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Jerusalem, Israel, May 1, 2005
Politics, Pain and the Torture of the Millions
On April 6, 2005 the US Senate postponed the approval of Dr. Lester M. Crawford’s
nomination as Commissioner of the FDA. Commenting on the FDA’s handling of the
Vioxx crisis, Sen. Edward Kennedy, D-Mass. said, "Personally, there has to be
recognition that there is a serious problem."
On April 7, 2005 the FDA relented to public pressure and published its decision
(“Decision”), to “protect and advance the health of the millions of Americans”, advising
Pfizer it should ‘voluntarily’ remove Bextra, its popular pain relieving product from the
shelf or the FDA would initiate formal withdrawal procedures. In addition, NSAID pain
relievers, COX-2 inhibitors and other pain relievers, both OTC and prescriptions drugs,
were required to place a warning of a potential cardiovascular risk on their boxes. (See:
http://www.fda.gov/bbs/topics/news/2005/NEW01171.html )
On April 15, 2005 the FDA posted a 22 Page memorandum, issued on April 6, titled
“Analysis and recommendations for Agency action regarding non-steroidal anti-
inflammatory drugs and cardiovascular risk”. The recommendations were adopted by the
FDA on the following day. The memorandum discussed, summarized and evaluated the
available research data and the significance of the research that led to this milestone
decision. (See: http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf)
Hereunder are quotations of the memorandum’s key observations, commented in Arial
font:
• “The data from controlled clinical trial comparisons of COX-2 selective and non-
selective NSAIDs do not clearly demonstrate an increased relative risk for the
COX-2 selective drugs, despite the substantial size of these studies.
Taken together, these observations raise serious questions about the so-called
“COX-2 hypothesis,” which suggests that COX-2 selectivity contributes to
increased CV risk. It, therefore, remains unclear to what extent the COX-2
selectivity of an individual drug predicts the drug’s potential for an increased risk
of adverse CV events compared to drugs that are less COX-2 selective.”
The FDA determined that the risks associated with COX-2 selective
products for cardiovascular event (“CV Risk”) are not higher when
compared to the risks in non-selective NSAID’s. The theories proposed by
Dr. Garret A. FitzGerald of the University of Pennsylvania and others have
been rejected.
• “Long-term placebo-controlled clinical trial data are not available to adequately
assess the potential for the non-selective NSAIDs to increase the risk of serious
adverse CV events.”
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Proof is not available to associate non-selective NSAIDs with CV Risk.
Because COX-2 selective drugs have the same CV risk as non-COX-2
selective – there is no proof for elevated CV risk associated with the whole
class.
• “We believe that it is reasonable from a public health perspective to assume that
valdecoxib does not differ from the other COX-2 selective agents with regard to
increased CV risk with chronic use…”
Bextra, the recently recalled product, is not different than Vioxx or
Celebrex with regard to associated CV risk.
• The FDA’s records associated Bextra with “increased risk of serious and
potentially life-threatening skin reactions… To date, the agency has received 7
reports of deaths from serious skin reactions in patients following treatment with
Bextra. The reporting rate for these serious skin reactions appears to be greater for
Bextra than other COX-2 selective agents. Further, the risk of these serious skin
reactions in individual patients is unpredictable, occurring in patients with and
without a prior history of sulfa allergy, and after both short- and long-term use,
which makes risk management efforts difficult.”
Bextra was not the only product associated with this specific risk.
Celecoxib (Celebrex) is also a sulfonamide and is therefore associated
with the same syndrome, so are the barbiturates, phenytoin, allopurinol,
adult and children ibuprofen products and associated drugs. Also
Sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole,
sulfacetamide, sulfanilamide, sulfathiazole, sulfabenzamide,
hydrochlorothiazide, Lamictal, Trileptal, chlorthiazide, metolazone,
chlorthalidone, indapamide, methyclothiazide, furosemide,
chlorpropamide, tolbutamide, tolazamide, glipizide, glyburide, Gleevec,
acetazolamide, penicillin and others are associated with the same
syndrome.
On November 13, 2002, Pharmacia and the FDA informed healthcare
professionals about the “rare spontaneous reports of hypersensitivity
reactions (i.e., anaphylactic reactions and angioedema) and skin
reactions, including cases of Stevens-Johnson syndrome, toxic epidermal
necrolysis, exfoliative dermatitis and erythema multiforme, have been
received for patients treated with BEXTRA.” The unpredictability of the
risk, which made the risk management efforts difficult, has not changed
since 2002 and is still relevant for all other products with the same
characteristics.
In 2004, the annual number of deaths reported on the FDA’s AERS
system, that were associated with Stevens-Johnson syndrome, following
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treatment with Bextra, is 3 (three) patients. About 160 patients were
associated with non-fatal Stevens-Johnson complications. These numbers
demonstrate an effective disease management for this rare ailment. If a
similar measure of risk becomes the standard for general drug approval,
very few drugs will remain available for use.
• “For celecoxib and rofecoxib these conclusions [that celecoxib, rofecoxib, and
valdecoxib are associated with an increased risk of serious adverse CV events
when compared to placebo] are primarily supported by the data from the APC and
APPROVe trials, respectively. In the APC trial a 2-3 fold increased risk of
adverse CV events was seen for celecoxib compared to placebo after a mean
duration of treatment of 33 months. … However, for celecoxib a nearly identical
long-term placebo-controlled trial (the PreSAP trial) and a similarly sized
placebo-controlled trial in patients at increased risk for Alzheimer’s disease did
not replicate these findings… The ADAPT trial in patients at risk for Alzheimer’s
disease, does not appear to have shown an increased risk for celecoxib 200 mg
twice daily compared to placebo for the composite endpoint of death, MI, or
stroke.”
Three long-term placebo controlled trials were available for analysis on
Celebrex. The APC and PreSAP are large-scale trials of nearly identical
design, with different results. The two almost identical trials reported totally
different results, because of the low level of the ‘signal’ that was measured
combined with high level of confounding variables that ‘mask’ the signal
with ‘noise’. At least there is no reason to prefer the negative ‘results’
measured by APC to those measured by both PreSAP and ADAPT.
• “The strongest data… come from the … (APPROVe) trial in which rofecoxib 25
mg once daily was compared to placebo for up to three years. A relative risk of
approximately two was seen for rofecoxib compared to placebo for serious
adverse CV events. It is noteworthy that the rofecoxib and placebo CV event
curves in a Kaplan-Meier plot did not appear to begin to separate until after
approximately 18 months of treatment… For rofecoxib, other long-term placebo-
controlled trials of equal or greater duration (the Alzheimer’s treatment trials) did
not replicate the APPROVe findings.”
The APPROVe trial is deficient by the same inherent problems identified
for the APC trial. However, APPROVe is a good example of how a “well
controlled” study leads to an erroneous conclusion with colossal
consequences.
The Graph at http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-
4090S1_04_Merck-VIOXX.ppt presents the great “puzzle”:
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On the first 18 months of the study, the accumulated number of CV events
for Rofecoxib and the Placebo arms is identical - 19 events, an annual
rate of 12.6 events per year for both groups. For the second 18-month
period, the number of CV events for Rofecoxib increased to 26 (17.28
events per year), while the CV event count for the Placebo group went
down to 6 (4 events per year).
The APPROVe patient population was initially 84% white, with a mean
age of 59 and 62% were male. The estimate for annual rate of heart attack
and Cerebral Infraction for a similar patient mix, at the age of 55-64 is 13.8
and at the age of 65-74 the number is 16.5 events per year.
The statistically insignificant increase in monthly event rate from the first
18 month period to the second for the Rofecoxib group should be partially
attributed to the 1.5 year aging of the Rofecoxib population and to chance;
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however, the statistically significant decrease in the average number of
monthly events cannot be attributed to the extremely positive effect of the
Placebo on the patients. Whatever explanation is offered to the puzzle -
the APPROVe trial provides no proof for a modified CV risk for the
Rofecoxib arm over time.
• Commenting on the insight gained from observational studies the report
commented: “The available data for the non-selective NSAIDs from the
observational studies are limited, and no consistent signals were observed.”
This FDA report unequivocally rejects Dr. David Graham’s allegations
during his high profile public appearances in conferences, the Senate,
Television and various media channels, citing a loss of 27,000 to 139,000
lives due to CV events.
Dr. David Graham, a 20-year veteran of the FDA, is the person who
boasted his key role leading to the withdrawal of nine significant drugs
over the past decade.
Dr. David Graham referred to the risks associated with Vioxx as “what
may be the single greatest drug safety catastrophe in the history of this
country or the history of the world.”
Following the FDA’s report, Dr. Graham should be reclassified from
‘whistleblower’, who revealed something covert on the FDA, into an ‘usher’
who shouted "fire" in a crowded theater. The FDA surely has the right and
duty to discharge an usher if he is the one who shouted "fire." (In Martin v.
Capital Cities Media, Inc. , 354 Pa.Super. 199, 223-225, 511 A.2d 830, 842-843
(1986))
The FDA report also puts Rep. Senator Chuck Grassley in an awkward
position, as the person who staged and protected Dr. David Graham since
November 18, 2004.
Dr. David Graham conferred his megalomaniac motivation: “when I
became an epidemiologist at FDA, the entire nation – all 290 million
people – became my patients … My religious faith taught me to preserve
their lives to the best of my ability and to do nothing to intentionally injure
or harm them.”
(http://www.corporatecrimereporter.com/graham122804.htm)
On April 27, 2005, a bill was proposed to the US Senate, to reform the FDA by forming a
new independent safety office within the agency. The bill will give the office new powers
to police the safety of drugs already on the U.S. market, including authority to
