1. Defining Success in Oncology Drug Development Richard Pazdur, MD CDER, FDA The views expressed are the results of independent work and do not necessarily represent the views or findings of the United States Food and Drug Administration or the United States

2. Basis for NDA Approval Demonstration of efficacy with acceptable safety in adequate and well-controlled studies Ability to generate product labeling that –Defines an appropriate patient population –Provides adequate information to enable safe and effective use –Approval for an indication, not drug

3. Activity vs. Benefit Biologic Activity--screening of a compound, phase II trial endpoint, an indication for further study Clinical benefit--what is meaningful to a patient The approval process is not a screening process for drug activity

4. Regulatory Terms Accelerated Approval--serious or life- threatening disease, benefit over available therapy. Use of surrogate; mandated phase IV trials Fast Track--life-threatening disease, potential to address unmet medical need. Rolling NDA, meetings Priority review--drug would be a significant improvement compared to available drugs. Review of NDA in 6 months

5. Oncology Trial Concerns Minimize bias –Blinding trials (few) –Endpoints that minimize bias –Internal consistency of subgroups, endpoints Magnitude of change of endpoint –Clinical significance –Underpowered trials--guessing treatment effect Isolating effect of drug

6. Risks in Developing Oncology Drugs Indication--lack of predictive models “Creative Indications”--progressively more refractory patient, market share Two trials versus one trial Dose ranging studies--moving away from MTD

7. Endpoints in Oncology Survival and improvement in patient reported symptoms considered clinical benefit Objective Response Rate and Time to Progression usually viewed as surrogates Exceptions : relatively non-toxic products such as hormonal therapies or some biologics

8. Endpoints 1990 to 2001 52 regular approvals; 10 accelerated 43/62 oncology drug applications were approved on endpoints other than survival Tumor response was basis in 27/52 supported by relief of tumor specific sxs in 10/27 Relief of tumor symptoms provided support in 13/52 regular approvals

9. Traditional Endpoints: Survival Non-inferior or improved survival constitutes “patient benefit” after consideration of toxicity and the magnitude of the benefit Non-inferior outcome ensures that a survival advantage associated with an approved drug will not be lost with a new agent

10. Traditional Endpoints: Survival Drawbacks –Requires large sample size and long follow-up –Confounder--Cross-over therapy may “wash out” a survival effect

11. Time to Progression--Advantages Could use a smaller sample size and shorter follow-up than trials that require a survival endpoint Differences will not be obscured by secondary therapy if cross-over effect exists “Time to symptomatic progression”

12. TTP: Problems Unblinded trials introduce bias Must evaluate all patients on a regular basis –Must evaluate all sites of possible disease –Complete ascertainment of all sites at baseline and follow-up (i.e., look for new sites) –Same type of assessment tool at each follow-up –Should use same evaluation schedule

13. TTP: Problems How much improvement constitutes benefit?

14. Response Rate Unique endpoint--treatment is “entirely” responsible for tumor reduction In contrast, survival and TTP have an effect of the natural history PLUS treatment effect Must consider duration of response Does not include stable disease Pick your criteria and stick with it

15. Complicated Picture of RR Number of CRs vs PRs? Duration of responses? Location of responses (e.g., liver vs skin)? Association with symptom improvement? Extent or bulk of metastatic disease?

16. Palliation and Patient Reported Outcomes Blinding and associated antitumor effects (response rates) lend credibility –Use simple instruments –Hypothesis-driven –Avoid multiple endpoints –Example: Photofrin PDT and dysphagia scale

17. Potential palliative endpoint: Health-related quality of life Pro: Patient’s perspective on treatment Con: –Blinding is essential, but difficult to do –Careful serial assessments Missing data makes interpretation problematic Multiple endpoints and comparisons to baseline must be adjusted for in the statistical analysis plan –Clinical significance of score changes may be unclear –Is additional information gained, compared to a careful recording of toxicity/symptom data?

18. Accelerated Approval- Subpart H (21CFR 314) For serious or life-threatening diseases Where the drug appears to provide benefit over available therapy Approval based on a surrogate that is reasonably likely to predict clinical benefit

19. 21CFR314 (continued) Subject to the requirement that the applicant verify and describe benefit Post-marketing studies would usually be underway The applicant shall carry out such studies with due diligence

20. Withdrawal Procedures Conditions –postmarketing study fails to verify benefit –applicant fails to perform required study with due diligence –postmarketing restrictions inadequate to assure safe use –failure to adhere to postmarketing restrictions –promotional materials false/misleading Requires a hearing

21. Endpoints Utilized Single arm trials : ORR Randomized Setting : Cytologic response, number of polyps, ORR, TTP, DFS, LVEF ; CHF

22. RR in Single Arm Trials

25. Randomized Trials

26. Randomized Trials (contd)

27. Uncertainty of Benefit to Ultimate Outcome Amifostine (Ethyol) Dexrazoxane (Zinecard) Anastrozole (Arimidex)

28. Timing of Confirmatory Trials Converted Indications

29. Issues Related to the AA Program As a Whole The importance of confirmatory trials being underway at the time of AA The approach of studying slightly different populations in the confirmatory setting than the AA population Relative merits of different trial designs –single arm in refractory populations –randomized trials in less refractory patients

30. Scientific Challenges Re-define diseases; surrogate validation Greater efficacy in selected population may result in smaller patient populations Dosing aimed at target rather than MTD Dose studies, chronic administration Exclude pts who would benefit due to unrecognized mechanisms

31. Regulatory Challenges Differences in oncology drug development/regulation compared to other therapeutic areas Coordination of Agency’s Centers (Drugs, Biologics, Devices) regarding oncology therapeutics Scientific foundation must precede regulatory decision-making