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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

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recommend banning further sales of drugs carrying unreasonable health risks. $500 million in spending over five years will be paid for the new office.

It is our prediction that as has been the case with bureaucracies, the new safety office will strive to be successful. Scores of drugs as risky as Bextra and Vioxx will be banned. Millions of patients will be ‘protected’ from ‘risks’ and remedy by the new office. The consequences and magnitude of suffering from loss of cure can be assessed by watching the helpless, tortured MS patients, who were recently deprived of Tysabri the most effective MS drug, which was pulled off the market following the death of a patient and the positive testing of another patient for the same rare neurological disorder. (see: http://www.elan.com/News/full.asp?ID=679361 )

Under the rule of the “empowered” FDA, who will take risk to develop a new drug that can be dropped by political or bureaucratic pressure? Who will fund the quest for the proof of absolute safety? Who will have the means to increase the costs of introduction of new drugs, when government and politics tightly control the means of marketing such drugs?

Aviel Shatz © Copyright, May 1, 2005 This article can be reproduced, as is, with no further permission from the author. Modified version should be approved by the author. This white paper follows up Intercon’s press release dated November 17, 2004, available at http://www.medicalnewstoday.com/medicalnews.php?newsid=16502 The introductory analysis is available at http://www.interconus.com/products_dynatrack.htm 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.