyone making a determination on outcomes

– Definitely “Yes”:• Statistical team creating the interim reports

• Primary investigator/Clinical Lead making continuation decisions

– Undecided:• Statistical team performing the final analysis

• Non-clinical personnel: investors, project coordination leads,

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Regulatory Issues: FDA Acceptance

• NonStop design suited for Phase II or exploratory trials, not confirmatory trials.

• Bring FDA representatives in early, explain the design fully and why it would be appropriate.

• Willingness to accept innovative statistical approaches varies from group to group.

• We do have one in progress and we are working with the FDA. . .

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Summary

• Philosophical shift from the typical hypothesis testing structure of a confirmatory Phase III design to an exploratory treatment selecting Phase II design.

• Recall goals:– Profile Safety.– Select most appropriate outcome,– Select most efficacious (yet safe) dose/regimen,– “Kill” ineffective compounds,– Generally: Get enough information to design a

successful confirmatory trial!

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Summary

• The NonStop strategy is not a panacea – it’s not useful for all drug development situations.

• Relatively few patients enrolled between taking a snapshot of the database for an interim analysis and the meeting to make decisions based on the interim analysis. Implies:– Fast data capture, processing.– Centralized Randomization– At the start of Phase II, one can specify a set of

treatment regimens that will very likely include the regimen(s) to be tested in Phase III.

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Conclusions

• A NonStop design can be a challenging, but efficient and cost-effective design for a Phase II exploratory study.

• With sufficient planning for quick data capture and management, as well as centralized randomization, this design can save a lot of time in the exploratory stage of a drug development plan.

• With preplanning and communication, this design can be accepted by regulatory agencies.

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A version of this presentation is available (PDF) at: www.RhoWorld.com