Flagrant Misrepresentation
Voluntary Withdrawal of Vioxx

The present controversy surrounding the voluntary withdrawal of Vioxx, with regard to COX-2 inhibitors, and the refusal by another major pharmaceutical to face the existing reality that profit must bow to safety, reflects a major policy shift with marketing trumping science. Vioxx is a
drug aimed mostly at seniors who are ill-equipped to either afford or contest the evolving state of affairs, which leaves them not only broke, but worse off than from the illness that they sought treatment for in the first place. The shaky proposition upon which COX-2 inhibitors first entered
the marketplace would make any respectable scientist blush, but more importantly represents a moral decay which if not recognized, will doom seniors first, and then the rest of us, to a state where safety is obsolete and profit prevails.

As is now well known by Merck’s voluntary withdrawal of it’s blockbuster drug, Vioxx, the COX-2 inhibitors are simply not safe. In fact, they cause thromboembolic and cardiovascular adverse events more commonly known as strokes and heart attacks, and the fact of the matter is these drugs were known by the pharmaceuticals to cause such catastrophic consequences, but nevertheless went to the marketplace because safety took a backseat to profit. As citizens, or consumers, or to be blunt, as guinea pigs for the pharmaceuticals, it is high time to protest. If we do not we will rot in our acquiescence to an industry that is mass producing disease that is far worse than the original ills it allegedly sought to cure.

Indeed, it would be disingenuous to proceed on the assumption that COX-2 inhibitors were produced for the purpose of alleviating disease since they were known in the drug industry to be nothing more than “me too” drugs since they were no better or effective than drugs already in the
marketplace, but substantially more profitable. As will be shown below, the industry was able to persuade physicians to go from older drugs which cost no more than eight cents a day, to tablets costing between one and three dollars a day despite the fact that there was no difference between the two in their efficacy.

The policy shift I am speaking about is reflected not so much in the conduct of Merck, who removed Vioxx from the marketplace because it became clear that whatever good was being provided by Vioxx, it was knocking off too many people by way of heart attacks and leaving others a shell of their former selves by way of strokes, but by the conduct of its main rival Pfizer who has an identical drug with the trade name of Celebrex. Pfizer paraded out its spin doctors, revealing three previously “undisclosed studies of Celebrex” to show that there are no safety
concerns regarding it’s drug. The trash that Pfizer is presently propounding represents a shift from conduct in which the pharmaceuticals, who have consistently engaged in deceptive practices, especially since around 1997 when their advertisements took direct aim at the consumer effectively bypassing the physician, from engaging in conduct that is negligent in nature to knowingly putting poison pills in the marketplace and then, despite overwhelming evidence of the catastrophic effects, employing the art of spin to keep them out there.

Pfizer spin doctors dredged up the studies to show that no safety concerns have been shown with respect to the use of its Blockbuster drug (in the industry a drug is not referred to as a Blockbuster until it generates $1 billion or more in sales a year), attempting to distinguish
Celebrex from Vioxx, despite the fact that they are the same. The Food and Drug Administration (FDA), who believe me is not your friend, had Crystal Rice, a spokesperson for the agency state “the issues raised by Vioxx will make us more concerned about the need for long-term data”.
The use of the term “data” is now an accepted and sanitized way of masking catastrophic consequences to people whose stories will likely remain unknown, both with respect to children left without parents, here mostly grandparents, as well as the condition of stroke victims and others who have been totally disabled thanks to the poison being spit out by the pharmaceuticals.

A LITTLE SCIENCE SHOULD GO A LONG WAY BUT IT WON’T

These drugs begin with a family of chemicals originally discovered in the prostate gland, and are thus known as prostaglandins. The prostaglandins are everywhere in the body and are responsible for producing Cyclooxygenase, or COX for short. The enzyme COX is known to have both beneficial and adverse effects. It is known to be the cause of pain and inflammation, but also to provide benefits such as protecting the stomach lining. It follows that if one can inactivate or inhibit its activity one can alleviate pain. The prototype of this family of drugs was simple aspirin, which is a weak organic acid that has the effect of inactivating this enzyme.

Inflammation is a normal protective response to tissue injury caused by any number of things ranging from physical trauma to exposure to toxic substances. It is the body’s way of alerting us that something is wrong and needs to be fixed. The physical manifestation of inflammation is
pain, hence all of the COX inhibitors are pain relievers, and have been referred to as arthritis drugs, since that has been their primary purpose, though they have also been useful for relieving headaches and menstrual cramping. Generally speaking, while the fact that inflammation causes pain is in reality good for us, it is a bad thing when inflammation is triggered by something that is innocuous, because something in our system is not functioning correctly.

When this happens it is considered an autoimmune disease. One common autoimmune disorder which most affects women from 40 to 60 years old is rheumatoid arthritis. The major symptom of rheumatoid arthritis is inflammation of the joints, no doubt a very painful disease. After aspirin came the first-generation of COX inhibitors such as ibuprofen and naproxen. As the name suggests they were called nonsteroidal anti-inflammatory drugs (NSAIDS). Although the NSAIDS were effective pain relievers they shared a common feature, namely, they also produced serious gastrointestinal effects ranging from ulcers and perforations to gastrointestinal bleeding. The NSAIDS were called COX-1 inhibitors.

If one could invent a drug that effectively functioned as a pain reliever but did not have the GI effects of the COX-1 inhibitors it would not only be a good thing for us, but a bonanza for the pharmaceutical who could bring such a drug to the market. By the late 1980s a good deal of research was being devoted to trying to isolate the COX that caused the inflammation without disturbing the COX which protected the lining of the stomach. Several groups of scientists working in the universities of California, Brigham Young, and Rochester simultaneously but independently, discovered the gene that became known as COX-2. Now all they had to do, through genetic engineering, was to produce the protein that would block COX-2, but not COX- 1.

As is almost always the case, the major pharmaceuticals, standing on the shoulders of publicly funded researchers, such as the National Institute of Health (NIH) funded academicians who identified the enzyme which permitted the pharmaceuticals to manufacture the COX-2 inhibitors
now commonly known, at least by most seniors, by their trade names Celebrex (made by G. D. Searle, which was bought by Pharmacia which is now Pfizer) and Vioxx made by Merck. The only justification for bringing the COX-2 inhibitors to the marketplace was that they could provide the same, but no better, relief from pain, without the GI side effects of the COX-1 inhibitors. Yet the FDA, still not your friend, would not let either Pfizer or Merck make the claim that their second-generation NSAIDS did not have the same GI effects as their older counterparts because there was insufficient scientific evidence to prove the same.

In a bitter irony, it was the very claim that these COX-2 inhibitors would not produce GI effects that allowed the pharmaceuticals to seek fast-track approval which permitted a drug company to gain FDA approval in six months, the rationale being their particular drug had therapeutic advantage over any other drug in the marketplace, or that there was no existing medication that would meet therapeutic need of the drug in question. Fast-track approval is simply one of the many breaks pharmaceutical companies have received from Congress and while the FDA insists its review is every bit as rigorous, you need only open a newspaper or medical journal and read comments about the scientists and physicians asserting Vioxx was not adequately studied before
receiving FDA approval. In fact, Vioxx and Celebrex, both of which went through the fast track process share that feature with other disaster drugs that went the same route, e.g. Fenfluramine.

Fenfluramine, and later Dexfenfluramine, were removed from US markets in 1997. They were commonly referred to as diet drugs and American Home Products (AHP) billed them as magic bullets for weight loss. In fact, the drugs were never effective for anything but temporary weight
loss which was regained as soon as one stopped taking the drug. It was strongly suspected that the drugs were toxic, causing damage to the brain well before FDA approval was sought. Later on they were also shown to cause valvular heart disease, and pulmonary hypertension, a deadly lung disease from which there is no cure. Although AHP has paid out billions to the victims in the Diet drug litigation it has been on a pay-as-you-go, business as usual basis rather than any lessons learned from the catastrophic consequences that were unleashed on an unsuspecting public.

The FDA was well aware that when Merck and Pfizer sought fast-track approval there were several other drugs already in the marketplace that were equally effective as pain relievers, and that despite the fact that the FDA was not convinced these me too drugs were any easier on the
stomach, it nevertheless let both Merck and Pfizer proceed fast-track. Merck, but not Pfizer, now admits Vioxx had to be removed from the market because of an increased risk of cardiovascular events associated with Vioxx. It is quite remarkable that Pfizer continues to assert that Celebrex is safe since it has the exact same mechanism as Vioxx, namely, inhibition of the COX enzyme.

As noted earlier, this enzyme is everywhere in the body and carries out important functions such as the well accepted premise that it protects the lining of the stomach, leading to the GI side effects that stem from inhibiting that function. It appears clear that this enzyme also has a
cardioprotective effect, and inhibition of that effect results in catastrophic consequences ranging from sudden cardiac death to debilitating strokes. It is therefore legitimate to pose the question of not only how these drugs were permitted to reach the marketplace, but on what basis a major
pharmaceutical such as Pfizer continues to promote the myth that Celebrex is safe despite overwhelming evidence to the contrary (the consumer group Public Citizen put Celebrex on its worst pills list several years ago). See, Worst Pills, Best Pills News Article April, 2001@
WorstPills.org. The answer to that question lies not in the science but the politics. In order to put the answer in proper context it is necessary to look at the history of the industry first.

THOSE WHO CANNOT REMEMBER THE PAST ARE CONDEMNED TO REPEAT IT

The regulatory history in this country begins in 1906, which is when Upton Sinclair wrote his classic novel “The Jungle” which exposed the filthy practices in the meat packing industry. In 1906 Congress promulgated The Food and Drug Act which prohibited introducing falsely labeled unadulterated foods, drinks and drugs into interstate commerce. This legislation gave rise to the FDA.

It was not until 1938, this time as a result of deaths from another poison pill, then a new sulfa drug, that Congress amended the act to require drug companies to prove that it’s drugs were safe before they could be marketed. Back then a prescription was not necessary to get a drug,
something that was not required until 1951. Nevertheless, standards for safety were few and far between.

In 1944 The Council on Pharmacy and Chemistry of the American Medical Association published standards which it believed should be followed prior to permitting a drug into the marketplace. See, COUNCIL ON PHARMACY AND CHEMISTRY, REPORT OF THE COUNCIL, LABORATORY AND CLINICAL APPRAISAL OF NEW DRUGS, JAMA, Volume 126, Number 15, Dec. 9, 1944, The report of the council stated it was,

Concerned not only with the evidence of safety but also the evidence adduced to support the claims made for new drugs. Too frequently this evidence is found inadequate..... The council suggested a new drug should pass through several phases of investigation before being declared suitable for distribution in commerce. In answering the question of whether a drug was suitable for distribution, the points the council indicated should be considered before declaring a drug safe and efficacious are: 1. Has the drug definite and desirable pharmacodynamic or chemotherapeutic actions? 2. Are its actions constant and reproducible? 3. Are these actions observed in different species of animals? 4. Is the mechanism by which its actions are produced a desirable one, or are the actions the result of an ultimately undesirable reaction of the animal? 5. Are the effects obtained in animals in which experimentally produced pathologic or functional changes comparable to human diseases have been made? 6. What is the therapeutic index of the compound (ratio of effective dose to toxic dose: ED50/LD50)? 7. Are the undesirable side actions of sufficient importance and severity to militate against its clinical use? 8. Is there an adequate margin of safety in it’s use?

In calling for evidence not just to prove a new drug was safe, but equally important whether it was efficacious for the purpose for which it was being recommended, the council insisted on testing to appraise the “therapeutic usefulness” of the drug, recommending that animal models
should be used first. Then, only if the drug shows some promise should the process continue with clinical trials in humans. Yet, it was not until 1962 when Congress passed the Kefaufer amendments that pharmaceutical companies were required to prove their drugs were not only safe but efficacious.

The Wild West atmosphere in the pharmaceutical industry can be discerned by looking at industry activity after Eugene Dobbs successfully synthesized estrogen in 1937. He was a British scientist who was being funded by the British version on the FDA and this discovery was never
patented as the government required the drug should be widely available to the public at a reasonable cost. The pharmaceuticals in this country could not wait to get this drug to market, since it was cheap and easy to make and without patent restrictions, a financial bonanza awaited.

The FDA was flooded with applications to market the drug by 1939. The applications themselves were so poor that the companies had to continually resubmit, and at one point the FDA advised them to form a committee and submit a single joint application. The drug which
emerged was called diethystilbestrol or DES. Initially approval was sought for “hormonal troubles”. In the forties a husband-and-wife team at Harvard came up with the notion that it could prevent miscarriage. Many physicians and researchers in the field questioned this proposition in the first place, since miscarriage was nature’s way of eliminating deformed or otherwise defective fetuses.

Although there was never any reliable evidence generated to prove that DES prevented miscarriage, that did not prevent the drug companies from promoting it as a wonder drug and it became wildly popular by the early fifties. This happened despite the fact that numerous researchers debunked the Smith’s theory as early as 1950. See, The Management of Threatened Abortion: A Study of 100 Cases, Crowder, et al., Am. J. Obstet & Gynec, 60: 896, 1950. By 1953, Dr. Dieckman carried out a large clinical study which once and for all attempted to prove that DES did not prevent miscarriage, and ironically there was some evidence that DES in fact
caused miscarriage. See, Does the Administration of DES During Pregnancy Have Therapeutic Value?, Dieckman, et al.,; Amer. J. Of Obst. & Gync., 66:1062, Nov. 1953. The drug nevertheless was promoted for the prevention of miscarriage by the major pharmaceuticals in this
country until 1970 when it was established that the drug caused clear cell cancer in the offspring of the women who ingested the drug. Subsequently, it was established that in addition to the cancers, the drug also caused infertility and sterility in the men and women whose mothers
ingested the drug.

The 1962 amendments requiring drug companies to prove a drug’s efficacy were simply ignored and not a single pharmaceutical ever attempted to present evidence to the FDA that DES was efficacious for the prevention of miscarriage. DES is hardly an isolated instance with one
researcher observing, “it’s been a scandal for years”, “they basically use the public as guinea pigs for the pre-1976 devices” March 24, 1992 Wall Street Journal article entitled “Health Risk, Amid Lax Regulation Medical Devices Flood a Vulnerable Market, Industry Protests as the FDA Now
Attempts to Reverse Decades of Laissez-Faire, “Using Public as Guinea Pigs”p.1. It would be an understatement to say that the history is simply not pretty.

IT’S THE POLITICS STUPID

In view of this history it was disconcerting to hear the president blaming frivolous lawsuits with driving up the costs of health care. It is no secret that drug litigation has become a cottage industry but the fact of the matter is that it is only because there are so many bad drugs on the
market. The magnitude of the problem is reflected in the fact that we now routinely read reports and analyses such as the one carried out by the Prudential Equity Group which predicts there will be some 16,632 lawsuits expected against Merck from the victims of Vioxx. See, Philadelphia Inquirer, October 2, 2004; Josh Goldstein.

Troglitazone, brand-name Rezulin, was another disaster drug that received fast-track review by the FDA. This was a drug that was supposed to be therapeutic for the treatment of diabetes. It hit the marketplace in the beginning of 1997 and by autumn 135 cases of severe liver damage
were reported, including at least five fatalities. Parke-Davis was the pharmaceutical who secured FDA approval in this country, and in England the British pharmaceutical company Glaxo- Wellcome manufactured and marketed the drug in the United Kingdom. The rapidity with which reports of liver damage were coming in prompted Glaxo to remove the product from British markets after some 90 days in the marketplace. Not us.

Parke-Davis insisted the drug was safe and continued to market it, in this instance with the blessing of the FDA advisory committee who were engaged in the traditional American practice of labeling away whatever adverse information surfaced about drug. Although in this particular
case the FDA officer assigned to the case, Dr. Robert Misbin, strongly disagreed, but made little headway in convincing the agency to take the drug off the market. Rezulin remained in the marketplace in this country until 2000 allowing Parke-Davis to generate over $2 billion in sales
with an additional 94 reported cases of acute liver failure, 64 of them fatal, obviously written off as the cost of doing business. These numbers become even more compelling in light of the fact that researchers believe less than 10% of all adverse incidents are reported to the FDA.

It is worth noting that the medical officer assigned to Rezulin later stated that had he been aware of the evidence of liver damage that was known but not reported to him at the time Rezulin was first evaluated by the FDA, he would have acted differently. See, Powerful Medicines, The Benefits, Risks, and Costs of Prescription Drugs, Alfred A. Knopf Publisher, a Division of Random House Inc., 2004 by Jerry Avorn, M.D. p 93. One fair inference that can be drawn in light of this fact is that, as in the case of the COX-2 inhibitors, fast-track approval was given to Parke-Davis despite the availability of alternative drugs to treat diabetes in the marketplace, it
was politics and not science at work.

Sometimes the politics are subtle and other times not-so-subtle as in the case of fenfluramine, brand-name Pondimen, the first of the two diet drugs that were removed from US markets in 1997. Ironically, although these drugs were removed because of evidence they caused valvular
heart disease and pulmonary hypertension, back in 1995 when Interneuron, the American pharmaceutical manufacturer of this drug sought approval from the FDA, one of the major fears was that the drug could cause brain damage. In fact the advisory committee reviewing the drug in September of 1995 refused to approve it for safety reasons. Generally, when that happens the message to the pharmaceutical manufacturer is to go back to the drawing board and answer the questions raised about safety or efficacy, or simply abandon future research since it is clear the benefits of this drug do not outweigh it’s risks.

Since the average period to get a drug to market ranges from six to ten years, it was surprising to see Interneuron back in front of the same advisory committee some six weeks later, in November of 1995. The only discernible difference was that in November, General Alexander Haig,
Nixon’s former chief of staff, who happened to be a member of the Interneuron Board of Directors, was present at the meeting. Although he did not utter a single word to the committee it seems that the safety concerns of September 1995 disappeared.

This drug provides a ready example that the victims are not limited to those who ingested medications after they reach the marketplace, but sometimes include researchers who for ethical reasons attempt to bring out the truth about events taking place in the laboratory. One such
researcher is John Lehmann, a neuroscientist who was working for the French pharmaceutical company Servier. He was doing testing in France for the purpose of demonstrating that the concerns about neurotoxicity, i.e., brain damage, were unwarranted. He was experimenting with
rodents and received some surprising results. It turned out rather than alleviating concerns about neurotoxicity, the results pointed to the fact that fenfluramine was in fact neurotoxic. When he sought to report these results the company demanded he bury the information and he refused.
The company then fired him.

Although he ultimately did report to the FDA it changed nothing, nor did the FDA take any steps to protect John from company efforts to depict him as incompetent, and branding him a liar as well. Although a highly competent neuroscientist, John has not worked for a pharmaceutical
company since this episode.

The above lends some perspective to looking at the current events surrounding the COX-2 inhibitors and hopefully provide an important message to those who are targeted by these drugs, namely seniors. Do not look to your government for any assistance or protection, and be very
careful lest you become part of the” data” which the pharmaceuticals view as part of the cost of doing business. This President’s support for the industry is best reflected by legislation the administration is seeking that will immunize a pharmaceutical manufacturer from liability if they can show they have obtained FDA approval to market their drug. This is due in part to the fact that the industry clearly has friends in this administration.

G. D. Searle was the manufacturer of Celebrex. From 1977 to 1985 the CEO, President, and then Chairman of the Company was our current Secretary of Defense, Donald Rumsfeld. It is worth noting that for his efforts at G.D. Searle he was named outstanding chief executive in the
pharmaceutical industry. Although the events surrounding the COX-2 inhibitors unfolded after his leaving the company, one can certainly surmise the administration’s position in this area has his fingerprints all over it. It is rare that direct evidence of the political dimensions of the
problem will ever surface. However, there are some facts that leave few other explanations.

You have already read about the connections between the industry through Donald Rumsfeld and Alexander Haig. Mitchell E. Daniels Jr., a former White House budget director was a senior vice president of Eli Lily, and the first President Bush served on its Board of Directors. Eli Lily
marketed DES, and was in fact the largest manufacturer of the drug in the country. The pharmaceuticals, like everyone else, want to get some bang for their buck.

In 2002 alone, the industry employed 675 lobbyists spending more than $91 million. See, The Truth About the Drug Companies, Random House Publishing Group, New York, by Marcia Angell, M.D., at p 198. Among these lobbyists were former politicians such as former U.S. Senator Orrin Hatch who opened his own firm and took on clients such as the pharmaceutical giant GlaxoSmithKline. It is therefore no surprise that when the need for regulation is greater what Congress is giving us is less regulation.

The already entangled relationship between the FDA and the pharmaceutical industry was formalized by Congress when it enacted the Prescription Drug User Fee Act in 1992 which authorized drug companies to fund the very approval process by which the drugs reach the marketplace. Dr. Marcia Angell observed that while these funds were to be employed only to expedite approval of drugs, they soon accounted for half the budget of the agencies drug evaluation center, making the FDA dependent upon the industry it is supposed to regulate. Id. at p. 8, See p.208.

You have read the standards the Council on Pharmacy and Chemistry as far back as 1944. Yet more than half a century later, in 1997, Congress passed the Food and Drug Administration Modernization Act, which lowered rather than elevated the standards for approving drugs, in
some instances allowing a single trial to be sufficient for securing FDA approval. When you add the reduction in standards to the fast-track approval policy of the agency (which gave us killers such as Rezulin, Pondimen, Redux, and now Vioxx and Celebrex), and the fact that the industry is funding at least half of the FDA staff who are approving these drugs, it should be no surprise that since 1992 ,13 different prescription drugs had to be withdrawn from US markets because of the deaths and catastrophic illnesses they caused.

Last but definitely not least is the 1997 legislation Congress enacted that allowed the drug companies to come right into your living room to push their propaganda. As Dr. Angell observed,

Once upon a time drug companies promoted drugs to treat diseases. Now it is often the opposite. They promote diseases to fit their drugs. Id., p. 8, See p.86.

Turn on your television and you’ll see beautiful people, usually with soothing music in the background telling you why you need to take this or that drug. Although the ads are everywhere today, they are far from the only source by which drug companies sell to consumers. They use
everything from top-notch Madison Avenue publicists to promote Company-initiated” news” stories to sales pitches which they bill as educational activities. Today some people are taking so many drugs at a time they can barely remember the names of what they are taking.

The above discussion should provide a framework for understanding the current events, especially Pfizer’s behavior, and hopefully be helpful in making sure that Celebrex does not become another Rezulin. It is quite ironic that the reason both Merck and Pfizer are in the position they are in is because of company greed. The fact that both drugs were blockbusters, that is, generating over $1 billion a year in sales, was not enough for them. Both companies carried out what are known as Phase IV trials which are postapproval studies. From a publichealth perspective these studies are supposed to follow the drug to make sure it is safe since in the marketplace it will reach thousands if not millions of people and effects may show up that did not surface in the premarket approval studies because the populations were too small to develop meaningful clinical results. Indeed, at times the FDA will condition approval on the pharmaceutical company carrying out Phase IV trials to ensure the drug is safe.

In the case of Celebrex and Vioxx however, the Phase IV trials were not carried out for safety purposes but because the companies wanted to expand their market shares, and wanted to persuade the FDA that in fact these two drugs caused less GI effects, so they could put the same
in their labeling. Things backfired however because both studies showed an increase in adverse thromboembolic and cardiovascular events, despite the efforts by both companies to rig the results. It may be useful to preface discussion of these trials with a more general statement of
their purpose.

The true purpose of clinical trials is to further knowledge in various fields of medicine. This falls under the umbrella of a branch of science known as epidemiology. In our context epidemiology is the study of the distribution and determination of health-related states, or events in specified populations for the purpose of making public health decisions. The studies are published in peerreviewed journals to keep physicians abreast of developments in the field. When properly carried out they are obviously useful tools in furthering knowledge and in making public health care decisions. When manipulated for the purpose of achieving a pre-designed result, it is not science at all but fraud.

Dr. Angell describes one such effort by Parke-Davis to expand the uses for Neurontin, a drug approved by the FDA in 1994 to treat epilepsy. She explained how the company called its plan a “publications strategy” which involves sponsoring minimal research and preparing journal articles on it, and paying academic researchers to put their names on those articles. Indeed, she cites a company memo which had in caps, “{OUR COMPANY} HAS DRAFT COMPLETE, WE JUST NEED AN AUTHOR” See, Angell p.158-9.Although this may seem a more blatant form of fraud, rigging the results can be done in any number of ways including withholding information, which is what Pfizer did in its Phase IV trial involving Celebrex.

Pfizer called this study the Celecoxib Long-Term Arthritis Safety Study (CLASS), and it’s purpose was to show that Celebrex was safer than the other NSAIDS on the market, in that it did not have the GI side effects of the other drugs. Pfizer presented results based on the first six months of a year-long clinical trial which compared Celebrex with Ibuprofen and Diclofenac, asserting that the “data” demonstrated Celebrex causes fewer GI problems. Dr. M. Michael Wolfe, an editer and noted gastroenterologist at Boston University wrote a favorable editorial
about the article. The problem of course was that when one looked at the data for the entire year there was no discernible difference between the GI effects caused by Celebrex and the older, and much cheaper, NSAIDS. When Dr. Wolfe learned that Pfizer had a full year’s data at the time they sent him only the first six months, he was quoted in the Washington Post as saying “I am furious...I wrote the editorial. I looked like a fool. But....all I had available to me was the data presented in the article” See, Angell p. 109. See also, “Missing Data on Celebrex: Full study altered picture of drug” Washington Post, August 5, 2001, A11.

Merck, not to be outdone by its main competitor, also launched a Phase IV trial complete with its own nifty little acronym, the VIGOR study (Vioxx Gastrointestinal Outcomes Research). In looking at how the FDA reacted to this study it becomes very clear the FDA is not your friend. The FDA has a policy of issuing “talk papers” to assist and guide personnel in taking questions from the public. The VIGOR study was the topic of one such “talk paper” and the following was written by the FDA in connection with the same:

The VIGOR study, a perspective, randomized, double – blind, one-year study, evaluated approximately 4000 patients on Vioxx 50 mg a day (twice the highest approved dose for chronic use) and approximately 4000 patients on the standard dose of Naproxen (1000 mg a day), a nonsteroidal antiinflammatory drug (NSAID). Patients who were under treatment with low-dose Aspirin for heart attack prevention were excluded from the study. The study demonstrated that Vioxx was associated with lower incidence of serious upper gastrointestinal (GI) adverse events of major bleeding, perforation, and obstruction compared to Naproxen. The reduction in risk over 50% in cumulative rates for Vioxx (.52%) compared to Naproxen (1.22%). See, FDA Talk Paper, April 11, 2002; FDA Approves New Indication and Label Changes for the Arthritis Drug, Vioxx.

One has to wonder who wrote the talk paper within the agency, since the FDA medical officers reviewing the study were not sufficiently convinced of any difference to permit Merck to make changes in its labeling with regard to the GI effects. More importantly, whoever wrote the paper had to be friendly to Merck because this study was just as rigged as Pfizer’s CLASS study, only differently so. It is well-known that of the NSAIDS, Naproxen had the most serious GI side effects, and to truly determine if Vioxx was safer, i.e., that it had less GI side effects, it should have been compared to either Ibuprofren or Diclofenac, which, just as in the CLASS trial, would have shown no difference between the two with respect to GI effects.

In any event both the CLASS and VIGOR trials not only failed to persuade the FDA to allow it to make claims in its labeling that the drugs were safer than the older NSAIDS, but these studies both found an increased risk of adverse thromboembolic and cardiovascular events. In fact, the VIGOR study showed a fivefold increase in heart attacks, as well as increases in adverse effects from strokes to blood clots. The FDA engaged in it’s usual practice of attempting to label away the problem.

On September 30, 2004, Merck announced a voluntary worldwide withdrawal of Vioxx based on a three-year trial to study the efficacy of Vioxx 25 mg to prevent recurrence of colorectal polyps in patients with a history of colorectal adenomas, ( another effort by Merck to expand it’s market
share ). According to Merck’s announcement, patients taking Vioxx for over 18 months were showing increasing cardiovascular events such as heart attacks and strokes, information that was developed in Merk’s VIGOR study carried out almost four years ago, with the results being
published in November of 2000. If there is any doubt Merck knew full well about these problems, it should be eliminated by their effort to label them away, in that the 2001 patient information sheet put out by Merck under the heading of “what are the possible side effects of Vioxx”, Merck states:

Heart attacks and other serious cardiovascular events, such as blood clots in your body have been reported in patients using Vioxx. See, Patient Information about Vioxx, Issued August 2004, Merck & Co., Inc., p 1.

In announcing the worldwide withdrawal of Vioxx, Chairman, President and Chief Executive Officer of Merck, Raymond V. Gilmartin, stated “we are taking this action because we believe it best serves the interests of patients”. If Merck was acting in the best interest of the patients Vioxx would have never seen the light of day. Indeed he goes on to say “Although we believe it would have been possible to continue to market Vioxx with labeling that would incorporate these new data, given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take”. He’s probably right about one thing, that is, if the company wanted to, the FDA would simply let it try to label its way out of this one as well.

Indeed, that is precisely the direction in which Pfizer is going and their spin doctors are going to go all-out despite not only the evidence that Celebrex is identical to Vioxx in its mechanism of action and therefore in its elimination of the cardioprotective effects of the Cyclooxgenase
enzyme it inhibits. The FDA is in the middle of its own scandal in that it now appears that one month before Merck announced the worldwide withdrawal it silenced one of its own scientists who was warning about the dangers of Vioxx.

Dr. David J. Graham, the associate director for science in the FDA’s Drug Center Office of Drug Safety told a Senate committee that he was ostracized and subjected to veiled threats and other forms of intimidation because he was the lead author in a research project that studied the records of 1.39 million Kaiser Permanente patients, including 40,405 treated with Celebrex, and 26,748 who were treated with Vioxx. One finding in this study was that high doses of Vioxx known as Rofecoxib, triples the risk of heart attack and sudden cardiac death. Instead of taking action against Merck and Pfizer, the agency turned on its own, which is similar to the treatment noted above of the medical officer in charge of Rezulin.

Indeed one FDA official called Dr. Graham’s study “scientific rumor” while the deputy director of the office Anne E. Trontell states she did not think any recommendations should be made in first place, and further has suggested that Merck be given notice before any of the findings became public, in her words, “so they can be prepared for extensive media attention that this will likely provoke”, shorthand for arming the spin doctors in advance. See, Newsday.com; FDA Accused of Silencing Scientist’s Early Warnings, Diedtra Henderson, AP Science Writer,
October 7, 2004.

It is somewhat incredulous that Merck’s chairman Mr. Gilmartin, was quoted in the Boston Globe as saying he was unaware of the heart risks, and that “it was, totally out of the blue”. We know that is not true, and well as we also know he will soon be out of a job because, according to the New York Post, Merck’s board has hired headhunters to hasten his exit from the scene. However, that has nothing to do with the victims of Vioxx, and appears to be more related to the $27 billion loss of value which Merck sustained in the financial markets. The litigation is, ofcourse, beginning. See, New York post, October 12, 2004, By Paul Tharp.

An MDL is no doubt in the offing and the victims of Vioxx and Celebrex will be traumatized again, only this time by our system of justice. To be sure, Merck and Pfizer will ultimately pay untold millions in damages, but not before prying into every aspect of each victim’s personal life, which will then be the subject of experts bought and paid for by the pharmaceuticals, who will do their utmost to assign blame either to the victim or to some unknown entity, anywhere but where it truly belongs. In short, litigation is no solution.

The pharmaceutical industry must be reined in. The practice of permitting the pharmaceuticals to market “me too” drugs as innovative therapeutic treatments must end. Drug companies should not be allowed to merge their research and development departments with marketing, since the
latter will always triumph over the former. Scientists earnestly seeking truth and understanding of complex issues cannot compete with salespeople who are interested only in scoring points and are disinterested in understanding complex problems. If the public does not become more involved and insist on the FDA being something more than a handmaiden to the pharmaceuticals, the cottage industry which has arisen in drug litigation will only continue to thrive.