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  • 1. Abigail, Ezekiel, and Freireich Mike Martin, MD My last Grand Rounds 12/19/8
  • 2. CAVEAT 1: MY ROLE IN THIS PRESENTATION IS TO BE IMPARTIAL CAVEAT 2: WITHOUT YOUR COMMENTS, THIS WILL BE VERY SHORT.
  • 3. SHOULD PATIENTS AND DOCTORS BE ALLOWED ACCESS TO ONCOLOGY DRUGS AFTER PHASE I EVALUATION IS COMPLETE? Central question
  • 4. ABIGAIL’S CASE Underlying question: How do you define RISK in someone with a terminal malignancy after all conventional options have been exhausted?
  • 5. Abigail • Honor student and high school athlete • Diagnosed at 19 with squamous cell carcinoma “invading her neck and lungs” • Died at 21 • Patient, family and MD were unable to obtain cetuximab – phase III trials were ongoing – Ineligible for trials
  • 6. Abigail Alliance • Founded by her father • Mission is to “expand access and compassionate use programs for developmental cancer drugs … run out of conventional treatment options” • Believes that FDA violates constitutional privacy and liberty rights of terminal ill • Believes current system is too statistics heavy – 50% v. 15% example • Suing and push legislation for reform Xyotax (novel formulation of paclitaxel) STELLAR 3 – Xyotax/carbo v. taxol/carbo STELLAR 4 – Xyotax v. vino/gem in PS2 Both large, phase III trials showed equivalence to comparator On sub-group analysis premenopausal women in both trials had a superior median OS to comparator regimen (9.4 v 7.7 months [p=0.03] and 10 months v. 5.6 months [p=0.039]) Fewer AE’s with Xyotax Confirmatory studies ongoing Not FDA approved/available outside of clinical trials AA would advocate for it to be available now for women with advanced NSCLC
  • 7. ACCESS Act • Introduced by Senators Sam Brownback and Arlen Specter May 21, 2008 • Seeks to create “a new conditional approval system for drugs, biological products, and devices that is responsive to the needs of seriously ill patients and for other purposes.” • And to “facilitate the availability of promising new drugs to seriously ill patients as early in the drug development process as possible, before general marketing begins”
  • 8. “The emphasis on statistical analysis of clinical information needs to be balanced by a reliance on clinical evaluation and patient- reported outcomes and considered with an understanding of the risks to patients from their disease”
  • 9. Drugs may apply for a Tier 1 approval after: “completed phase I clinical investigation” and there is “preliminary evidence that the product may be effective … case histories … mechanism of action, data from animal and computer models … or other preliminary information … benefit versus historic controls” Tipifarnib?
  • 10. Sponsor must be “actively pursuing marketing approval with due diligence” Patient eligibility: “seriously ill” and provides “written informed consent” “exhausted all treatment options approved … which the patient is a reasonable candidate for” REASONABLE is not defined in the legislation. Is it REASONABLE to treat a woman with advanced NSCLC and a PS2 with what you AND/OR she feels is an inferior treatment? Who decides what is reasonable? There is lower toxicity with Xyotax so is it reasonable to treat ANYONE with conventional Taxol?
  • 11. Also “consideration of a patient’s ineligibility for participation in clinical trials, the lack of source supply or geographic factors.” “sponsor … may charge … without notifying the Secretary or seeking or obtaining prior approval of the amount charged” Pretty much all “are immune from liability” Geography is not defined, don’t feel like driving across town? How to you define geography across an appropriate income spectrum? Amtrak goes almost everywhere? Should you have to ride Amtrak to get chemo first? Charge without pre-approval of amount? Can we even pay for drugs that are approved? No one is responsible except the patient?
  • 12. Abigail and ASH 2008 • Should these agents be available NOW? • Is it “cruelty” to with hold them? • Fostamatinib Disodium (Syk inhibitor) for a patient with primary refractory DLBCL to both R- CHOP and R-ICE? – ASH 2008 abstract 3; a Phase I/II trial with a 21% response rate in 23 heavily pretreated patients with DLBCL • Ofatumumab (novel anti-CD20 mab) for a patient with multiply relapsed/refractory CLL – PR 51% with median OS of 13.7 months in phase II trial (ASH 2008 abstr 328) versus median OS of 9.0 months for historic controls (based on an L&L review)
  • 13. EZEKIEL’S CASE Underlying question: How to you make sure that a system is fair to all.
  • 14. Ezekiel Emanuel, MD PhD • Breast oncologist • Chair • Department of Bioethics • The NIH Clinical Center • National Institutes of Health
  • 15. Ezekiel • “Abigail was too frail to qualify” for a clinical trial • Hopkins oncologist told Abigail’s father that cetuximab could save her life • The AA … “fights to ensure that cancer patients, no matter how sick and weak, can have their insurance companies buy any experimental drug that has passed safety testing.”
  • 16. FDA and Ezekiel • 1938 Federal Food, Drug and Cosmetic Act required manufacturers to prove that drugs are safe • After thalidomide … 1960 Amendments required proof of efficacy before drugs could be sold
  • 17. “The benefit of a few desperate patients would come at a steep cost to the rest of us, especially the … Abigail’s of tomorrow. … much harder to enroll in research studies … to show whether a drug really was effective or not.”
  • 18. Case and point? • Late ‘80s and early ‘90s BMT for mBC • People convinced with little data • States enacted laws mandating insurance companies pay for BMT • 20,000 women were transplanted • Difficult to enroll the 1,000 women eventually needed to demonstrate a lack of benefit and increased toxicity
  • 19. “Precious time was wasted due to delayed enrollment. Thousands of women were unnecessarily subjected to BMT and hundreds died … millions, if not billions, of dollars were spent on a substandard treatment.”
  • 20. “Delays research … access to fewer proven treatments. Add the requirement that insurance companies pay for drugs that we don’t know work, and you have a formula for financial disaster.”
  • 21. “This is the height of irrationality born of desperation.”
  • 22. A FEW THOUGHTS FROM FREIREICH In defense of the Abigail Alliance
  • 23. Emil J Freireich, MD, DSc (Hon) • Ruth Harriet Ainsworth Chair • Distinguished Teaching Professor • Director, Special Medical Education Programs • Director, Adult Leukemia Research Program • The University of Texas • MD Anderson Cancer Center
  • 24. “You don’t ban cars because people die in car accidents” Do no harm?
  • 25. “… creating a new drug to bringing it to the market is approximately 15 years; 60% of that time … getting an IND …” “If someone is dying of cancer, that is not the FDA’s business”
  • 26. “… an establishment like MD Anderson … has a proposal, they should be able to go ahead with their study without the interference of the FDA … There is no reason to do randomized trials with a drug that looks very promising.”
  • 27. “The bottom line is that there is no rational argument against the Abigail Alliance and their mission. Once a drug completes phase I, it should be the decision of the patient and their physician of whether or not that drug is right for them.”
  • 28. Thoughts? Does the legislation match the goals of the AA? Senator_mccaskill@mccaskill.senate.gov

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