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Jerusalem, Israel, May 22, 2005
Bextra – Under the skin of politically driven decision
Introduction:
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, Senator 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’ withdraw 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 prescription 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 FDA adopted the recommendations 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)
On May 2, 2005 Intercon posted a 6 page White paper, titled “Politics Pain and the Torture of the American
People”. The White paper discussed the FDA’s Analysis and recommendation on the CV risk associated with
NSAIDs. (See:
http://www.interconus.com/Politics_Pain_and_the_Torture_of_the_American_People_May_1_2005.pdf )
The current White paper is a follow up to the May 2, 2005 document. The paper discusses the Analysis,
Conclusions and Recommendations, quoted from the FDA’s memorandum. The paper analyzes the FDA’s
analysis regarding the removal of Bextra from marketing.
On November 14, 2004, Intercon posted a white paper, titled “VIOXX pain – a story of business and
statistics errors”. The White paper discussed the statistical analysis methodological errors that led to the
erroneous decision to remove Vioxx from marketing. (see: http://www.interconus.com/Vioxx_Pain.pdf )

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FDA’s April 6th
memorandum highlights:
The quotations hereunder were copied from the FDA’s Memorandum, dated April 6, 2005, titled
“Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and
cardiovascular risk”.
FDA’s Analysis:
“While other COX-2 selective and non-selective NSAIDs also have a risk for these rare, serious skin
reactions, the reported rate for these serious side effects appears to be greater for Bextra than for other
COX-2 agents. To date, the agency has received 7 reports of deaths from serious skin reactions in
patients following treatment with Bextra.”
FDA’s Conclusions:
“Valdecoxib is associated with an increased rate of serious and potentially life-threatening skin
reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme)
compared to other COX-2 selective agents and is the only NSAID with a boxed warning for this
adverse event in its approved package insert. In the absence of any demonstrated advantage over other
NSAIDs, the overall benefit versus risk profile for valdecoxib is unfavorable for marketing.”
FDA’s Recommendation:
“The agency should ask Pfizer to voluntarily withdraw Bextra (valdecoxib) from the U.S. market. In
the event Pfizer does not agree to a voluntary withdrawal, the agency should initiate the formal
withdrawal procedures; i.e., issuance of a Notice of Opportunity for Hearing (NOOH).”
Intercon’s Executive Summary:
Following a thorough review of the FDA’s April 6th
Memorandum and available data, including the AERS
data for the year 2004, we have reached the following conclusions regarding the recommendation to withdraw
Bextra from marketing:
• The FDA’s Adverse Event Reporting System (AERS) with its current detail and coverage of data was
not designed for and is not appropriate to be a base to major determination on actual risks of a drug.
At the outmost, the system at its current form can provide ‘signals’ for gross emerging trends.
• Out of 34,911 AERS reports linking drugs and death outcome, 4 reports were linked with Bextra.
Such magnitude does not justify the urgency of the measures taken by the FDA.
• The “rare skin reaction” associated with Bextra is caused clinically by allergic response to
Sulfonamides. Both Bextra and Celebrex are Sulfonamides, while Vioxx is a sulfone that is not
clinically associated with Stevens-Johnson Syndrome (SJS). Yet, Bextra is linked with three
outcomes of Death caused by SJS; Vioxx, a sulfone, is nevertheless linked with seven events of death
from SJS.
• The same “rare skin reaction” is also associated with 1,854 patients reported on CDER, 172 of those
events are associated with all COX-2 drugs. 239 events were linked with outcome of death outcome

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in CDER; Four death events link Bextra with death outcome – just 1.6% of the “rare skin reaction”
crisis.
• The safety standard for drugs’ removal, as applied by the FDA on Bextra, withdrawing from
marketing drugs associated with ‘increased rate’ of ‘potentially life-threatening’ reports to the AERS,
calls also for the withdrawal of 32 other drugs, some are critical life sustaining drugs. The FDA will
probably not enforce such ‘standard’, for the obvious lack of support of either connection or an
association between the observed cause (drug) and effect (death) between those drugs and the serious
skin event. Such harsh and unreasonable standard should also not be applied on Bextra.
• The FDA concluded that Bextra lacks “any demonstrated advantage over other NSAIDs”. Among
other advantageous properties, Bextra is the most COX-2 selective drug in the market, after the
removal of Vioxx. Celebrex is far less COX-2 selective than Bextra.
Intercon’s recommendations:
• Bextra and Vioxx should be reinstated for marketing.
• AERS database use should be restricted to identifying ‘signals’.
• The concepts, standards and methodologies associated with ‘risk’ assessment enforced by the FDA on
marketed and new drugs should be re-evaluated by open consideration.
Intercon’s Analysis:
On the rational and legitimacy of making major decisions based on AERS data:
The Adverse Event Reporting System is a computerized database comprising adverse events reported by
health care professionals, pharmaceutical companies, and consumers after a drug is marketed. Post-marketing
surveillance data provides important information about the occurrence of rare adverse events that go
undetected in clinical trials, or the adverse events that occur with a medicine as it is used in clinical practice,
outside the strict confines of a controlled clinical trial.
However, post marketing surveillance data should be interpreted in the strict context of its limitations
Among the limitations on the use of AERS data are:
• The absence of a control group that is not exposed to medication precludes the analysis of causativity.
• Spontaneous reports are limited in their ability to establish causality. An adverse event report does not
establish a causal link between the event and the medication, only that the observer believed the
suspect drug might be involved in the adverse event and therefore took the initiative to report the
event to the manufacturer or the FDA.
• The volume of reports for any individual drug is influenced by the length of time on the market,
severity of underlying illness, the manufacturer’s marketing and post market surveillance activities,
and whether the event was already recognized on the product label.
• Manufacturers, distributors and packers of FDA approved pharmaceuticals drugs and biologics, have
mandatory reporting requirements to the FDA. If they receive voluntary reports from healthcare
providers or consumers, or become aware of reports, they are required to report these to FDA.
However, there are no federal laws or regulations that require hospitals or other health care providers

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to report suspected pharmaceutical-related adverse events to FDA. Reporting by individual healthcare
providers is voluntary. Therefore, the reporting coverage from the various sources is not uniform.
• Potential for reporting bias: Adverse events, reports of which are not actively solicited, are typically
underreported.
• Spontaneous reporting is uncontrolled, subject to the possible influence of biases that affect its
content. Reports are dependent on the initiative of the independent health care providers, susceptible
to reporting bias including an increase in reporting due to the “Weber effect”, increased publicity and
enhanced awareness of the potential side-effects.
• FDA public statements, media publicity, and manufacturer warning letters to doctors increase
awareness of particular adverse reactions and increase spontaneous reporting.
• Adverse event reports derived from clinical practice are often incomplete and lack information crucial
for attempting to determine whether a medication caused the adverse event.
• Adverse event reports list multiple drugs and multiple outcomes per case, hindering the calculation of
accurate statistics on relationship between us of drug and outcome.
• AERS data alone cannot be used to calculate incidence rates of adverse events because of lack of
accurate information about both the total number of patient exposures to a drug and the total number
of patients experiencing a particular adverse event.
• Prescription data are also crude estimates of patient exposure because of uncertainty of patient
compliance.
Despite these recognized and documented restraints and the FDA's caveats for use of AERS data, on this
crisis the FDA have uncharacteristically applied AERS data to explicate its critical policy decision on Bextra.
Use of the data gathered by AERS for drug safety comparisons is beyond its credible scope because of the
many factors that influence the reporting accuracy and uniformity. Nevertheless, the FDA’s analysts based
their recommendation to withdraw Bextra from the market on the following statement: “the reported rate for
these serious side effects appears to be greater for Bextra than for other COX-2 agents. To date, the agency
has received 7 reports of deaths from serious skin reactions in patients following treatment with Bextra.”
To facilitate the reader’s independent assessment of the FDA’s recommendation, the CDER case data for the
year 2004 was transformed by Intercon into analytical database, available for public review, downloadable
from Intercon’s web site. The analysis hereunder was facilitated, applying Intercon’s DataSet V software.
DataSet V is available for free, limited time use. Download the CDER database and the DataSet V setup from
Intercon’s download page at: www.ds-dataset.com/download.html

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The scope of AERS’ data and the scope of events associated with Bextra:
The AERS database for the year 2004 reports on 272,295 patients, 205 K of these patients are associated with
one or more Outcome codes. 261 K events are associated with the 205 K patients - multiple Outcomes may be
associated to a patient. Four death reports ‘associated’ with Bextra out of 34,911 reports with death outcome,
0.01145%. Bextra is not a priority cause of concern to the public safety.
Figure 1 and Table 1 present the distribution of Outcome codes, on the AERS 2004 database.
Table 1: Distribution of reports by Outcomes code
Figure 1: Distribution of Outcome codes by type
COX-2 selective NSAIDs linkage with Serious Skin Disorder
Bextra has been withdrawn from the market, because it “is associated with an increased rate of serious and
potentially life-threatening skin reactions (e.g., toxic epidermal necrolysis, SJS, erythema multiforme)
compared to other COX-2 selective agents”. Table 2 summarizes the number of patients associated with the
various outcomes, for the three COX-2 selective drugs.
The number of events where Bextra has been associated with any event of Erythema Mutliforme is 1 (one),
compared to 6 for Celebrex and 32 for Vioxx. The number of TEN events for Bextra and Celebrex is 2 (two),
and 11 for Vioxx. The number of any Stevens Johnson Syndrome event for Bextra is 26, for Celebrex is 12
and 80 for Vioxx.
CA 1,311 (congenital anomaly)
DE 34,911 (death)
DS 13,164 (disability)
HO 94,189 (hospitalization)
LT 17,611 (life-threatening)
RI 12,768 (required intervention)
OT 87,114 (other)
Total Reports 261,068

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The FDA’s memorandum explained: “The occurrence of these serious skin reactions in individual patients is
unpredictable, occurring with and without a history of sulfa allergy (valdecoxib is a sulfonamide)”
Bextra (valdecoxib) is a sulfonamide, so is Celebrex. Vioxx on the other hand is a sulfone. As sulfone, Vioxx
does not cause SJS reactions in patients allergic to sulfonamides. Nevertheless, 67% of all Stevens Johnson
Syndrome reported events are associated with Vioxx. 71% from all events on all outcomes are associated with
Vioxx. If the non-sulfonamide Vioxx is associated with SJS, including 7 associations that are linked to Death,
it is not justified to find cause and effect on the similar phenomena on Bextra.
The FDA refers to the three types of the Serious Skin reactions as ‘serious’. The number of reported SJS with
death outcome is 11, out of 118 reported events, death ratio of 9.3%. The number of patients who died from
all three skin reactions is 12, out of 172 reports, ratio of 6.9%.
All Skin reactions Erythema Multiforme Toxic Epidermal Necrolysis Stevens-Johnson Syndrome
Vix Cbx Bex Total Vix Cbx Bex Total Vix Cbx Bex Total Vix Cbx Bex Total
Hospital 48 7 7 62 15 2 1 18 6 1 1 8 27 4 5 36
Intervention 4 1 1 6 2 1 3 2 1 3
Death 7 1 4 12 1 1 7 4 11
Other 27 8 14 49 7 1 8 2 1 1 4 18 6 13 37
Disability 23 2 1 26 6 6 2 2 15 2 1 18
Life Threat 14 1 2 17 2 1 3 1 1 11 2 13
Total 123 20 29 172 32 6 1 39 11 2 2 15 80 12 26 118
Table 2: Summary of Outcomes reported on COX-2 selective drugs, associated with Skin reactions
Association between all drugs and ‘Serious Skin reaction’
The FDA’s Memorandum refers to the Skin reactions as ‘serious and rare’. Serious implies low survival rate.
There were total of 992 SJS events reported to AERS, out of these, 116 were linked with death (11.6%) –
compared with 9.3% linked with death and associated with COX-2 drugs.
There were 239 events of all Skin disorders with death outcome, associated with 1,854 (12.9% compared with
6.9% for the COX-2 drugs). Morbidity from SJS and the other Skin disorders is lower on COX-2 drugs than
all drugs (including the COX-2 drugs).
Skin disorder reports contributed 172 reports out of 1,854 events (9.27%), and 12 out of 239 (5% ) events
with Death outcome.
FDA’s official reasoning for removal of Bextra was: “FDA has received 7 spontaneous reports of deaths from
these reactions. The reporting rate for these serious skin reactions appears to be greater for Bextra than other
COX-2 selective agents.” In 2004, 4 events associated with Bextra and Steven-Johnson Syndrome, none from
TEN or Erythema Multiforme types.

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In 2004, there were 239 events of Skin reaction, associated with all drugs reported in AERS. Bextra
contributed 1.6% to this health crisis. Bextra also contributed 3.44% to the health crisis associated with the
Steven-Johnson Syndrome.
Graph 2: Distribution of number of events reported in AERS
by outcome codes, for all drugs, by PT code.
SJS Toxic
Epidermal
Necrolysis
Erythema
Multiforme
Total
Congenital anomaly CA) 4 0 4 8
Death (DE) 116 64 59 239
Disability (DS) 48 13 20 81
Hospital (HO) 376 158 201 735
Life Threat (LT) 78 35 34 147
Other (OT) 321 88 144 553
Intervention (RI) 49 16 26 91
Total 992 374 488 1854
Table 3: Count of events by linked outcome code, for all drugs, by associated PT code.
‘Serious skin disorder’ events associated with COX-2 selective drugs
The FDA report recommended the removal of Bextra, because “Valdecoxib is associated with an increased
rate of serious and potentially life-threatening skin reactions …compared to other COX-2 selective agents”.
Table 4 presents all the drugs associated with serious and potentially life-threatening skin reaction, compared
to all drugs. The ‘other’ outcome is not listed.

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Comparing between COX-2 selective agents, Vioxx is ‘associated’ with 114 events, Bextra is ‘associated’
with 16 ‘associated’ events. If the criteria established on the FDA memorandum for drug withdrawal will be
enforced, 32 drugs will be withdrawn from marketing, including Zocor, Lipitor, Zoloft and Insulin.
Drug name Approximate
Annual #
Prescriptions
2004 (K)
Drug
share
(%)
Death Disability Hospitali
sation
Life
threatening
Required
intervention
Total
VIOXX 11,400 1.408 7 29 55 18 5 114
ASPIRIN 8,400 1.038 14 9 50 10 4 87
PREDNISONE-
PREDNISOLONE 46,950 5.799
12 5 49 8 1 75
FUROSEMIDE 41,100 5.076 15 3 43 7 1 69
ZOCOR 24,750 3.057 3 6 21 3 1 34
AVONEX 300 0.037 7 1 25 0 0 33
METHOTREXATE 3,900 0.482 8 1 18 2 3 32
ACETAMINOPHEN 171,300 21.158 6 1 18 3 3 31
LIPITOR 64,800 8.004 1 4 19 4 1 29
FOLIC ACID 12,600 1.556 4 2 20 2 0 28
ATENOLOL 45,600 5.632 5 1 16 4 2 28
DURAGESIC 3,600 0.445 7 1 14 3 3 28
CISPLATIN 0.228 0.000 5 1 17 1 4 28
OMEPRAZOLE 12,900 1.593 7 1 17 1 1 27
HUMIRA 231 0.029 5 2 13 3 3 26
HYDROCHLOROTHIAZIDE 120,000 14.822 2 1 17 2 3 25
DEXAMETHASONE 1,200 0.148 4 1 15 4 1 25
REMICADE 2 0.000 4 0 17 4 0 25
OXYCONTIN 5,400 0.667 10 1 10 0 3 24
ALLOPURINOL 8,800 1.087 2 3 14 4 0 23
IRESSA 87 0.011 4 0 12 1 6 23
THALOMID 105 0.013 15 0 6 0 0 21
LISINOPRIL 45,000 5.558 2 2 14 2 0 20
SYNTHROID 43,500 5.373 2 2 14 2 0 20
SIMVASTATIN 25,500 3.150 2 3 12 2 0 19
DIGOXIN 14,400 1.779 4 0 13 0 2 19
ZOLOFT 28,950 3.576 1 3 14 0 1 19
COUMADIN 5,700 0.704 3 2 14 0 0 19
PAXIL 11,100 1.371 2 3 11 1 1 18
FOSAMAX 18,000 2.223 3 2 10 1 2 18
LAMICTAL 3,700 0.457 2 2 10 3 0 17
INSULIN 11,400 1.408 4 0 11 1 1 17
TAXOL 0.282 0.000 4 1 7 4 1 17
BEXTRA 10,700 1.322 4 1 8 2 1 16
COZAAR 8,250 1.019 2 1 10 3 0 16
(‘Other’ outcome excluded from analysis)
Table 4: Summary of Serious Skin reaction, detailed by associated Drug - sorted by the descending
number of reported events.

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Table 5 lists Outcome numbers, normalized by Intercon’s approximation for annual number of scripts.
Approximation is understated for OTC products. Bextra is associated with 1.5 events of any type per million
scripts and 0.37 events of death per million scripts, not high risk compared to the other drugs. Physicians and
patients, subjected risk of 1 to 3 million should keep the privilege to make their own risk benefit decision.
Drug name Death Disability Hospitalisation Life
threatening
Required
intervention
Total
VIOXX 0.61 2.54 4.82 1.58 0.44 10.00
ASPIRIN 1.67 1.07 5.95 1.19 0.48 10.36
PREDNISONE-
PREDNISOLONE
0.26 0.11 1.04 0.17 0.02 1.60
FUROSEMIDE 0.36 0.07 1.05 0.17 0.02 1.68
ZOCOR 0.12 0.24 0.85 0.12 0.04 1.37
AVONEX 23.33 3.33 83.33 0.00 0.00 110.00
METHOTREXATE 2.05 0.26 4.62 0.51 0.77 8.21
ACETAMINOPHEN 0.04 0.01 0.11 0.02 0.02 0.18
LIPITOR 0.02 0.06 0.29 0.06 0.02 0.45
FOLIC ACID 0.32 0.16 1.59 0.16 0.00 2.22
ATENOLOL 0.11 0.02 0.35 0.09 0.04 0.61
DURAGESIC 1.94 0.28 3.89 0.83 0.83 7.78
CISPLATIN 21,929.82 4,385.96 74,561.40 4,385.96 17,543.86 122,807.02
OMEPRAZOLE 0.54 0.08 1.32 0.08 0.08 2.09
HUMIRA 21.65 8.66 56.28 12.99 12.99 112.55
HYDROCHLOROTHIAZIDE 0.02 0.01 0.14 0.02 0.03 0.21
DEXAMETHASONE 3.33 0.83 12.50 3.33 0.83 20.83
REMICADE 1,581.65 0.00 6,722.02 1,581.65 0.00 9,885.33
OXYCONTIN 1.85 0.19 1.85 0.00 0.56 4.44
ALLOPURINOL 0.23 0.34 1.59 0.45 0.00 2.61
IRESSA 45.98 0.00 137.93 11.49 68.97 264.37
THALOMID 142.86 0.00 57.14 0.00 0.00 200.00
LISINOPRIL 0.04 0.04 0.31 0.04 0.00 0.44
SYNTHROID 0.05 0.05 0.32 0.05 0.00 0.46
SIMVASTATIN 0.08 0.12 0.47 0.08 0.00 0.75
DIGOXIN 0.28 0.00 0.90 0.00 0.14 1.32
ZOLOFT 0.03 0.10 0.48 0.00 0.03 0.66
COUMADIN 0.53 0.35 2.46 0.00 0.00 3.33
PAXIL 0.18 0.27 0.99 0.09 0.09 1.62
FOSAMAX 0.17 0.11 0.56 0.06 0.11 1.00
LAMICTAL 0.54 0.54 2.70 0.81 0.00 4.59
INSULIN 0.35 0.00 0.96 0.09 0.09 1.49
TAXOL 14,184.40 3,546.10 24,822.70 14,184.40 3,546.10 60,283.69
BEXTRA 0.37 0.09 0.75 0.19 0.09 1.50
COZAAR 0.24 0.12 1.21 0.36 0.00 1.94
(‘Other’ outcome excluded from analysis)
Table 5: Outcome counts per million scripts.
The sorted list of drugs presenting higher ‘risk’ than Bextra, measured by associations per million scripts
includes CISPLATIN, TAXOL, REMICADE, IRESSA, THALOMID, HUMIRA, AVONEX, DEXAMETHASONE, ASPIRIN,
VIOXX, METHOTREXATE, DURAGESIC, OXYCONTIN, COUMADIN, ALLOPURINOL, FOLIC ACID, OMEPRAZOLE,
COZAAR, FUROSEMIDE, PAXIL, PREDNISONE-PREDNISOLONE.

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Various NSAIDs demonstrate different ‘advantages’:
The FDA’s Memorandum concluded: “In the absence of any demonstrated advantage over other NSAIDs, the
overall benefit versus risk profile for valdecoxib is unfavorable for marketing”. The conclusion implies that
all NSAIDs, including Bextra are equal on ‘advantage’ measure, for all patients. The conclusion also implies a
standard by which a drug must ‘demonstrate advantage’ over other drugs, or be withdrawn from the market.
Vioxx, Celebrex and Bextra are different chemically. Celecoxib and Bextra are sulfonamides, extensively
distributed into tissues. Vioxx is a sulfone, which is not as well distributed into tissues and is metabolized
principally by cytosolic reduction. The chemical differences result in major variation also in the degree of
COX-2 versus COX-1 inhibition and other effects unrelated to COX-2 inhibition at the tissue level.
Due to the limited scope of this Paper, attention is directed to single differentiating attribute, overlooked by
the FDA’s researcher. Figure 3 compares NSAIDs by relative selectivity to COX-2 and COX-1. From the
three COX-2 selective molecules in the US market, Vioxx was the most COX-2 selective, followed closely by
Bextra (valdecoxib). Celebrex (Celecoxib) is the least COX-2 selective. After the removal of both Vioxx and
Bextra from the market, only the least selective drug remains available, for the time being.
Figure 3. Relative selectivity of agents as inhibitors of human COX-1 and COX-2 displayed as the ratio of
IC80 concentrations. Inhibitor curves for compounds against COX-1 and COX-2 were constructed in a human
modified whole blood assay and used to calculate IC80 concentrations. The IC80 ratios are expressed
logarithmically so that 0 represents the line of unity, i.e., compounds on this line are equiactive against COX-
1 and COX-2. Compounds appearing above the line are COX-1-selective, those below the line COX-2-
selective. Source: The FASEB Journal. 2004;18:790-804. - Cyclooxygenases: new forms, new inhibitors, and
lessons from the clinic, Timothy D. Warner and Jane A. Mitchell

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Aviel Shatz © Copyright, May 1, 2005
Disclaimer.
Intercon has not received or been promised any compensation by Merck, Pfizer, the FDA or any other major
participant in the discussed controversy. None of its officers or employees owns any equity or derivatives in
those same companies.
This article can be reproduced, as is, with no further permission from the author.
Modified version should be approved by the author.
Reference material and analytics are available on request.
Aviel Shatz is the Chairman and CTO at Intercon System Inc., at avi@ds-dataset.com
Intercon Systems Inc. web site can be reviewed at www.interconus.com
Intercon Systems Inc. is a world-class developer of Patient Longitudinal Data systems and Analytics.
Technology development offices are located in Jerusalem, Israel.
Tel. 888-202-9801
Corporate US offices are located at 1155 Phoenixville Pike #103,
West Chester, PA 19380, Tel: 610-516-1622.