March 12, 2003 ODAC Meeting Opening Comments by FDA Dr. Richard Pazdur Acc...

2. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard PazdurAccelerated Approval “Accelerated approvals have been granted with the trial design using single arm trials in refractory populations as stated previously. These trials obviously allow more rapid trial completion and hence expedite drugs to patients with life-threatening diseases.”

3. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard Pazdur Deceleration Begins “An alternative trial design uses a randomized trial allowing accelerated approval on the basis of an interim analysis of surrogate endpoints, for example, response rate or time to progression.”

4. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard Pazdur Deceleration Deepens “Randomized trials also may optimize the evaluation of novel cytostatic agents by allowing an assessment of slowing or retarding or preventing tumor progression. This may simply not be possible with single arm trials.”

5. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard Pazdur Costs Up – Translation Slows “Obviously randomized trials are more expensive than single arm trials and take more time. “

6. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard Pazdur  Ethics Takes A Backseat to P-Values “Survival analysis can be complicated and confounded by cross over and subsequent therapy.”

7. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard Pazdur Phase IV Trials Will Be CompletedOr Else “The mandatory confirmatory trials to demonstrate clinical benefits are equally important as the initial trials demonstrating an effect on a surrogate endpoint leading to that drugs approval.”

8. March 12, 2003 ODAC MeetingOpening Comments by FDADr. Richard Pazdur The Patients Will Have to WaitDo You Want Your Drug Approved or Not? “Hence confirmatory trials must be an inherent and integral part of a comprehensive drug development plan and drug development strategy. “

9. Major Policy ShiftInStandard for Accelerated Approval Accelerated Approval ~ Regular Approval

10. The New FDA RealityPunitive Regulation for New Cancer DrugsMajor Policy Shift Number 1 FDA Will Aggressively Enforce Phase IV Trials – Even If the Agency’s Policies Make Them Difficult or Impossible to Enroll and Complete FDA Will Pull Drugs That Work Off the Market – Iressa -Even When There is No Clinical or Compelling Regulatory Reason for The Action

11. The New FDA RealityPunitive Regulation for New Cancer DrugsMajor Policy Shift Number 2 Accelerated Approval Will Be Granted Only After a Sponsor Substantially Meets a Clinical Endpoint Sufficient for Regular Approval Based on Interim Analysis of a Randomized Phase III Trial

12. The New FDA RealityPunitive Regulation for New Cancer DrugsMajor Policy Shift Number 3 Denial/Delay of Accelerated Approval to Maintain a Large Pool of Desperate Dying Patients to Ensure Enrollment (Under Duress) in Unethical Phase III Trials

13. The New FDA RealityPunitive Regulation for New Cancer DrugsWhat Is Wrong With This Picture? The Fast Track Program was created by Congress to preclude undue regulatory delay in the delivery of progress to patients The FDA’s Deceleration of Accelerated Approval for new cancer drugs is a unilateral rejection of Congress’ intent at FDA staff level The policy shifts happened in plain view of the FDA’s leadership and the ODAC A vast number of patients have died prematurely as a result of Decelerated Approval!

14. Decelerated ApprovalSorafenib - A Clear Example? BAY 43-9006/Sorafenib – Found Compellingly Safe and Effective for Renal Cell Cancer after a Phase II Clinical Trial High Response Rates with a Substantial Number of Durable Responses – Clinical Benefit/Survival Advantage Highly Likely Based On Phase II Results No Accelerated Approval Application Submitted at End of Phase II in 2003

15. The New FDA RealityPunitive Regulation for New Cancer DrugsSorafenib - A Compelling Example Randomized, Double-Blind, Placebo-Only Controlled, No Cross Over Trial in Refractory Terminal Renal Cell Cancer Patients Patients Die Prematurely in Placebo Arm – Thousands More Die Outside Trial Waiting for Sorafenib Spring 2005 – Interim Review – Placebo Arm Proven Too Unethical to Continue Without Cross Over – Drug Remains Unapproved

16. Fast Forward ToSeptember 12, 2005 ODAC MeetingRevlimid A Clearly Effective Well-Targeted Drug for Myelodysplastic Syndrome – An Almost Universally Fatal Disease – Based on Two Single-Arm, Highly Ethical Phase II Clinical Trials

17. September 14, 2005 ODAC MeetingOpening Comments by FDADr. Richard Pazdur Revlimid “On several occasions, as will be mentioned by the FDA reviewer, we have recommended to the sponsor before they began the study, that we look at randomized studies of this drug in MDS to have a better understanding of the disease in relationship either to other therapies or the natural history of the disease.”

18. Celgene Keeps Its Own CounselProceeds With An Ethical Single-Arm, Phase II Registration Trial Single-Arm Trial Proves Expected An Undeniable Efficacy of the Drug in an Identifiable Subset of MDS Patients

19. ODAC Agrees With Celgene that Revlimid Is Effective, Should Receive Regular Approval, and That the Proposed Risk Management Plan Is Adequate

20. September 14, 2005 ODAC MeetingFDA’s Reaction to ODAC Dr. Richard PazdurThe Mantra “I want to bring people back to the kind of regulations, and there is a mantra, adequate and well-controlled trials, adequate and well-controlled trials, adequate and well-controlled trials. I am mentioning that three times, because I think that is at the heart of the question here.”

21. Dr. Maha Hussain – ODAC September 14, 2005Later in the Meeting On RevlimidA Question to Celgene from ODAC “And why you chose not to do a Phase III trial when you were asked to do that?” [randomized, placebo-controlled trial]

22. Dr. DeLap for CelgeneSeptember 14, 2005Celgene’s Response “We are going to go to Phase III. We are going to be doing a placebo-controlled trial. I have to say that in discussing that trial with the investigators, there is actually reluctance to put patients on placebo for very long based on the benefit that has been seen here.”

23. Dr. DeLap for CelgeneSeptember 14, 2005Celgene’s Response Continues “The patients who receive placebo, receive that for 4 months. If they are not responding, and we think that essentially, none of them are likely to respond from what we know, then, they will have the opportunity to go on to lenalidomide and continue on that as long as that seems to be benefiting them.”

24. The Outcome for RevlimidOn October 3, 2005 FDA Decided to Extend Its Review Timeframe for Three Months to Review the Risk Management Plan Already Deemed Acceptable by ODACThis Safe, Effective and Much Needed Drug Remains Unapproved

25. Patient Protection?The FDA is Asking for An Unethical, Unnecessary Randomized TrialWhileCelgene Negotiates for Ethical Treatment of Patients

26. We Have A ProblemThe FDA’s Decelerated Approval Initiative is an Extreme Case of Form Over SubstanceWhere the Substance at IssueIs Life Itself

27. Deactivate Decelerated Approval

28. Working for Patients