Transcript Document 7278058

Abigail Alliance
for Better Access to Developmental Drugs
DECELERATED APPROVAL
November 8, 2005
Moving Backward for
Cancer Patients
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. Richard Pazdur
Accelerated 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.”
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. 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.”
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. 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.”
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. Richard Pazdur
Costs Up – Translation Slows
“Obviously randomized trials are more
expensive than single arm trials and take
more time. “
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. Richard Pazdur
Ethics Takes A Backseat to P-Values
“Survival analysis can be complicated
and confounded by cross over and
subsequent therapy.”
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. Richard Pazdur
Phase IV Trials Will Be Completed
Or 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.”
March 12, 2003 ODAC Meeting
Opening Comments by FDA
Dr. Richard Pazdur
The Patients Will Have to Wait
Do 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. “
Major Policy Shift
In
Standard for Accelerated Approval
Accelerated Approval ~ Regular Approval
The New FDA Reality
Punitive Regulation for New Cancer Drugs
Major 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
The New FDA Reality
Punitive Regulation for New Cancer Drugs
Major 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
The New FDA Reality
Punitive Regulation for New Cancer Drugs
Major 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
The New FDA Reality
Punitive Regulation for New Cancer Drugs
What 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!
Decelerated Approval
Sorafenib - 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
The New FDA Reality
Punitive Regulation for New Cancer Drugs
Sorafenib - 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
Fast Forward To
September 12, 2005 ODAC Meeting
Revlimid
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
September 14, 2005 ODAC Meeting
Opening Comments by FDA
Dr. 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.”
Celgene Keeps Its Own Counsel
Proceeds With An Ethical SingleArm, Phase II Registration Trial
Single-Arm Trial Proves Expected
An Undeniable Efficacy of the Drug
in an Identifiable Subset of MDS
Patients
ODAC Agrees With Celgene that
Revlimid Is Effective, Should Receive
Regular Approval, and That the
Proposed Risk Management Plan Is
Adequate
September 14, 2005 ODAC Meeting
FDA’s Reaction to ODAC
Dr. Richard Pazdur
The Mantra
“I want to bring people back to the kind of
regulations, and there is a mantra, adequate
and well-controlled trials, adequate and wellcontrolled trials, adequate and well-controlled
trials. I am mentioning that three times,
because I think that is at the heart of the
question here.”
Dr. Maha Hussain – ODAC
September 14, 2005
Later in the Meeting On Revlimid
A 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]
Dr. DeLap for Celgene
September 14, 2005
Celgene’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.”
Dr. DeLap for Celgene
September 14, 2005
Celgene’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.”
The Outcome for Revlimid
On October 3, 2005 FDA Decided to
Extend Its Review Timeframe for
Three Months to Review the Risk
Management Plan Already Deemed
Acceptable by ODAC
This Safe, Effective and Much
Needed Drug Remains Unapproved
Patient Protection?
The FDA is Asking for An Unethical,
Unnecessary Randomized Trial
While
Celgene Negotiates for Ethical
Treatment of Patients
We Have A Problem
The FDA’s Decelerated Approval
Initiative is an Extreme Case of
Form Over Substance
Where the Substance at Issue
Is Life Itself
Deactivate Decelerated Approval
Banish Mantras – They are Not
the Stuff of Open Minds
Reactivate Accelerated Approval
and Find Ways to Accelerate It
Further
Abigail Alliance
for Better Access to Developmental Drugs
Working for Patients