(PowerPoint)

Abigail, Ezekiel, and Freireich

Mike Martin, MDMy last Grand Rounds 12/19/8

CAVEAT 1: MY ROLE IN THIS PRESENTATION IS TO BE IMPARTIAL

CAVEAT 2: WITHOUT YOUR COMMENTS, THIS WILL BE VERY SHORT.

SHOULD PATIENTS AND DOCTORS BE ALLOWED ACCESS TO ONCOLOGY DRUGS AFTER PHASE I EVALUATION IS COMPLETE?

Central question

ABIGAIL’S CASE

Underlying question: How do you define RISK in someone with a terminal malignancy after all conventional options have been exhausted?

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

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/carboSTELLAR 4 – Xyotax v. vino/gem in PS2

Both large, phase III trials showed equivalence to comparatorOn 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 ongoingNot FDA approved/available outside of clinical trials

AA would advocate for it to be available now for women with advanced NSCLC

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”

“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”

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?

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?

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?

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)

EZEKIEL’S CASEUnderlying question: How to you make sure that a system is fair to all.

Ezekiel Emanuel, MD PhD

• Breast oncologist• Chair • Department

of Bioethics• The NIH Clinical

Center• National Institutes of

Health

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.”

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

“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.”

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

“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.”

“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.”

“This is the height of irrationality born of desperation.”

A FEW THOUGHTS FROM FREIREICH In defense of the Abigail Alliance

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

“You don’t ban cars because people die in car accidents”

Do no harm?

“… 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”

“… 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.”

“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.”

Thoughts?

Does the legislation match the goals of the AA?

Senator_mccaskill@mccaskill.senate.gov