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Defining Success in Oncology Drug Development

Learn about the essential criteria for oncology drug success from FDA's Richard Pazdur. Explore key regulatory terms, oncology trial concerns, risks in drug development, and important endpoints in oncology research. Understand the significance of traditional and alternative endpoints in evaluating drug efficacy.

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Defining Success in Oncology Drug Development

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  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

  23. RR in Single Arm Trials

  24. 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

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