David Egilman, MD, MPH

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David Egilman, MD, MPH

• Clinical Associate Professor
• Brown University
• degilman_at_egilman.com

• What is the evaluation standard? Primun non
  nocere
• Is the current label adequate? No
• What is to be done?

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Primum non NocereFirst - Do No Harm

• My bias Primum non Nocere
• I have served as an expert in some pharmaceutical
  litigation, but not against GSK.
• Brown receives from GSK and wants as much as
  it can get from any Pharma company.

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Primum non Nocere

• Efficacy is always relative if there is an
  existing therapeutic option.
• We do not use placebo controls when alternative
  therapy exists. We do not allow this for cancer
  or HIV drugs.
• 2. We should not approve low efficacy drugs
  when compared to placebo because Pharma can
  will sell anything.
• 3. We know glucose is not a surrogate. It does
  no good to die with a normal A1-C.
• - Sulfonylurea (SUs) studies increase risk of
  MI in the face of glucose control.
• - Comparison to bad drug (SUs) makes Avandia
  look less bad.

Bell, D.S.H. Commentary Do Sulfonylurea drugs
increase the risk of cardiac events? Canadian
Medical Association Journal. Jan 17, 2006. 17
4(2) pg. 185.
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Primum non Nocere A1-c is not a surrogate for
this endpoint
Just like the Vioxx patients who died without
joint pain and The nifedipine patients who died
with normal blood pressure and The Seldane
patients who died without stuffy noses
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Primum non Nocere

• Is this a Hint?
• Should we test this class for real endpoints
  before it is marketed?
• Rezulin
• Withdrawn March 2000 (Liver failure)
• Pargluva
• Clinical Development Discontinued (CV death)
• Tesaglitazar
• Clinical Development Discontinued (CV renal)
• Farglitazar
• Clinical Development Discontinued (CV renal)

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Primum non NocereTest Before You Sell

• Paint testing The manufacturer or one who holds
  himself out to be the manufacturer must know the
  qualities of his product and he cannot escape
  liability on the ground that he did not know it
  to be dangerous. Manufacturing Chemists
  Association
• Paint warnings Each manufacturer can ably cope
  with the toxic material situation by constantly
  safeguarding the public through the products he
  manufactures and by the repetition of
  instructions to salesmen, service men, and others
  who can intelligently instruct the consumer of
  the advantages of providing adequate ventilation
  and of maintaining personal hygiene.
• National Paint, Varnish and Lacquer Association
  Policy July 1939.

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Primum non Nocere This is No Warning
The table only refers to patients with Congestive
Heart Failure (emphasis added)
MI adverse events not statistically significant
Avandia Prescribing Information, April 2006
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Primum non Nocere Its an ANTI-WARNING (Provides
false reassurance)
Because this GSK table focused on patients with
pre-existing heart failure, it suggests that
Avandia is safe for all other patients.
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Primum non Nocere GSK Doesnt think its a warning
Contrary to FDA briefing doc. claim that the
table constitutes a warning GSK does not list
ischemic events in the Avandia Patient
information Sheet
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Primum non Nocere So what is this table?
Not a warning
It is a CYA
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Primum non Nocere What is there to cover-up?
Example COMBO INSULIN AVANDIA
Rosiglitazone and insulin consistently showed a
doubling of risk CV death or MI or more
FDA Briefing Document, pg. 73
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Primum non Nocere
In the UK
CONTRAINDICATIONS - cardiac failure or history
of cardiac failure (NYHA class I to IV) - hepatic
impairment. - for use in combination with
insulin.
In the US
CONTRAINDICATIONS AVANDIA IS CONTRAINDICATED IN
PATIENTS WITH KNOWN HYPERSENSITVITY TO THIS OR
ANY OF ITS COMPONENTS
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Primum non Nocere In the US we encourage the use
of this deadly combination
AVANDIA IS INDICATED FOR USE IN COMBINATION WITH
INSULIN (emphasis added)
GSK Briefing Document, pg. 11
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Primum non Nocere A Black Box is Not
EnoughBecause DTC is Pandoras Box
Pharma Knows How to Communicate with Doctors
the Public
For more information, talk to your GSK sales
representative.
How about making them use these methods to get
the word out on risks? DTC, DETAIL REPS, PENS,
DINNERS, GHOST WRITTEN PAPERS CME
Lasser et al. Adherence to Black Box Warnings
for Prescription Medications in Outpatients. Arch
Intern Med. 2006 166338-344. Smalley et al.
Contraindicated Use of Cisapride Impact of Food
and Drug Administration Regulatory Action. JAMA.
2000 284 3036-3039.
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Primum non Nocere A Black Box is Not Enough

• STUDIES SHOW DOCTORS IGNOR BLACK BOXES
• 7 in 1000 outpatients received a prescription
  violating a black box warning.
• The FDAs 1998 regulatory action regarding
  cisapride use had no material effect on
  contraindicated use.

Avandia offers no treatment advantages but offers
unique disadvantages
REJECTED
If this were an NDA it would be
Avandia has got to go until safety is adequately
tested
Lasser et al. Adherence to Black Box Warnings
for Prescription Medications in Outpatients. Arch
Intern Med. 2006 166338-344. Smalley et al.
Contraindicated Use of Cisapride Impact of Food
and Drug Administration Regulatory Action. JAMA.
2000 284 3036-3039.
16
Primum non Nocere A1-c is not a surrogate for
this endpoint
Just like the Vioxx patients who died without
joint pain and The nifedipine patients who died
with normal blood pressure and The Seldane
patients who died without stuffy noses
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Thank you for trying Dr. Johann-Lang