1. 1 Statistical and Practical Aspects of a Non-Stop Drug Development Strategy Karen L. Kesler and Ronald W. Helms Rho, Inc. Contact: kkesler@RhoWorld.com

2. 2 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?

3. 3 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.

4. 4 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.

5. 5 NonStop Overview  Score statistic Number of subjects per treatment group Boundary for pruning Boundary for stopping for efficacy  Treatment pruned: safety Administrative Boundary

6. 6        NonStop Overview

7. 7 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?

8. 8 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?

9. 9 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

10. 10 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).

11. 11 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.

12. 12 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)

13. 13 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.

14. 14 How to select a primary outcome An 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

15. 15 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...

16. 16 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

17. 17 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

18. 18 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.

19. 19 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,

20. 20 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...

21. 21 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!

22. 22 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.

23. 23 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.

24. 24 A version of this presentation is available (PDF) at: www.RhoWorld.com   