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. 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

4. 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

5. Should Oncology Drug Regulation Be Different? Life-threatening nature of diseases--patient access vs necessary data for approval Drugs multiple action modes; combinations Risk/benefit ratio--different perspective on serious adverse events; highly trained specialists using drugs rather than GP Product label and off-label uses

6. Should Oncology Drug Regulation Be Different? Investigational nature of discipline--Cancer Centers, Cooperative Groups, NCI Wide variety of products used by oncologists--chemotherapy, biotherapy, devices, supportive care, diagnostics Multidisciplinary approaches Represents over 100 diseases/indications

7. 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

8. 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

9. Endpoints for traditional approval: Survival Defined as the time from randomization to death Unambiguous endpoint that is not subject to investigator interpretation or bias from unblinded studies Assessed daily

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

11. 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

12. 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”

13. 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

14. TTP: Problems How much improvement constitutes benefit?

15. 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

16. 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?

17. 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

18. 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?

19. 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

20. 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

21. Accelerated Approval Docetaxel (Taxotere) Irinotecan (Camptosar) Doxorubicin HCl liposome (Doxil--2 indications) Capecitabine (Xeloda) Cytarabine liposomal injection (Depocyt) Temozolomide (Temodar) Amifostine (Ethyol)--sNDA Celecoxib (Celebrex) Gemtuzumab (Mylotarg) Gleevec (imatinib mesylate) (STI 1571)

22. 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

23. Challenges for Oncology Drug Regulations New “targeted therapies” –Re-define definitions of diseases –Greater efficacy in selected population may result in smaller patient populations –Novel surrogates to be validated –Dosing aimed at target rather than MTD –Dose studies, chronic administration

24. Challenges Greater number of candidate drugs –Careful selection of agents to demonstrate clinical benefit by oncology community –Patient accrual to trials need to be increased –Patients entering trials should reflect the patient population which will eventually use the drug –International studies, international agreement of endpoints and study design and approval criteria