Vioxx recall controversy heats up in Canada

While the validity of FDA panel's recommendation to allow sales of Vioxx to resume in the US is in serious doubt due to conflicts of interest of panel members (10 panel members have financial ties to Merck and Pfizer), Merck is now getting into a row with Health Canada. (Related article: Merck and Pfizer ignored drug safety; focused on profits alone)

According to an interview published in The Globe and Mail, a leading Canadian newspaper, the Canadian Minister of Health Ujjal Dosanjh, has charged Merck of holding back safety data from drug regulators after it voluntarily recalled Vioxx worldwide in September 2004. “I can tell you that I am extremely concerned and disappointed with Merck [Frosst Canada] withholding data from Health Canada, even after it pulled the drug. I think they have an obligation and they have some explaining to do,” Ujjal Dosanjh said yesterday. (Related article: Merck could have found out Vioxx risks earlier)

The Health Minister has shown his frustration with Merck as the company failed to provide the data that was asked of them. It is clear from the interview that Merck dragged its feet on Vioxx safety data both prior to recall of Vioxx and subsequent to that. Health Canada representatives attended the FDA panel discussions in the United States last week. The agency issued an advisory on Cox-2 drugs in December 2004, and according to the transcript of an tele-conference published on its website, the Health Minister has promised to investigate the safety of these drugs. He calls the Cox-2 drug investigation as "one of the most demanding and costly that the department has undertaken in recent years in the area of post-market drug safety." (Related article: Merck knew of Vioxx risks, according to WSJ)

Ten Health Canada scientists and physicians are working full-time on the review of all Canadian and international studies, tests, trials, adverse effects reports, and other scientific evidence. Health Canada has been widely criticized for its poor performance in handling Vioxx recall process in Canada. (Related links: Louisiana Medicaid, Kaiser Permanente, New Zealand, European Union, and Australia limit/ban Cox-2 drug prescriptions) That was one major reason why the agency moved more aggressively in the case of Adderall XR recall despite the pressure by the FDA not to do so.

Merck Frosst, the Canadian operations of Merck, issued a statement today that the Company has at all times and will continue to cooperate with Health Canada in matters concerning Vioxx. "We are perplexed with the comments made to the Globe & Mail by Health Minister Ujjal Dosanjh" said Company spokesperson Marlene Gauthier. "The Company responded in writing to Health Canada's request for information and has offered to meet with Health Canada officials at their convenience. We had not received any verbal or written feedback to our letter until we saw the Minister's comments in the newspaper" she added.

Related developments

Merck shareholder lawsuits to be tried in New Jersey

Making sense of FDA panel recommendations on Vioxx, Celebrex, and Bextra

Useful links

The Globe & Mail

Health Canada

Merck Frosst

Vioxx, Bextra decision in doubt due to conflicts of interests

Ten of the scientists who recommended that Vioxx sales be allowed to resume and Bextra continue to be sold in the United States all had financial ties to Merck and Pfizer, according to publicly available information analyzed by The Center for Science in the Public Interest and The New York Times. In other words, any reasonable person cannot expect them to be fair, though some of the panel members claimed that their ties to drugmakers did not influence their decisions. (Related article: Making sense of FDA panel recommendations on Vioxx, Celebrex, and Bextra)

In fact, had these ten members not been on the panel, the panel would have voted to ban both Vioxx and Bextra. In other words, FDA that has sided with Merck and Pfizer in the Cox-2 drug safety debate put together a panel so that it could make favorable recommendations. Prior to the panel hearings, FDA tried to stop Dr. David Graham and Professor Curt Furberg from attending these and gave in only after pressure from lawmakers. Both scientists had criticized the drugmakers and the FDA for mishandling of Vioxx recall. After the favorable vote from the panel, stocks of both Pfizer and Merck surged and some analysts are starting to speculate that the legal problems of the companies may be less of an issue going forward. (Related article: Merck and Pfizer ignored drug safety; focused on profits)

FDA helps Merck and Pfizer, even if it means risking American lives

• FDA has done everything in its power to help Merck and Pfizer so far. Cox-2 drugs, whose safety has not been studied yet, got fast-track approval. Then the agency failed to act after disclosures about deaths and injuries started to come in. It tried to silence its own expert, Dr. David Graham, who presented solid evidence that Vioxx should have never even been approved.
• Since the recall of Vioxx, Merck actually became even more aggressive in its stance and surprised many on Wall Street by refusing to make any provisions for its Vioxx liabilities which are estimated to be as high as $55 billion by some analysts. Now it is becoming clear that Merck must have known that FDA will come to its rescue. 140,000 Americans are estimated to have been injured by Vioxx and death estimates range from 30,000 to 50,000.
• Similarly, despite publication of research that highlighted risks of Celebrex and Bextra, Pfizer continued to stand by the safety of the drugs and refused to recall them. It too knew that FDA will put together a panel that will make favorable recommendations. (Related article: Pfizer may have known Celebrex risks)

The decision to recommend that Vioxx sales be allowed shocked most industry observers particularly because of the background of Vioxx recall. Merck voluntarily recalled the drug after it found that the drug was just not safe to be on the market. Then a series of studies released from October 2004 to middle of February highlighted that:

1. All Cox-2 drugs raise the risk of heart attacks and strokes.
2. These drugs do not provide any more benefit than an Aleve or Ibuprofen for almost all arthritis patients but cause serious side effects.
3. Merck and Pfizer fought Coke-Pepsi style over Vioxx, Celebrex, and Bextra.

It is no secret that FDA has become a dysfunctional agency due to its strong ties to the pharmaceutical industry. Not only does the pharmaceutical industry employs lobbyists to lobby the FDA, it is also one of the largest contributors of campaign funds (almost all go to the Republican Party).

Doctors and scientists often have unacceptable conflicts of interest

• It is also impossible to find many scientists and doctors in the United States that do not have ties to pharmaceutical firms. Since these folks are so desperate for research grants, they often rely on the drugmakers to fund these research projects.
• When researchers conduct research and if they come up with conclusions that could damage drug sales, the drug companies do not allow publication of the research or discussion of the results by the scientists.
• Until recently, researchers did not disclose conflicts of interests when publishing papers in medical journals.
• Doctors and scientists often get invited to all expenses paid trips, supposedly for education and technical discussions, but are in reality luxurious vacations for them, all paid for by drug companies. It is also common for doctors to be showered with gifts and giveaways from the drugmakers.

Related developments

Louisiana Medicaid restrictions for Celebrex and Bextra

New Zealand bans/restricts Cox-2 drugs

Australia limits/bans Cox-2 drug prescriptions

Merck could have found out Vioxx risks earlier

Merck shareholder lawsuits to be tried in New Jersey

The federal Judicial Panel on Multidistrict Litigation granted motions by several parties, including Merck, to transfer all Vioxx shareholder suits pending in federal courts nationwide into one consolidated Multidistrict Litigation (MDL) for coordinated pre-trial proceedings. It is important to understand that these lawsuits are different than those filed by arthritis patients who claim to have been injured by Vioxx. As previously reported, these Vioxx product liability cases are scheduled to be tried at the Eastern District Court of Louisiana before District Judge Eldon E. Fallon.

According to an estimate by AP, Merck is facing approximately 700 lawsuits from patients who claim that they have been seriously injured after taking Vioxx. In three days of hearings by a FDA panel, the decision was unanimous that Vioxx indeed raised the risk of heart attacks and strokes but the panel still recommended that Vioxx sales be allowed to resume in the United States. (Related article: Making sense of FDA panel recommendations on Vioxx, Celebrex, and Bextra)

Vioxx attorneys claim that total number of plaintiffs could run into tens of thousands, and a previous FDA estimate puts the number of Americans injured by Vioxx at 140,000. No accurate estimates are available for injuries outside the US but drug agencies in the European Union, Australia, Germany, and New Zealand have placed strong restrictions on prescriptions of Cox-2 drugs that are still on the market (Celebrex, Bextra, Arcoxia, Mobic, Dynastat, and their brand name variations).

Merck has announced its intention to market Vioxx again in consultation with the FDA in the United States. It is not known what will happen to Vioxx in other countries and how drug regulators in these countries will respond to FDA's decision to allow sales of Vioxx.

Merck shareholders have also filed lawsuits against the company in the Vioxx case claiming that Merck's handling of Vioxx recall has hurt its stock price. The shareholder cases, now designated as “MDL 1658-In re Merck & Co., Inc., Securities, Derivative & ‘ERISA’ Litigation,” include all federal securities, shareholder derivative and ERISA actions. Those cases are now being transferred to the United States District Court for New Jersey before District Judge Stanley Chesler, who will now set the schedule for pre-trial matters.

Merck is also facing lawsuits in other countries around the world. Analysts do not believe that resumption of Vioxx sales is likely to benefit Merck much. The company is also being investigated by the Department of Justice and Securities and Exchange Commission (SEC).

Related news today:

Louisiana Medicaid program restricts prescriptions of Celebrex and Bextra

Celebrex found to be safe for liver cirrhosis patients

Louisiana Medicaid restricts Celebrex, Bextra prescription

While the Ministry of Health in New Zealand has concluded that the risks of Cox-2 drugs like Vioxx, Celebrex, and Bextra outweigh their benefits, a FDA panel has recommended that despite such a high level of risks, these drugs should stay on the market with black-box warnings. This is a result of highly confusing research available at this time regarding the safety of these drugs and this poses several challenges to healthcare providers. For instance, Kaiser Permanente has banned Bextra till more data is available on its safety.

In a few weeks it will be known what decision the FDA takes but other decision-makers are trying to play it safe due to ongoing Vioxx, Bextra, and Celebrex litigation. In light of recent news reports that the pain-relieving drugs Celebrex and Bextra might increase risk for heart attacks and strokes, the Louisiana (United States) Department of Health and Hospitals is placing safeguards in the Medicaid Pharmacy Program to ensure these drugs are prescribed only with caution. (Related article: Vioxx sales may resume in the US)

Dr. Fred Cerise, secretary of the state Department of Health and Hospitals, will issue a letter to prescribing practitioners and pharmacists within the DHH Medicaid program March 1 informing them of the new policy regarding these drugs. The letter states that because of possible health risks associated with the use of Cox-2 inhibitors, effective March 15, Medicaid will fill these prescriptions only for recipients who demonstrate a medical need for these medications over an alternative pain reliever such as ibuprofen. The Louisiana Medicaid Drug Utilization Review Board, which provides direction on clinical appropriateness of medications to the Medicaid Pharmacy Program, suggested the state adopt this policy in light of recent reports about these possible adverse events. (Related article: European Union drug authority bans, restricts Cox-2 drugs)

“This is an aggressive, responsible approach to patient safety that will ensure better health outcomes for our Medicaid recipients,” Cerise said. “A ‘New England Journal of Medicine’ report showed our Medicaid recipients are prescribed these newer and more costly drugs at a higher rate than 46 other states,” said Medicaid Medical Director Dr. Roxane Townsend, who also provides consultation to the Drug Utilization Review Board. “This is often because of aggressive marketing for these drugs, not because of genuine medical needs for our patients. In many cases, an older and perhaps safer pain reliever would be just as effective and would not pose such a serious risk.” (Related article: Hundreds of millions of dollars spent on direct-to-consumer advertising for Vioxx, Celebrex, and Bextra by Merck and Pfizer)

Under the new prescribing policy, Medicaid patients could not have prescriptions for these drugs filled without the prescribing practitioner documenting medical justification for using Celebrex or Bextra instead of another pain reliever. Since Cox-2 inhibitors are meant to treat pain without causing damage to the stomach lining, patients with a history of stomach problems, or elderly patients at-risk for stomach problems, are the types of patients appropriately prescribed these medications. For those without such a history, a different medication would be prescribed in place of Celebrex or Bextra.

Such action by Louisiana may prompt other similar agencies and HMO's to place restrictions on prescription of Cox-2 drugs, particularly after overwhelming evidence that for vast majority of patients, Cox-2 drugs do not provide any additional benefits than Aleve does but could cause significant damage to the heart.

Recommended article: Merck and Pfizer fought a Coke-Pepsi style marketing battle over Vioxx, Celebrex, and Bextra

Useful links:

Louisiana Department of Health and Hospitals

Medicaid

New Zealand bans, restricts Cox-2 drugs

MedSafe, the Ministry of Health in New Zealand says the increased risk of heart attack and stroke (cardiovascular events) outweighs the benefits of COX-2 inhibitor drugs for the general population. This is in total contrast to the recommendations of the Food & Drug Administration (FDA) panel in the United States which found that despite the higher risks from Cox-2 inhibitor drugs, these should be left on the market. That means that Vioxx which was recalled in September 2004 due to safety concerns is likely to show up on pharmacy shelves in the US, though with a black box warning, and Celebrex and Bextra will also likely to be available, again with black-box warnings.

MedSafe is advising New Zealand nationals, who are at high risk of cardiovascular events, to see their doctor to discuss stopping treatment with COX-2 inhibitors immediately. Others taking the medicines, but not at high risk should discuss cessation of the COX-2 inhibitor at their next scheduled doctor's appointment and consider alternative treatment options. (Related article: Celebrex and Bextra have same risks as Vioxx, argues Merck)

"We don't have enough information yet to quantify the risk associated with each of the five Cox-2 inhibitors currently available in New Zealand," Ministry spokesman Dr Stewart Jessamine said. "But our preliminary conclusions are that all COX-2 inhibitors may increase the risk of developing a heart attack or stroke to some degree in some patients." New Zealand has more choices for arthritis patients than in the US and the Cox-2 drugs available there are Celecoxib (Celebrex), Etoricoxib (Arcoxia), Meloxicam (Mobic), Parecoxib (Dynastat), and Valdecoxib (Bextra). (Related article: Making sense of FDA panel recommendations on Vioxx, Celebrex, and Bextra)

Dr Jessamine said those at high risk were patients with a previous history of heart attack or stroke; a strong family history of heart disease; a history of diabetes, smoking, hypertension, or who are on treatment for high cholesterol. "Unfortunately despite reviewing extensive amounts of data, there is still not enough information to quantify the risk associated with each of these medicines, or to determine which patients are at increased risk or whether aspects of treatment such as dose or duration of use affect the degree of risk," Dr Jessamine said. (Related article: European Union authorities restrict/ban prescription of Cox-2 drugs)

Medsafe is seeking further information from the pharmaceutical industry and the published literature before making a final decision on the safety of these products. The Medicines Adverse Reactions Committee will discuss Medsafe's preliminary conclusions and any further data published or submitted on the safety of the COX-2 inhibitors at its March 2005 meeting. Any FDA or European regulatory agency findings made in the interim will also be considered at this meeting.

Recommended article: Pfizer claims Celebrex and Bextra safe drugs

Celebrex found to be safe for cirrhosis patients

Pfizer, the maker of celecoxib (or Celebrex), received some more good news from scientists on the safety of Celebrex for patients that suffer from cirrhosis of the liver. The study shows that Celebrex can be safely used for short periods of time in such patients. (Related article: Pfizer claims both Celebrex and Bextra are safe)

In the paper titled "Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites," published in Hepatology Journal, the group of scientists Joan Clària, Jeffrey D. Kent, Marta López-Parra, Ginés Escolar, Luís Ruiz-del-Arbol, Pere Ginès, Wladimiro Jiménez, Boris Vucelic, and Vicente Arroyo compared Celebrex against naproxen (or Aleve) and placebo. They found that short-term prescription of Celebrex does not impair kidney function. Aleve, on the other hand, significantly inhibited platelet aggregation. (Related article: Aleve cardiovascular safety affirmed by FDA panel)

Readers may recall that while Celebrex has been found to have adverse side effects on the heart but in the COX-2 inhibitor drugs category, Celebrex was perceived as a relatively safer drug, according to the FDA panel that recently reviewed the available science in three days of hearings. While the panel recommended that Celebrex be allowed to stay on the market with a black box warning, this study is another indication that Cox-2 drugs like Vioxx, Celebrex, and Bextra do have small benefits for patients with very specific problems. (Related article: Making sense of FDA panel recommendations on Vioxx, Celebrex, and Bextra)

The Cox-2 inhibitor drugs block the Cox-2 enzyme in the body and scientists speculate that it is the main reason this class of drugs affects the heart through the changes it produces to substances involved in the initial stages of blood clotting and the body's response to blood clots. But this study shows that this same mechanism apparently helps people with liver problems.

Celebrex is not totally out of the woods yet. MedSafe, the Ministry of Health in New Zealand, has essentially banned all Cox-2 drugs including Celebrex, Bextra, Dynastat, Arcoxia, and Mobic. Similar steps have already been taken in the European Union and Australia.

The study was funded by the Spanish Ministry of Science and Technology (Ministerio de Ciencia y Tecnología), Instituto de Salud Carlos III, and Pfizer/Pharmacia.

Recommended article: Vioxx sales may resume in the US


Useful links:
Hepatology
Ministerio de Ciencia y Tecnología
Instituto de Salud Carlos III
Medsafe

Aleve safety affirmed by FDA panel

When Vioxx was recalled in September 2004, almost all drugs in the Cox-2 inhibitor drugs category came under scrutiny. Then came a series of studies on Celebrex and Bextra that highlighted some of the risks of these drugs, causing even more confusion. As readers may recall, a FDA panel has recently recommended that Vioxx sales may resume with a black-box warning and Pfizer allowed to keep both Celebrex and Bextra on the market, though with black-box warning on Celebrex (Bextra already carries a black-box warning). (Related article: Making sense of FDA panel recommendations on Vioxx, Celebrex, and Bextra)

Another drug that got caught in the confusion is naproxen (marketed as Aleve in the United States). Other common brand name is Naprosyn. In a study by the National Institute of Health and FDA, it was found that Aleve was responsible for an apparent increase in heart problems. While the FDA issued an advisory at that time, it was primarily a precautionary step.

During the discussions held last week, Arthritis and Drug Safety and Risk Management Advisory Committees clarified conflicting reports about the safety of Aleve that have confused and, in some instances, alarmed consumers and healthcare professionals. The discussion at the Meeting of the Advisory Committees affirmed the safety of Aleve and distinguished the safety profile of naproxen, the active ingredient in Aleve, from selective COX-2 inhibitors and other non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), based on the weight of clinical data presented at the meeting. Some members of the panel even suggested that naproxen should be the standard by which future pain relievers should be measured for cardiovascular safety. (Related article: Analysis of FDA panel's recommendations with regards to Vioxx, Celebrex, and Bextra)

The presentations and discussions before the Committees also clarified that the widely publicized suspension of the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) on December 20, 2004 was precipitated not by Aleve safety concerns, but rather by administrative and practical issues.

Recommended article: European drug regulators ban, limit Cox-2 drugs

Making sense of recommendations on Vioxx, Celebrex, Bextra

The hearings of the FDA panel, while coming up with some shocking recommendations, also caused a lot of confusion. On one hand, expert after expert has argued for years that Vioxx, Celebrex, and Bextra are such dangerous drugs that they should have never been approved or recalled much earlier. On the other hand, the panel recommended that all three drugs are safe for marketing, despite their huge risks, provided a black-box warning is added. (Related article: Implications of FDA panel's recommendations on Vioxx, Celebrex, and Bextra)

So what should an arthritis patient make of it? There is plenty of research out there on all three drugs but nothing that provides a definitive answer either way. No wonder the panel members have called for more research, ban on direct-to-consumer advertising, and severe restrictions on prescriptions. (Related article: European authorities ban/restrict Cox-2 drugs)

So how will FDA respond to the recommendations? No one knows. In most cases, FDA simply accepts the advice of advisory panels though it can come up with a different decision in the case of Vioxx where the vote was a close one. If the requirement was a two-thirds or three-fourths vote, Vioxx would not have been allowed back on the market. Since the recall of Vioxx, FDA has come under strong criticism from all quarters, including politicians in Washington that generally do not criticize the FDA or the pharmaceutical companies (that are among the largest contributors to Republican lawmakers). So it would not be a surprise if FDA did reverse the panel's recommendations in the case of Vioxx, but that would pose a lot of problems for the agency considering that Merck has taken a very aggressive approach since the recall of Vioxx in September 2004. (Related article: Merck knew of Vioxx risks earlier)

While investors have generally cheered the recommendations of the panel, the analysts are still very cautious. Readers of this website may recall the Sanford Bernstein analyst, Richard Evans' estimate of Merck's Vioxx liabilities to be as high as $55 billion if Vioxx plaintiffs could prove negligence. Evans is not changing his opinion despite what is generally perceived as positive news for Merck. "Even if Vioxx returns, we don't see a change in product liability," he said in a research report. "Plaintiffs have to show two things: that they were harmed by the product and that the manufacturer failed to warn." And it is pretty obvious that Merck did fail to warn and might have even hidden damaging information about Vioxx from consumers and doctors.

By admitting that Vioxx and other drugs in the Cox-2 class like Celebrex and Bextra have similar side effects, Merck is simply trying to say that it was not the sole culprit in the crime. Indeed it makes Merck's position no better than before the panel's recommendation, but it does make the case of Vioxx victims stronger. And also, makes Pfizer subject to more lawsuits from Celebrex and Bextra patients. (Related article: Merck and Pfizer ignored drug safety; focused on profits)

Recommended article: Celebrex and Bextra to stay on market with stronger warnings

Implication of FDA decision on Vioxx, Celebrex, Bextra

The latest news that Vioxx sales may resume in the United States and that Celebrex and Bextra can stay on the market with black box warning may sound like good news for Merck and Pfizer but it has shocked and confused a lot of people. At first instance, this decision by the FDA panel seems heartless and callous. How could any scientist vote for keeping a drug on the market when according to the FDA, 140,000 Americans have been injured by Vioxx alone? And in another estimate by Public Citizen, 100,000 deaths and 2.1 million serious injuries a year result from adverse reactions due to Celebrex and Bextra.

So let us analyze what has really happened here and how it will impact the those injured and family members of those deceased after taking any of these three drugs. We are also hopefully answering all the emails that we have received from our readers.

What did the FDA panel really say?

• All three drugs in the Cox-2 class, that is, Vioxx, Celebrex and Bextra have serious side effects, particularly on the heart. In other words, the panel said today what Merck or Pfizer never told the patients. A drugmaker should disclose every single piece of information that it knows about the drug. Both Merck and Pfizer failed in their duties to inform doctors and patients, and instead, fought Coke-Pepsi style marketing battles. (Related article: Merck and Pfizer fought Coke-Pepsi style marketing battles)
• Just because the drugs may be sold does not mean that they are as safe as they were made out to be by Merck and Pfizer in their direct-to-consumer advertisements for Vioxx, Celebrex, and Bextra. What the scientific community has said is that these drugs do have benefits as well as risks and as long as patients and doctors understand both they can jointly decide what is best for them. (Related article: European Medicines Agency also leaves Vioxx, Celebrex, and Bextra on the market but with strong warning and restrictions)
• Doctors understand that there is simply no drug without side effects. Doctors like to have more choices so that they can determine what is best for their patients.

How does it impact patients of Vioxx, Celebrex, and Bextra?

• Actually there is plenty of research that came out during the panel hearings that validates what arthritis patients (and family members of those who died due to any of these drugs) have known for a while - that these drugs injured them. If these people would have known what came out in three days of hearings, they would have either not taken these drugs or taken them knowing what the risks are. (Related article: Vioxx doubled heart risks, study finds)
• Merck and Pfizer are still liable for any injuries that their drugs caused. The fact that the panel agreed today that these drugs do increase possibility of heart attacks and strokes makes their case more solid. Having these drugs on the market changes nothing insofar as Vioxx litigation is concerned.
• While Merck will argue that Vioxx alone is not the culprit and try to drag Pfizer into the legal mess, it does not change the fact that Merck made a product that injured Americans and people all over the world.

Recommended article: Merck knew of Vioxx side effects

Vioxx sales may resume in the United States

Vioxx may be back soon in drugstores in the United States. According to the recommendation of the FDA panel, while Vioxx does increase the risk of heart attacks and stroke, it is safe enough to be sold in the United States. (Related article: Celebrex and Bextra have same risks as Vioxx, argued Merck)

Earlier the panel also voted to let Celebrex and Bextra remain on the market with black box warnings.

Vioxx was recalled voluntarily by Merck in September 2004 when it was found that Vioxx doubled the risk of heart attacks. Since then, Merck has been a target of hundreds of class action lawsuits that are scheduled to be tried in Louisiana.

The panel's advice is non-binding on the FDA but in most cases FDA follows the advice. It is expected that FDA will come up with a final decision on resuming sales of Vioxx within a matter of weeks. (Related article: FDA scientist argued that Vioxx should have never even been approved)

According to FDA's estimates as many as 140,000 Americans have been injured by Vioxx. Many consumer rights groups and doctors have demanded that the FDA ban the drug along with other Cox-2 drugs like Celebrex and Bextra. However, doctors would have been left with fewer choices of painkillers if all Cox-2 drugs were banned.

In summary, it means that all Cox-2 drugs will stay on the market in the United States simply because they are all dangerous to varying degrees. (Related article: Europe restricts, bans Cox-2 drugs)

The vote on Vioxx was very close with 17 members voting in favor of bringing it back on the market and 15 opposing the decision.

What does it mean for 140,000 Americans injured by Vioxx?

According to preliminary analysis, the decision has only minimal change on Vioxx litigation if they were actually hurt by the drug. The decision does help Merck to some extent since it will now start to receive revenue from Vioxx once again.

Recommended article: Australia limits or bans prescription of Cox-2 drugs

Celebrex, Bextra to stay with strong warning

The FDA panel that has been reviewing Cox-2 drugs like Vioxx, Celebrex, and Bextra unanimously agreed moments ago that both Celebrex and Bextra do cause heart problems in many patients. In other words, it did not agree with Pfizer's assertions that Celebrex and Bextra are safe drugs. However, the panel found that the drug do have some benefits, and therefore, there is no need to recall either Celebrex or Bextra at this time. (Related article: Pfizer may have not disclosed all Celebrex risks)

The panel has, however, recommended that Celebrex carry the strictest form of warning, highlighted in a black box, on the label. Pfizer's other drug, Bextra, also carries a black box warning. A black-box warning is a way to tell doctors and patients that the drug has risks and should be prescribed when there is no other alternative.

The European Medicines Agency (EMEA) and (Australian) Therapeutic Goods Administration came up with similar recommendations on Celebrex and Bextra.

Celebrex is a blockbuster drug for Pfizer and a lot of patients like it even though many studies have shown that the drug is no better than an over-the-counter painkiller. Many of these patients still pleaded with the FDA to leave the drug on the market. (Related article: Merck wants to sell Vioxx again)

Celebrex belongs to the Cox-2 class of drugs that are also called lifestyle drugs, meaning that they do not cure a disease but provide relief from a suffering. With very aggressive direct-to-consumer advertising, Pfizer convinced millions of Americans to take Celebrex. However, sales drop rapidly after the heart risks were disclosed in a series of studies in December 2004 and during January and February this year. (Related article: Pfizer warned by FDA for misleading Celebrex, Bextra advertisements)

Recommended article: FDA expert blasts Merck, Pfizer, and Cox-2 drugs

Europe restricts, bans Cox-2 drugs

The European Medicines Agency (EMEA), the regulatory body responsible for drug regulation in all European Union countries (a role similar to that of the FDA in the United States), has announced a number of regulatory actions for the COX-2 inhibitor class of medicines following discussions at the 14-17 February 2005 meeting of the Committee for Medicinal Products for Human Use (CHMP). This news comes at the same time that Merck intends to start selling Vioxx again. (Related article: Merck, Pfizer ignored drug safety; focused on profits alone)

The CHMP concluded that the available data show an increased risk of cardiovascular adverse events for COX-2 inhibitors as a class. The data also suggest an association between duration and dose of intake and the probability of suffering a cardiovascular event. These findings are very similar to those of the Therapeutic Goods Administration (TGA) in Australia that has also banned/limited prescription of Cox-2 drugs. This class of drugs includes Vioxx, Celebrex, Bextra, Arcoxia, Prexige, and variations of their brand names all over the globe. (Related article: Celebrex and Bextra have same risks as Vioxx, argues Merck)

The following urgent safety restrictions have been taken for COX-2 inhibitors available in the European Union:

1. A contra-indication (meaning that the drug should not be taken) is introduced for all COX-2 inhibitors in patients with ischaemic heart disease (not enough blood to the heart) or stroke.
2. As a further measure, a contra-indication is introduced for etoricoxib (Arcoxia) in patients with hypertension (high blood pressure) whose blood pressure is not under control.
3. A warning is introduced for prescribers to exercise caution when prescribing COX-2 inhibitors for patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking, as well as for patients with peripheral arterial disease.

Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment
These are interim measures pending the finalization of the class review, expected in April 2005.

The Committee also concluded that more research is needed in the field to evaluate the cardiovascular safety of COX-2 inhibitors, and that ongoing cardiovascular trials should continue as planned. Companies like Merck, Pfizer, and Novartis had provided EMEA with information on their drugs. All drugmakers of Cox-2 inhibitor drugs have argued that their drugs are safe. They have made similar arguments to the ongoing FDA advisory committee meeting in the United States. (Related article: Pfizer claims Celebrex, Bextra safe drugs)

It is important to understand the position of Pfizer which has argued that there is no class effect, or in other words, Celebrex and Bextra are different from Vioxx despite having the same working mechanism. Merck, on the other hand, is arguing that if there is a problem with Vioxx, then it must be extended to other Cox-2 drugs like Celebrx and Bextra. It is very likely that Merck may be putting this argument forward merely for competitive reasons. (Related article: Merck and Pfizer fought Coke-Pepsi style marketing battle over Vioxx, Celebrex, and Bextra)

The review of COX-2 inhibitors by the European Medicines Agency began in October 2004 at the request of the European Commission. Hearings were held with the Marketing Authorisation Holders on 18 January and 15 February 2005. The whole process is not complete yet and these are merely interim decisions. The FDA will conclude its meeting today and then decide its course of action within a few weeks. (Related article: FDA tries to protect Merck and Pfizer)

This decision by EMEA stops short of banning the whole class of Cox-2 drugs. While both Celebrex and Bextra will continue to be sold in Europe, their prescriptions will be highly limited. But EMEA has specifically banned the use of Arcoxia among patients with high blood pressure.

The decision by EMEA is based on the same argument that world-famous FDA scientist Dr. David Graham has made. His research has shown that there is a class effect and there is simply no need for Cox-2 drugs on the market. (Related article: Dr. David Graham blasts Merck, Pfizer, FDA, and Cox-2 drugs)

Recommended article: Vioxx class action lawsuits to go ahead in Louisiana

Merck wants to sell Vioxx again

Merck is planning to bring Vioxx back on the market after voluntarily recalling it in September 2004 after a study showed that Vioxx doubled the risk of heart attacks. This announcement was made by a Merck scientist during the ongoing advisory committee meeting organized by the FDA. According to estimates by the FDA, as many as 140,000 Americans have since been seriously injured by Vioxx and there is enormous amount of evidence about the deadly effects of Vioxx. (Related article: Celebrex and Bextra have same risks as Vioxx, argues Merck)

This announcement has not shocked many Vioxx patients and family members of those killed by Vioxx since Merck has shown no remorse so far for keeping a dangerous drug on the market for so long. Research has also shown that for Merck, profits were more important than human lives. The firm continues to deny that Vioxx was responsible in any way for deaths and injuries. (Related article: Merck and Pfizer ignored drug safety; focused on profits)

Since the recall of Vioxx, hundreds of lawsuits have been filed against the firm and Vioxx attorneys estimate that the final count of plaintiffs will run into tens of thousands in the United States alone. Merck has admitted no guilt and has vowed to vigorously fight each lawsuit. During the four month period since the recall of Vioxx, several studies have shown that not only does Vioxx has serious side effects, especially among the elderly arthritis patients, Merck knew all along how dangerous the drug was. (Related article: Merck could have found out Vioxx risks earlier)

Critics and consumer rights group charge that Merck engaged in a program designed to dodge any safety questions related to the drug. In the hearings on Thursday, Dr. David Graham, the FDA expert argued that not only Vioxx but other Cox-2 drugs are equally dangerous and should not be on the market simply because they provide no benefits to patients. (Related article: Pfizer also claimed that Celebrex and Bextra are safe drugs)

It is early to assess the impact of this announcement by Merck since the FDA could still ban Merck from selling Vioxx. Since the recall of drug, Merck has pretended as if nothing has happened and has not allocated even a penny for its Vioxx liabilities that are expected to be as much as $55 billion. Some analysts predict that Merck will either be acquired or file for bankruptcy. Today's announcement may be just a desperate attempt by Merck to influence panel members. (Related article: Merck vows to defend itself after federal judges consolidate all Vioxx class action lawsuits for trial in Louisiana)

Several patients pleaded with the panel that some Cox-2 drugs should be on the market despite assertion by many scientists that these drugs did nothing more than what an Aspirin does but have far worse side effects.

Recommended article: Merck and Pfizer fought Coke-Pepsi style marketing battle over Vioxx, Celebrex, and Bextra

David Graham blasts Merck, Pfizer, FDA & Cox-2 drugs

Highly respected FDA scientist Dr. David Graham, who is being harassed by his superiors at the agency and was barred from presenting his research was finally allowed to do so after intervention by Senator Grassley, has essentially argued very convincingly that there is no real value in having Cox-2 drugs like Vioxx (since recalled), Celebrex, and Bextra on the market.

Dr. Graham, with Yale Medical School and John Hopkins on his resume, has made himself highly unpopular among pharmaceutical firms like Merck and Pfizer and their cronies inside the FDA by exposing the cozy relationship between the drug companies, the politicians in Washington, and the top brass at the FDA. It is common knowledge that not only did Merck and Pfizer knew that Cox-2 drugs had serious side effects on the heart, even the FDA did nothing to stop the injuries, that are now estimated to be at least 140,000 in the United States alone. (Related article: Merck and Pfizer ignored drug safety; focused on profits)

The only area in which Dr. Graham agrees with Merck is that the problem is not with Vioxx alone. Other drugs like Celebrex, Bextra, Prexige, and Arcoxia have the same problem, as argued by Merck. He did say, however, that Celebrex and Bextra in smaller doses do not pose as much risk as Vioxx does. (Related article: Pfizer still claims that Celebrex, Bextra safe)

A few other findings that Dr. Graham presented:

• Vioxx is so dangerous that it can cause harm immediately, not after a year and half as Merck has claimed. (Related article: Vioxx doubled heart risk, study finds)
• Naproxen (sold as Aleve) is no good alternative to Vioxx, Celebrex, and Bextra.
• Painkiller Mobic, which has become quite popular since the Vioxx recall, also showed an "increased risk" for heart attacks in preliminary data. (Related article: Use of Mobic restricted outside the US)

It is important to remember that both Merck and Pfizer received approvals for their Cox-2 drugs using a fast-track process. That process allows the drug companies to not study long-term side effects of drugs prior to their approval. This puts the patients at risk since they are taking drugs for which enough information is not available. The problem got even worse in the case of Vioxx and Celebrex because these drugs were marketed like consumer products when many doctors knew that they were only just as good as an Aspirin for pain relief though had serious side effects on the heart. (Related article: Merck and Pfizer fought Coke-Pepsi style marketing battle over Vioxx, Celebrex, and Bextra)

Dr. Graham has argued that Vioxx should have never been approved. He criticized the drug approval process that allows drug companies to not conduct long-term trials. He also implied that the FDA was not doing its job of protecting the health of American people.

Other related developments:

Vioxx class action law suits to be tried in Louisiana

FDA tries to protect Merck and Pfizer

Australia limits/bans use of Cox-2 drugs

Celebrex attorneys seeking plaintiffs

Pfizer claims Celebrex, Bextra safe drugs

As reported earlier, the Coke-Pepsi style marketing battle between Merck and Pfizer is not over yet. The two companies showed elements of their bitter relationship at the ongoing meeting at the FDA to evaluate if Celebrex and Bextra should be recalled. Pfizer once again reaffirmed the safety of its drugs Celebrex and Bextra. (Related article: Merck and Pfizer ignored drug safety; focused on profits)

While Merck argued that the adverse side effects of Vioxx should be present in all other drugs in the Cox-2 inhibitor drugs class, Pfizer disagreed, as it has all along. While all Cox-2 drugs work using the same principle, Pfizer has argued since the recall of Vioxx that its drugs Celebrex and Bextra are different at molecular level. Not all experts agree with Pfizer's assertions though. A series of studies released during last two months have shown that even Pfizer and Bextra have serious side effects for arthritis patients, particularly the elderly. (Related article: Latest update on Celebrex, Bextra, Arcoxia, and Prexige)

FDA medical officer James Witter put the skepticism of scientists in a few words, but very eloquently, "The absence of evidence is not evidence of absence. There is still more we need to know (about Celebrex and Bextra)". (Related article: Bextra banned by Kaiser Permanente)

Pfizer presented an analysis of 41 studies comparing Celebrex to older nonsteroidal anti-inflammatory drugs (NSAIDs) including naproxen (Aleve) and ibuprofen. The studies show that the risk of heart attacks with Celebrex is "consistently similar" to that seen with NSAIDs or even no painkiller use. Pfizer's analysis, however, only presented data comparing Celebrex to older drugs and not to a placebo. Placebo comparisons are important to fully understand the risks of a drug. (Related article: Pfizer may have hid Celebrex side effects)

Pfizer has also not provided any additional information on Bextra arguing that the drug is very similar to Celebrex. The company is also submitting only its own research and has not provided any independent research in support of its arguments about the safety of Celebrex and Bextra. (Related article: Pfizer's position on safety of Celebrex)

From Wednesday's hearings it is not apparent what the outcome will be. There are many opinions. Consumer groups and many scientists have called for a recall of Celebrex and Bextra till their risk profiles are better studied. Other doctors are suggesting that the drugs be left on the market but with a stronger warning so that these drugs are used only in very special cases, not like they were used prior to recall of Vioxx when these drugs were basically marketed as consumer products. (Related article: Aggressive direct to consumer advertising by Merck and Pfizer)

Attorneys preparing for Vioxx and Celebrex related lawsuits are also watching the hearings carefully since any thing that the drug companies say in these hearings can be used against them. That has made the discussions somewhat dull since all scientific details are not coming out. Another major problem with the hearings is the missing data from world-renowned expert Dr. David Graham. Since his research contradicts FDA's position and shows that FDA did not do its job, he has been prohibited by the agency from presenting his controversial findings. He continues to be mistreated by his superiors within the agency and despite intervention by Senator Grassley, he is unable to share his findings.

Recommended article: Safety of Celebrex and Bextra questioned by European Medicines Agency

Merck, Pfizer ignored drug safety; focused on profits

Since the recall of Vioxx, several experts have argued that Vioxx and other Cox-2 drugs like Celebrex and Bextra were just glorified Aspirins that became blockbuster drugs merely because of slick direct-to-consumer advertising by Merck and Pfizer. They were more often marketed to people who did not need them and would derive the least benefit, and were priced several times more than what an over-the-counter painkiller like Aleve or Ibuprofen costs. And that's not all. The side effects of all of these drugs were much worse than what Merck and Pfizer disclosed. (Related articles: Pfizer may have hid Celebrex side effects and Merck could have found out Vioxx risks earlier)

It has since been reported that Merck and Pfizer engaged in a Coke-Pepsi style marketing battle flooding the airwaves with direct-to-consumer advertisements. After the recall of Vioxx, Pfizer was warned by the FDA for misleading Celebrex and Bextra ads. As Merck and Pfizer misled both arthritis patients and doctors, Merck was busy training its sales reps to dodge questions from doctors about the safety of Vioxx.

The FDA in the meantime was more busy trying to build a case why Americans should not be allowed to import prescription drugs from Canada so that it could help its friends in the pharmaceutical industry. No wonder drug safety took a back seat, resulting in as many as 140,000 Americans being injured by Vioxx alone.

Published studies of prescription painkillers Vioxx, Celebrex, and Bextra were largely geared to developing new uses for those drugs and were much less concerned with the question of whether they increased users' risk of heart attacks and strokes, according to a review of the medical literature by the Center for Science in the Public Interest (CSPI). (Related article: Arthritis patients misled by Merck advertising)

That patients taking COX-2 inhibitors might be at greater risk of experiencing cardiovascular events became known in the medical community in 2001, when researchers from the Cleveland Clinic published a warning in the Journal of the American Medical Association. Yet even after that report, none of the clinical trials published in the medical literature was designed to gauge that risk. And while CSPI found that many of the studies were funded by the drug companies themselves, even the independently funded trials failed to assess the overall cardiovascular impact of this class of drugs. (Related article: Vioxx doubled risk of heart attacks, study finds)

CSPI could determine the source of funding for 145 out of 237 published clinical trials of those drugs, known as COX-2 inhibitors. And of those 145, 103 were funded directly or indirectly by Merck and Pfizer, the companies behind the drugs, and 41 were funded by government or non-profit institutions.

Nearly 85 percent (87 of 103) of the industry-funded trials that have appeared in the academic literature since 2001 involved testing the pain relief afforded by COX-2 inhibitors for off-label uses, according to CSPI. Just 16 (15.5 percent) of the trials funded by drug companies evaluated any type of health risk associated with the drugs, and only five (4.9 percent) of those had anything to do with cardiovascular risk. Three of those were funded by Pfizer, and sought only to measure narrow questions such as those involving drug-drug interactions among cardiovascular patients. (Related article: History of Vioxx and its recall by Merck)

When research is funded by a company, it can refuse permission of publication of the findings for any reason whatsoever. In one specific case, Merck forced one of its scientists to withdraw her name from a published paper when the results showed a correlation between Vioxx and heart attacks.

"Drug companies are effusive in their self-congratulation over their big research and development budgets, but they tend to spend that money figuring out how to sell more drugs instead of answering these critical safety questions," according to Merrill Goozner, director of the Integrity in Science project at the CSPI. "The idea is to get results published in a wide range of journals so that salespersons can deliver reprints to physicians in those specialties."

Merck, for instance, funded 12 physicians associated with the Altoona Center for Clinical Research to test Vioxx against a traditional non-steroidal anti-inflammatory drug made by one of its rivals for arthritis of the knee. The results, published last year in the Journal of the American Geriatric Society, showed both worked, both were well tolerated and Vioxx offered slightly faster pain relief.

CSPI's review comes as the Food and Drug Administration is holding a three-day hearing to evaluate the magnitude of the cardiovascular risk posed by Vioxx and other COX-2 inhibitors. Its findings quantify problems finally being recognized by leading voices in the medical community. Merck has argued at the hearings that Vioxx alone is not the problem in the Cox-2 drugs class. Even Celebrex and Bextra are equally dangerous.

In the meantime, Merck has a lot of explaining to do in the courts. Hundreds of class action lawsuits have been filed against Merck and these will now be heard in Louisiana.

Recommended article: Celebrex attorneys plan to sue Pfizer

Vioxx class action lawsuits to be tried in Louisiana

A panel of federal judges has issued an order assigning a Louisiana judge to hear all pre-trial matters in federal lawsuits alleging damages caused by the now-withdrawn arthritis drug Vioxx, HarrisMartin Publishing is reporting. (Related article: Celebrex attorneys prepare for class action lawsuits against Pfizer)

In the meantime, in ongoing hearings at the FDA, Merck is arguing that Celebrex and Bextra are as dangerous as Vioxx since they all belong to same Cox-2 inhibitor drugs class.

The product liability cases, now designated as "MDL 1657-In re VIOXX Product Liability Litigation," include all federal cases involving personal injury or economic losses arising from the use and/or purchases of Vioxx. This is not the court that Merck had wanted. The company was seeking a more conservative business-friendly court. This choice by the federal judges is likely to help Vioxx plaintiffs. (Related article: Vioxx attorneys soothe nerves of victims threatened by Merck's aggressive approach)

In a statement released by Merck, the company said that it intends to vigorously defend itself. "Merck acted responsibly every step of the way - from researching the drug prior to approval - to monitoring the drug while it was on the market and - to voluntarily withdrawing the drug when it did. Merck based its decisions on the data from well controlled clinical trials and acted in the best interest of patients," the company said in a written statement. (Related article: Tough Vioxx litigation expected)

Since the recall of Vioxx in September 2004, the company is facing hundreds of lawsuits from tens of thousands of plaintiffs. Merck is also being investigated by the Securities and Exchange commission (SEC), the Department of Justice (DOJ), and Congressional committees. State of New York has also sued Merck. Plaintiffs in other countries are also suing Merck and there is speculation that Merck may be forced into bankruptcy due to an estimated $38-55 billion in Vioxx liabilities.

Pre-trial activity for all Vioxx claims filed in federal courts throughout the country will be overseen by Judge Eldon E. Fallon in the U.S. District Court for the Eastern District of Louisiana.

The Judicial Panel on Multi-District Litigation (JPML) issued the official transfer and consolidation order today from its headquarters in Washington, D.C., a little more than three weeks after a panel of seven federal judges held a hearing on the matter in Ft. Myers, Fla.

Last October, plaintiffs in a Vioxx personal injury case brought in the Eastern District of Louisiana were the first to file a motion to create a Vioxx multi-district litigation docket, or MDL. Merck, which voluntarily withdrew the drug from worldwide markets on Sept. 30, 2004, also filed consolidation motions in numerous cases pending in federal courts. (Related article: Litigators prepare for Vioxx class action lawsuits)

During a hearing held Jan. 27 in Ft. Myers, attorneys representing plaintiffs in several of the more than 600 federal lawsuits that have been filed since the Vioxx withdrawal, argued that the cases should be transferred and consolidated before a single judge in Louisiana, Indiana, Texas, Illinois, New Jersey, California, Pennsylvania or Oklahoma, among other locations. Merck recommended that the panel consolidate the Vioxx claims in the District Court of Maryland, or federal courts in Indiana, Pennsylvania or Illinois. (Related article: Merck's aggressive approach to Vioxx lawsuits)

Merck is also a defendant in many class action lawsuits alleging violations of securities laws. The company said that it is still awaiting a decision from the panel with respect to the shareholder suits, designated as "MDL 1658-In re Merck & Co., Inc., Securities, Derivative & 'ERISA' Litigation."

Recommended article: Vioxx litigation update provided by Merck

Celebrex, Bextra have same risks, argues Merck

In ongoing testimony at the meeting organized by the FDA, Merck is essentially arguing that Pfizer's claims of safety of drugs like Celebrex and Bextra are not valid. (Related article: Pfizer reaffirms Celebrex safety) Pfizer has all along argued that despite both drugs being members of the same Cox-2 inhibitor drugs class, Celebrex and Bextra have different molecular structures; and hence, they are different and safe. Or in other words, both Bextra and Celebrex need not be recalled. (Related article: Australia limits or bans Cox-2 drugs)

Research released yesterday by the New England Journal of Medicine suggested the entire class of Cox-2 medicines may pose some level of risk to patients' hearts. Several other studies released since the recall of Vioxx have highlighted varying degrees of risks with Celebrex and Bextra. Many scientists think that over-the-counter painkillers are fine for most arthritis patients though drugs like Aleve can also cause damage if taken over extended periods of time. The FDA is only reviewing drugs belonging to the Cox-2 category and that also included drugs like Arcoxia and Prexige which are not yet approved in the United States. There is no discussion planned to consider a recall of drugs like Aleve. (Related article: Celebrex attorneys have already started to seek plaintiffs for class action lawsuits against Pfizer)

In the meantime, the New England Journal of Medicine has published three studies that show that the whole class of Cox-2 drugs has serious adverse side effects.

1. Dr. Robert Bresalier of the University of Texas M.D. Anderson Cancer Center found that Vioxx almost doubled the risk of heart attacks, strokes and other major adverse events.
2. Dr. Scott Solomon and fellow scientists at Brigham and Women's Hospital and Harvard Medical School found that Celebrex doubled or even tripled deaths from heart attack, stroke or heart failure, depending on the dose. (Related article: Pfizer's position on safety of Celebrex)
3. Dr. Nancy Nussmeier of the Texas Heart Institute at St. Luke's Episcopal Hospital in Houston and her colleagues studied Bextra in heart surgery patients. They found that 7.4 percent of those given the drugs had an adverse event -- such as heart attacks, kidney failure, ulcers and complications of wound healing -- compared with 4 percent of those given placebo alone.

Dr. Jeffrey M. Drazen writing an editorial in the New England Journal of Medicine, which released the three studies above ahead of time due to their implications on the ongoing hearings, says that a substantial number of deaths could have been prevented if the FDA, Merck and Pfizer had focused on understanding the risks. On the other hand, both Merck and Pfizer fought a Coke-Pepsi style marketing battle. Dr. Drazen reminds his fellow scientists, "As we apply new science to develop new medicines, we must not forget that our first job is to do no harm." Sadly enough, that is exactly what Merck and Pfizer scientists did not do. A lot of evidence has since emerged that dangers of Vioxx were known years ago and both FDA and Merck simply shut their eyes. (Related articles: 140,000 Americans injured by Vioxx alone and FDA tries to protect Merck and Pfizer)

Dr. Bruce Psaty and Dr Curt Furberg argue that Cox-2 drugs were never any better than Aleve or Aspirin. "In clinical trials, NSAIDs, aspirin, and acetaminophen are just as effective in relieving pain as the COX-2 inhibitors." So the question is, Why should Cox-2 drugs be on the market? Isn't it the right time to recall Celebrex? Or recall Bextra? Or even recall both?

Recommended article: Merck could have found out Vioxx risks earlier

Vioxx doubled heart attack risk, new study finds

As FDA discusses if Vioxx type drugs like Celebrex and Bextra should be on the market in the United States, another study has shown how dangerous Vioxx was to arthritis patients. The largest prospective trial ever examining the anti-inflammatory drug Vioxx, manufactured by Merck, as a chemoprevention agent found that the risk of developing a cardiovascular "event" - heart attacks and/or strokes - was almost double in patients who received the drug, compared to patients who took the placebo, according to a study published in The New England Journal of Medicine. (Related articles: Merck could have found out Vioxx risks earlier, Update on Celebrex, Bextra, Prexige, and Arcoxia, and Pfizer continues to affirm Celebrex safety)

The risk was first discovered and reported last September by the study's safety monitoring board and led to the shutdown of the colon cancer chemoprevention trial and subsequent recall of Vioxx from the U.S. market. The study was funded by Merck Research Laboratories. (Related article: Merck knew of Vioxx side effects much earlier than declared)

The trial, known as APPROVe (Adenomatous Polyp Prevention on Vioxx), was the longest test yet of Vioxx as a chemoprevention agent, and was designed to determine whether the drug could prevent the re-growth of precancerous colon polyps in people who had already had polyps removed. The prospective chemoprevention study randomized 2,586 participants from 108 centers in 29 countries to receive either 25 mgs. of Vioxx daily or a placebo drug for three years, 2001-2004. The trial was stopped September 30, 2004 - approximately two months before its planned completion. (Related article: History of Vioxx and its recall by Merck)

According to Robert S. Bresalier, M.D., of The University of Texas M. D. Anderson Cancer Center and lead author of The New England Journal of Medicine study, 46 of the 1287 patients randomized to take Vioxx daily had confirmed cardiovascular events over a three year period - mostly heart attacks or strokes. In the 1,299 patients given a placebo drug, there were 26 events. Each group, however, had the same number of deaths and not all were related to heart attacks or strokes. (Related article: 140,000 Americans injured by Vioxx)

This study examined data on the 2,586 patients enrolled in the trial, all of whom had a history of adenomatous colon polyps. The most notable trend, according to Bresalier, was that patients did not begin to experience cardiovascular problems such as heart attacks or strokes until after 18 months of treatment. "In the first 18 months, the risks for the two treatments were similar," Bresalier says. (Related article: Why Merck did not recall Vioxx earlier?)

Other cardiac problems, such as hypertension-related events, pulmonary edema and congestive heart failure-related events were much more prevalent in the Vioxx-treated group compared to the placebo group and presented earlier. The data on these cases, however, is less firm, Bresalier notes, because, unlike heart attacks or strokes, these problems were not "adjudicated," or validated by a separate committee. This was not a cardiovascular trial, reminds Bresalier, so while investigators reported all events, only the most serious were fully examined. (Related article: Merck and Pfizer fought a marketing battle over Cox-2 drugs)

"Because patient benefit is the most important criteria for any study, it was appropriate to stop the trial," Bresalier says. "We don't know why Vioxx increased this risk, but we now have an opportunity to study whether subpopulations of patients are more susceptible than others."

"I think it's unfortunate that we've perhaps lost a class of drugs which potentially has very important roles in a variety of diseases - arthritis, cancer prevention, cancer treatment, treatment of Alzheimer's disease, treatment of precancerous lesions, not only in the colon but in the esophagus and many other organs," says Bresalier. "What we don't know is, if the cardiovascular results seen in Vioxx represents a class effect of COX-2 inhibitors or if this is an individual effect to this drug. I don't think we can tell this from this one trial or from the trials that are out there at the moment. That's going to be the real question."

Recommended article: FDA reviews Vioxx, Celebrex, and Bextra

Celebrex, Bextra recall hearings begin tomorrow

After failing to recall Adderall, a drug deemed so dangerous that Canadians are advised not to throw the unused drug in the garbage or flush it down the toilet, Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the FDA start their joint meeting to review Cox-2 inhibitor drugs (that includes drugs like Vioxx, Celebrex, Bextra, Prexige, Arcoxia, etc.) on February 16.

Adding to the controversy and lack of faith in the process is the fact that world-renowned FDA scientist Dr. David Graham is not being allowed to present his findings that are likely to embarrass the agency. With the appointment of Dr. Lester Crawford as the chairman, President Bush has simply promised more of the same at the FDA - not so admirable performance by the agency when it comes to improving the life of Americans (for example, in such matters as drug safety or being able to import prescription drugs from Canada). (Related article: FDA tries to protect Merck and Pfizer)

The review of the Cox-2 drugs will start with a couple of interesting developments during last two days as the committees try to determine if FDA should recall Celebrex and Bextra:

1. Chicago Tribune has found out that the FDA knew as early as 2002 that Vioxx was injuring Americans but did nothing. FDA's lack of action motivated Merck to keep the drug on the market resulting in 140,000 injuries by Vioxx.
2. Vioxx and Celebrex increased patients' risk of heart attack and stroke by about 20 percent while Bextra increased the risk by 50 percent, according to a study by WellPoint, the largest provider of health benefits in the United States. Pfizer pretended yesterday as if it know nothing about it. (Related article: Pfizer reaffirms Celebrex safety)
3. A research paper published in the medical journal Annals of Internal Medicine by Tai-Juan Aw, Steven Joseph Haas, Danny Liew, and Henry Krum showed higher blood pressure among patients taking Cox-2 drugs. Vioxx was the worst of all drugs and the effect was more pronounced in the elderly. The doctors are cautioning that prescription of drugs like Arcoxia, Prexige, Celebrex and Bextra be highly restricted due to potential hazards of elevated blood pressure. (Related article: Australia has already limited or banned use of Cox-2 drugs)

In the meantime, Americans are totally confused about what to do. Sales of prescription arthritis drugs continue to decline as Americans seek pain relief from drugs like Aleve and Ibuprofen. Victims of Vioxx, Celebrex, and Bextra have already filed hundreds of class action lawsuits against Merck and Pfizer as both firms refuse to take responsibility.

Recommended articles:

Celebrex attorneys seek plaintiffs

Tens of thousands of Vioxx class action lawsuit plaintiffs

Celebrex recall

FDA tries to protect Merck and Pfizer

The last thing that you would expect from a Republican senator is to go after pharmaceutical companies, particularly at a time when the pharmaceutical industry association is lead by a former Republican Congressman Billy Tauzin. But contrary to what anyone would expect, Senator Charles E. Grassley has indirectly decided to take on both Merck and Pfizer. It is no secret that pharmaceutical companies have contributed millions of dollars to election of Republicans, including President Bush, and have succeeded in get their favorite legislation passed. In addition to that, the president (and the FDA) has done everything possible to help the industry by not allowing import of prescription drugs from Canada and working to change the laws related to class action lawsuits.

Since the recall of Vioxx by Merck in September of last year, the FDA has consistently sided with Merck. Not only did FDA fail to act earlier on concerns about Vioxx and could have thus prevented injuries to 140,000 Americans, it also has since decided to protect Merck. Many experts speculate that there is something more to the story. This speculation has become even more widespread because of the treatment meted out to renowned scientist Dr David Graham, an expert at the FDA, who has been harassed since the day he came out with his revelations against Vioxx and the role of Merck and FDA. He has even argued convincingly enough that Vioxx should have never been approved.

So any reasonable person would expect that when the FDA holds its meeting to decide if other Vioxx type drugs (for example, Celebrex, Bextra, Arcoxia, Prexige, etc.), often referred to as Cox-2 drugs, should be on the market, Dr. David Graham should be allowed to present his arguments. But top officials of the Food and Drug Administration have forbidden Dr. David Graham to discuss before the panel a large study of that very question, according to Dr. Gurkirpal Singh of Stanford University School of Medicine, Dr. Graham's co-author, quoted in the New York Times. Dr. Singh is no stranger to the Vioxx controversy. When he started to look at Vioxx as part of his research, he was actually threatened by Merck officials. (Related article: Merck knew of Vioxx risks)

Senator Grassley, who has held hearings in the past on Vioxx recall and is leading the investigation on behalf of the US Congress, has now written a letter to FDA's acting commissioner, Dr. Lester Crawford, asking him to explain why FDA is not allowing facts to come out. It is also important to point out that Dr. David Graham was about to lose his job until Senator Grassley intervened. Since then Dr. Graham has been treated like a pariah at the agency (as he said in an interview with the Fortune magazine) and has been granted a whistleblower status. His crime: Fighting for American people. (Related article: Why Merck did not recall Vioxx earlier?)

It is very likely that the FDA will come up with some complicated explanation why Dr. Graham's research is not good enough for presenting. That is exactly what happened when Dr. Graham came up with the estimate on injuries caused by Vioxx. It was only after the intervention by Congress and persistence of Dr. Graham that the study was finally published. (Related article: Vioxx recall controversy shows that reform needed at the FDA)

For those who are watching how Merck and Pfizer deliberately hid damaging information about Vioxx, Celebrex, and Bextra, the behavior of FDA officials is no surprise. Not only does the pharmaceutical industry employ approximately 600 lobbyists in Washington, it actually has dedicated teams and budget to lobby FDA officials exclusively. In fact, there are reports that FDA tried to influence Health Canada's decision to recall Adderall.

Recommended article: Update on Celebrex, Bextra, Arcoxia and Prexige

Merck and Pfizer fought a marketing battle over Cox-2 drugs

As has been reported previously on this website, (Previous article: Merck could have found out Vioxx risks earlier) Merck was less interested in improving the life of arthritis patients and more interested in improving its bottomline. While the second goal is a noble one (after all it is a business), but that goal should not come at the expense of killing and injuring people (FDA estimates that as many as 140,000 Americans have been injured by Vioxx).

Several studies have shown that Merck:

1. Did not conduct study that could have shown the side effects of work
2. Attacked any critic of Vioxx
3. Did not publish any research that showed that Vioxx was linked to heart diseases
4. Hired consultants whose only job was to defend Vioxx at medical conferences and in medical journals
5. Aggressively marketed Vioxx to patients who were least likely to benefit from it
6. Trained its sales staff to dodge all questions related to Vioxx safety and its side effects. (Related article: Why Merck did not recall Vioxx earlier?)

The New York Times is now reporting that Merck was actually fighting a Coke-Pepsi style marketing battle with Pfizer (the maker of Celebrex and Bextra, both of which are being investigated by drug agencies worldwide and will either be recalled or end up with black box warnings, as Australian drug agency has done). (Related article: Australia bans/limits Cox-2 drugs)

While Merck and other pharmaceutical companies continue to market prescription drugs aggressively directly to consumers, experts blame many deaths and injuries on such advertisements that only show the benefits, without fully highlighting the risks and side effects. In the NYT article, Merck is quoted as having said that when doctors had "misinformation" or a "lack of information" about Vioxx, the company tried to "neutralize" them.

It is important to point out that American doctors are not totally innocent either. Doctors often attend all-expenses-paid retreats sponsored by drug companies that are supposedly education seminars. Very unlikely that they will hear anything else other than the marketing pitch of a drug company. Drug companies often sponsor research and many researchers in the past have not disclosed their conflicts on interests. It is also very common for a drug company to deny permission to publish the findings if they are contrary to what the company has been saying in its advertisements or in documents submitted to the FDA. (Related article: Vioxx death responsibility lies with doctors too)

Since the recall of Vioxx in September 2004 and filing of hundreds of Vioxx class action lawsuits, many attorneys and media representatives have been able to access internal Merck documents that clearly show that Merck was simply selling a totally ineffective product that had serious side effects to patients who did not need the drug. And in doing so it was violating all ethics of medical science and normal business, so that it could make its bottom line look great. (Related article: Vioxx patients misled by Merck advertising)

Merck was so effective in misleading everyone that it even convinced smart doctors that Vioxx was a terrific drug. Dr. Robert Plasko of Palm Beach Gardens, Florida, received Vioxx from Merck pharmaceutical sales representative Angie Henderson for approximately nine months in 2003. As a result of Dr. Plasko's taking Vioxx and his subsequent heart damage, Dr. Plasko is now disabled, and was forced to give up his medical practice of sixteen years as an endocrinologist. Dr. Plasko states in his suit that as a consumer and a physician, he was misled by Merck and its sales staff, and that he hopes this litigation will serve as a means to prevent such corrupt activity from happening again in the future. (Related article: All Cox-2 drugs advertised heavily by Merck and Pfizer)

In a related development, readers may recall the case of Dr. Curt Furberg, a professor at Wake Forest University, whose participation in the federal drug safety committee that is set to meet next week was in doubt because he criticized Cox-2 drugs. The FDA has consistently sided with Merck in the Vioxx recall mess. Now it is being reported that after all Professor Furberg will be participating in these deliberations where the most important decision taken will be related to likely recall of Celebrex and Bextra.

Merck's competitor Pfizer in the Coke-Pepsi style marketing war is also seriously hurt from the controversy. While it initially grabbed most of the market share from Vioxx after its recall, but after damaging information about Celebrex and Bextra came out, its sales have been hurt. There here is widespread speculation that tens of thousands of Vioxx class action lawsuit plaintiffs will drive Merck into bankruptcy, it is unclear what will happen to Pfizer. If Celebrex and/or Bextra is recalled, Pfizer could be in serious trouble. The Wall Street Journal is reporting that even before the fate of Celebrex and Bextra is decided, Pfizer plans to cut about $2 billion from its costs and to overhaul the way it markets drugs to doctors. It may be recalled that Pfizer has been warned by the FDA for misleading ads related to Celebrex and Bextra.

Recommended article: Celebrex attorneys are now seeking plaintiffs

Australia limits or bans use of Cox-2 drugs

The Australian Government has put serious restrictions on Vioxx type drugs (often called with their more technical name, Cox-2 drugs, and includes drugs like Celebrex, Bextra, Arcoxia, Prexige, and dozens of other brand names that vary by country). The Therapeutic Goods Administration (TGA) is the Australian agency equivalent to the Food and Drug Administration (FDA) in the US. It is important to note that the countries in the European Union have only one agency, that is, the European Medicines Agency. Other than these two, almost all other countries have their own independent agencies though they actively coordinate their drug regulation work with agencies like the FDA and EMEA.

TGA has now introduced new measures on the prescribing of Cox-2 inhibitors following the findings of a review into the safety of this family of medicines. After the worldwide recall of Vioxx by Merck in September 2004, drug agencies have been reviewing the whole family. The FDA and EMEA are scheduled to meet next week. (Related article: Status report on Celebrex, Bextra, Arcoxia, and Prexige prior to review)

The TGA will immediately require manufacturers of Cox-2 inhibitors to place new highlighted explicit warnings in product information about the increased risk of cardiovascular adverse events from this group of drugs. The new warning statements are to be highlighted with a black boxed margin. The TGA is also advising people who are taking more than 200mg a day of celecoxib (Celebrex) or more than 15 mg a day of meloxicam (Mobic; Movalis) to review their treatment regime with their doctors. (Related article: FDA puts strong black box warning on Bextra label)

The TGA believes that most Australians using these drugs will be taking low doses that already meet this dosage advice, but some patients, particularly with rheumatoid arthritis or a rare bowel condition, may be taking 400 mg or 800 mg of celecoxib (Celebrex) a day and some patients with arthritis may be taking more than 15 mg of meloxicam a day. (Related article: Pfizer continues to assert safety of Celebrex)

This recommended dose reduction may result in some patients with arthritis having increased symptoms but the review of Cox-2 inhibitors clearly indicated there is an increased risk of heart attacks and strokes with high doses of these drugs.

The TGA determined that the exact size of the risk and the exact duration of therapy associated with increased risk are still unknown, and so have recommended that Cox-2 inhibitors should be prescribed only when other treatments cannot be tolerated or have caused serious adverse effects. While Vioxx showed a very clear cut risk, that has not been the case with other Cox-2 drugs like Celebrex and Bextra. The regulators from EMEA and FDA will have the same challenge next week. There is conflicting information on these drugs and while many doctors and consumer rights groups are demanding that all of these drugs be recalled, Wall Street analysts are betting that FDA and EMEA are likely to do what TGA has done rather than impose an outright ban. (Related article: Largest US HMO bans Bextra)

Concerning meloxicam, there are theoretical grounds for regarding the drug as having reduced cardiovascular risks. The drug has less selective Cox-2 inhibition than celecoxib or rofecoxib (Vioxx). Clinical study data are more meager, with most studies limited to no more than six months duration. The Committee notes that a Prescription Event Monitoring study in the UK and an observational study in Quebec, Canada, provided reassurance that the cardiovascular risk at up to 15 mg is acceptable. (Related article: Merck could have found out Vioxx risks earlier)

The TGA is also taking a few more steps in the interest of public health in Australia:

1. It is proposed to cancel the registration of the drug parecoxib (Dynastat), an injectable version of Bextra, because of the risk of cardiovascular events. Dynastat is marketed in Australia and is approved as a single dose at the time of surgery to reduce post-operative pain;
2. It is proposed to withdraw the indication of management of arthritis of the drug valdecoxib (Valdyne, Dynoral - known in some countries as Bextra) which is converted to parecoxib in the body. Valdecoxib has not been marketed in Australia. Valdecoxib has been associated with an increased risk of cardiovascular events in cardiac by-pass graft patients. The use of Valdecoxib for 5 days as an analgesic in patients without increased cardiovascular risk will remain; it is proposed to greatly limit the approved uses of two other Cox-2 inhibitors which have not yet been marketed in Australia. They are etoricoxib or Arcoxia and lumiracoxib or Prexige. In both instances, ADEC was not sufficiently assured of the safety of these drugs for anything other than short term use in patients without increased cardiovascular risk.
3. Concerning parecoxib and valdecoxib, TGA was not assured from other available data that the safety of parecoxib in other surgical patients or the safety of valdecoxib other than when used for short periods in patients without cardiovascular risk, had been studied adequately.

Recommended article: Pfizer highlights recall risks of Celebrex and Bextra

Source: TGA

Celebrex attorneys seeking plaintiffs

It is pretty obvious now that both Merck and Pfizer did all that they could possibly do to not let damaging information about Cox-2 drugs like Vioxx, Celebrex, and Bextra come out. In a series of reports published and reluctant admission by Merck, it is becoming clear that Merck either did not publish some data or purposely abandoned studies that had the potential to disclose adverse side effects of Vioxx.

Similarly, reports indicated that a 1999 clinical trial showed clear cardiovascular risks in elderly patients taking Celebrex. As late as October of 2004, however, in response to the Vioxx recall, Pfizer said that no studies had ever shown increased Celebrex-related cardiovascular risks. Now Pfizer has acknowledged that, in a 1999 study where Celebrex was tested as a treatment for Alzheimer's disease, patients taking Celebrex quadrupled their risk for a heart attack versus those taking a placebo. This study was not published until June of 2001, four months after the FDA conducted a safety review of Vioxx and Celebrex. (Related article: Pfizer reaffirms Celebrex safety)

Naturally, such disclosures help the cause of victims of Vioxx, Celebrex, and to a limited extent, Bextra, who have been demanding compensation for their suffering. While the trials are not going to be easy and Merck has vowed to aggressively defend itself in the Vioxx class action lawsuits, Vioxx and Celebrex lawyers are going ahead with recruiting plaintiffs and preparing for the lawsuits. (Related article: Tens of thousands of Vioxx class action lawsuits plaintiffs expected)

Manhattan personal injury firm Weitz & Luxenberg has launched an aggressive marketing campaign seeking patients injured by the arthritis and pain medication Celebrex. This highly respected law firm is joining a group of dozens of other law firms that have been advertising online as well as on television and in the print media to motivate the victims to come forward.
Personal injury law firms such as Weitz & Luxenberg are concentrating on the most serious Celebrex-related injuries; heart attacks, strokes, and death, paying particular attention to the dosage and frequency with which the drug was taken when evaluating potential lawsuits. These cases are relatively easy to win because it is much easier to prove how harm was done. It does not mean that someone who had only minor injuries can not join a lawsuit but they have a weaker case in phase one of the trials. (Related article: How to find the right attorney for drug recall and personal injury cases?)

In the firm's most recent television advertisement, a Celebrex tablet falls into a glass of water, which immediately turns murky. An announcer says, "Don't let Pfizer muddy the legal waters around Celebrex. Suppressed clinical trials prove it's dangerous medicine." In subsequent frames, tablets with the firm's name drop into the glass, and the water begins to clear. The announcer goes on to say, "Weitz & Luxenberg has already accepted cases and begun a landmark investigation." As the water becomes completely clear, the announcer concludes, "Be clear about your rights as a Celebrex user." (Related article: Tips on case review by an attorney)

In the meantime, Pfizer is already feeling the impact of revenue loss from Celebrex and Bextra. Since the recall of Vioxx, Pfizer has continued to stand by the safety of both Celebrex and Bextra though research has shown that they both have cardiovascular risks. The FDA has warned Pfizer for running misleading ads for Celebrex and Bextra and Kaiser Permanente has banned Bextra (after the FDA asked Pfizer to put a stronger warning on the label). Consumer rights group like Public Citizen have demanded that both Celebrex and Bextra should be recalled. The FDA and European Medicines Agency are meeting next week to decide the fate of all Cox-2 drugs including Arcoxia and Prexige.

In a related development, the New York Times is reporting that Pfizer is set to announce a major layoff at a meeting with analysts and investors in New York on April 5. Merck has already laid off over 5,000 employees after it recalled Vioxx in September, 2004. A spokesman for Pfizer, Andy McCormick, is quoted as telling the New York Times that the company was examining ways to cut costs but would not discuss specific plans until its meeting in April. "We have initiated a comprehensive review of our entire business, pharmaceuticals, consumer and animal health," he said, "looking for better efficiencies and streamlined decision making."

Recommended article: Celebrex, Bextra class action lawsuits explode

Merck could have found out Vioxx risks earlier

The New York Times (NYT) is reporting that Merck does not tell the truth when it is not convenient for it in the Vioxx recall case. The paper is reporting that "...(Merck) was poised to begin a major cardiovascular study of the drug in 2002, and abruptly dropped the project just before it was set to start. The trial was scheduled to produce data by March 2004 but may have provided answers about Vioxx's risks even earlier if patients had shown ill effects." (Related article: Merck knew of Vioxx side effects, according to WSJ)

Merck recalled Vioxx on September 30, 2004 when it was found that it increased the risk of heart attacks. As many as 140,000 Americans alone are estimated to be injured by Vioxx. Merck consistently acted to make sure that bad news about Vioxx was never researched or if anything bad came up, it never got published. The company threatened Dr. Gurkipal Singh, an adjunct professor of medicine at Stanford University, when he started to investigate side effects of Vioxx. It also forced a Merck scientist to withdraw her name from a published paper linking Vioxx to heart attacks according to Drs. Daniel Solomon and Jerry Avorn of Boston's Brigham and Women's Hospital who were collaborating with Merck on the study. (Related article: Will Vioxx recall bankrupt Merck?)

According to the documents reviewed by The Times, Merck had done a lot of work in preparation to start the study but abandoned it. It is not clear why Merck did so. NYT quotes from an internal Merck memo that announced the stop of the study, "...upper management is in the process of reviewing the various study options."

What makes this analysis by The Times intriguing is that work on the Valor trial was abandoned at a time when both the FDA and Merck were trying to figure out if Vioxx label needed to be changed to reflect higher cardiovascular risk, as concluded from the so-called VIGOR study.

Since Vioxx litigation started, newspapers and Vioxx lawyers have been able to get access to thousands of internal Merck documents. At the same time, due to the pending investigations and legal proceedings, the company is very guarded in its response and can conveniently refuse to answer questions from reporters citing legal proceedings. But it is obvious that as the Vioxx class action lawsuits proceed forward, Merck executives will have no choice but to tell the truth. Even Merck CEO Raymond Gilmartin will be deposed in the court and tell the inside story of how Merck continued to market Vioxx to millions of people worldwide when many in the company clearly knew that something was not right.

In a related story, Pfizer, the maker of Celebrex, is doing something similar. For instance, it has decided to exclude data from independent agencies in arguing that Celebrex is a safe drug. (Related article: Pfizer reaffirms Celebrex safety) Similarly, it is not submitting any data on Bextra, which has been banned by Kaiser Permanente due to safety concerns, arguing that there is no need since it is similar to Celebrex.

Recommended article: Tens of thousands of Vioxx class action lawsuit plaintiffs

Merck knew of Vioxx side effects

Recently obtained records from Vioxx manufacturer Merck clearly indicate that a committee monitoring the safety of the drug in a clinical trial had early data pointing to higher risk of heart attacks after a mere 4 months, according to an investigation by The Wall Street Journal, a business publication. (Related article: Why Merck did not recall Vioxx earlier?)

Merck has consistently denied that it ever knew that Vioxx was a dangerous drug and was injuring arthritis patients. The company continues to maintain its innocence and has repeatedly claimed that it came to know of problems only during the last week of September 2004 and acted quickly to recall Vioxx on September 30, 2004. Many articles and reports since then have pointed out that Merck may not be telling the whole story. WSJ found last year that the company was actively training it sales staff to dodge questions from doctors about the safety of Vioxx. The company forced one of its scientists to withdraw her name from a study that showed a link between Vioxx and heart diseases. It also tried to attack anyone who would question the safety of Vioxx through aggressive direct-to-consumer advertising and hired consultants who defended the drug at medical conferences and in scientific journals. (Related article: Merck shows no sympathy for Vioxx victims)

It may be recalled that Merck with the active collaboration of the FDA used the fast track process to get Vioxx approved and now FDA scientist Dr David Graham says that Vioxx should have never been approved. Dr Eric Topol, highly respected cardiologist and an early critic of Vioxx and other Cox-2 drugs, has also argued that these drugs are simply not worth the risk that they pose to patients. Both Merck and its competitor Pfizer (the maker of Celebrex and Bextra) deny that Cox-2 drugs are a problem. (Related article: Update on other Cox-2 drugs like Arcoxia and Prexige)

The new documents will definitely strengthen the case of Vioxx patients who have been attacked by Merck as if they (and not Merck) are the problem. No wonder, Vioxx victims have had no choice but to join forces in class action lawsuits against Merck. Analysts expect that Vioxx class action lawsuits plaintiffs may run into tens of thousands since an estimated 140,000 Americans alone have been injured by Vioxx.

In Vioxx litigation developments so far, Merck has been arguing that Vioxx did not hurt even a single patient and those that are making any such claims already have an existing medical condition. Emergence of such evidence shows that Merck may have a lot of explaining to do in the courts.

Recommended article: Vioxx litigation update

Update on Celebrex, Arcoxia, Prexige, & Bextra

Next week is going to be critical for the manufactures of arthritis drugs belonging to the category of Cox-2 drugs. A series of meetings have been organized by the US Food & Drug Administration (FDA) and European Medicines Agency (EMEA). The following are the major companies that will be presenting why their drugs should be on the market:

• Merck makes Vioxx (since recalled) and Arcoxia
• Pfizer (Celebrex and Bextra)
• Novartis (Prexige)

Below is an update on each drug based on the documents released by the manufacturers prior to the meeting:

Celebrex

Celebrex has gotten into a lot of trouble since the recall of Vioxx. As data disclosing more risks of taking Celebrex came out and Pfizer was warned by FDA of running misleading ads, consumer groups have been demanding that Celebrex be recalled. In data presented to FDA, Pfizer has chosen to ignore all research conducted by independent researchers. Instead it has submitted only Pfizer data from 41 of its own patient trials involving more than 40,000 patients that shows no evidence that Celebrex increased heart problems. While there is widespread speculation that Celebrex will be recalled, Wall Street analysts are betting that it will instead get a stronger warning. (Related article: Celebrex safety update)

Bextra

Bextra already carries a strong warning after its serious side effects were discovered. Kaiser Permanente has already banned the drug. Experts expect that if any COX-2 drug will be banned, it is more likely to be Bextra. Pfizer is not submitting any additional information, arguing that it is similar to Celebrex. (Related article: Bextra safety update)

Arcoxia

Since the recall of Vioxx, Merck wants to have another drug to capture the market share that it has lost (Related article: Vioxx recall may bankrupt Merck). The company's financials have been hurt and there is even speculation that the company may file for bankruptcy due to mounting class action lawsuits in injuries to 140,000 Americans.

But there is bad news for Merck. “The results appear to demonstrate that (Arcoxia) is worse than each comparator” with regard to deaths and serious cardiovascular problems, FDA staff reviewers comment in an analysis posted on the agency Web site. The drug is not sold in the US but is sold in 51 countries in Europe, Latin America and Asia. FDA is unlikely to approve this drug now.

Prexige

Prexige showed that it was safer on the gastrointestinal tract than other painkillers. But the risks of heart attacks, strokes and deaths were “similar” to what was seen with Vioxx, the FDA reviewers wrote in their analysis.

Recommended article: Vioxx side effects reconfirmed

Will Vioxx recall bankrupt Merck?

"Absolutely not," Merck CEO Raymond Gilmartin said, when asked by CBS Marketwatch (a financial news website) if Merck faces bankruptcy. "Anyone who looks at the strength of our balance sheet and our cash flow will see that."

Several analysts have been speculating that Merck may have to declare bankruptcy for the following reasons:

1. Merck's Vioxx liabilities are expected to be very high. While no accurate estimates are available since it all depends on how many class action lawsuits are filed and what awards the plaintiffs get from juries, but current estimates range all the way from $18 billion to $55 billion.
2. Merck has made no provisions whatsoever for its Vioxx liabilities. Since the settlements will be spread out over years and Merck has the resources to delay the settlement (and drag Vioxx litigation for a long time), the company is betting that it need not scare investors right now by talking about its liabilities. It may be noted that Merck shareholders are not that naive and many of them have already filed class action lawsuits alleging that Merck did not disclose vital information related to side effects of Vioxx.
3. The number of Vioxx class action lawsuit plaintiffs is now being estimated to be in tens of thousands, according to some Vioxx lawyers. According to an analysis by the Associated Press, as many as 700 lawsuits worldwide have been filed against Merck, though Merck disclosed only 575 as of December 31, 2004.
4. Vioxx attorneys are actively interviewing patients who may be eligible to join class action lawsuits.
5. Merck is also being investigated for violations of laws by the US Department of Justice (DOJ), Securities & Exchange Commission (SEC), and the United States Congress. All of these investigations could mean a lot of legal trouble for the firm. (Related article: SEC is investigating Merck in Vioxx recall case)

Analysts have also been speculating that Merck may be acquired by another firm since it does have some good drugs in its portfolio and is working on a few other good drugs. Plus, it also has an excellent pool of scientists despite a massive layoff recently. Gilmartin, however, denied in his interview that any merger was in the works. This is fairly typical and it does not mean that Merck will not be acquired. (Related article: Vioxx recall hurts Merck financially)

If Merck does get acquired, very likely the new company will simply settle the lawsuits and move on. Merck has refused to express any regret so far for being responsible for as many as 140,000 injuries in America alone. On the other hand, Merck has mounted an aggressive campaign against Vioxx victims. (Related article: Merck shows no sympathy for Vioxx victims)

MassHighTech, a technology journal, is reporting that Gilmartin did not even use once the word "Vioxx" while he spoke at Northeastern University's CEO Breakfast Forum this morning, held in Boston.

According to an analysis of Merck's balance sheet, it is fairly clear that the company has deep pockets and may be able to meet its Vioxx liabilities. Plus, it is also very likely that President Bush may be able to change the US laws making it harder for Americans to sue Merck. The President again mentioned it in his State of the Union address and Business Roundtable (an association of chief executive officers of leading U.S. corporations) President John J. Castellani welcomed his comments, "We are focused, as is the President, in reducing costs to business and consumers by curbing lawsuit abuse. This abuse costs our economy $246 billion per year, and has increased a hundredfold over the past 50 years. The real tragedy is that those harmed get less than 50 cents on the dollar in today's court system." (Related article: Merck vows to fight Vioxx class action lawsuits vigorously)

In a related development, Pfizer Chief Executive Henry McKinnell told Dow Jones Newswires on Wednesday that the company has no plans to recall Celebrex from the market.

Recommended article: Vioxx litigation update

Pfizer reaffirms Celebrex safety

Pfizer on Monday disputed an allegation by Public Citizen that the company hid and downplayed the results of a test of the arthritis drug Celebrex that clearly showed a higher risk of heart attacks. (Related article: Consumer group asks FDA to ban Celebrex) Pfizer said that "definitive conclusions about cardiovascular risk cannot be drawn from this study." Like arguments presented by Merck in the past that Vioxx did not injure arthritis patients (on the other hand, they already had a medical condition that made them sick), Pfizer is saying something similar that participants in the study who took Celebrex were already quite sick and that is why the higher heart attack risks seen in those patients who took Celebrex. (Related article: Pfizer's position on safety of Celebrex)

In this study, Pfizer admitted that Celebrex patients experienced "more cardiovascular events than patients taking a placebo. However, Celebrex patients "were up to four times more likely to have key cardiovascular risk factors" vs. the placebo patients, thus impairing the findings.
However, disclosure of this study contradicts a series of statements by Pfizer in form of press releases and interviews by its CEO Hank McKinnell. (Related article: FDA warns Pfizer about misleading Celebrex ads)

Dr. Gail Cawkwell, Pfizer's medical team leader for Celebrex was essentially evasive and pleaded ignorance on many disturbing questions about the study. For instance, she said she did not know whether the study's safety data had been presented at a conference in Sweden in 2000 and that she also did not know why Pharmacia (the company that discovered Celebrex and Bextra and was acquired by Pfizer in 2002) did not send the results to the F.D.A. in time for the broader review. (Related article: Pfizer refuses to recall Celebrex)

There is no consensus yet among scientists that the study cited by Public Citizen conclusively shows that Celebrex should be immediately banned. Linda E. Lévesque; James M. Brophy; and Bin Zhang (of McGill University) writing in the Annals of Medicine find that risks for heart attacks were very high with Vioxx but did not find the same level of risks with Celebrex. But they are aware of other studies that do show risks with Celebrex. "Until evidence to the contrary is available, new agents with COX-2 inhibitory potency similar to or greater than that of rofecoxib (Vioxx) should be used only with extreme caution, even in populations at relatively low risk for cardiovascular events," the scientists recommend. (Related article: FDA limits Celebrex and Bextra use after Vioxx recall)

The New York Times quotes Dr. Kenneth Brandt, a professor of medicine at Indiana University School of Medicine, and one of the members of the panel that reviewed Celebrex in 2001, as saying that if the safety panel had known about the study, it might have recommended that both Vioxx and Celebrex be taken with greater caution.

Dr Eric Topol, world-famous cardiologist and considered to be an authority on the side effects of Cox-2 inhibitor drugs, is not convinced that Celebrex is as dangerous as Vioxx based on the study disclosed by Public Citizen, though he has always advised caution in prescribing it till more information is available. He is quoted in Forbes as saying, "I'm not trying to discount the importance of the study. It should have been published." Garret FitzGerald, a pharmacologist at the University of Pennsylvania, however, says in the same Forbes article that although the results are "far from conclusive," they do point toward increased risk for Celebrex.

Apart from personal injury attorneys who have been filing lawsuits against Pfizer citing problems with Celebrex and Bextra, the investors are equally concerned. "That we now have two different data sets showing a CV [cardiovascular] signal is increasingly worrisome, yet we don't think withdrawal of the product is in the offing -- a more realistic outcome, in our opinion, would be revisions made to product labeling that could then impact future commercial performance," the Prudential analysts wrote in a report analyzing the impact of Celebrex recall on Pfizer.

Celebrex and Bextra were not the only Pfizer drugs in news yesterday. The trial of Christopher Pittman began with claims from the defense that he was led to kill his grandparents by the antidepressant drug Zoloft. Pittman, who had threatened suicide, was put on Zoloft three weeks before the slayings, and his dose was doubled just two days earlier. In October of 2004, the Food and Drug Administration ordered Zoloft and other antidepressants to carry "black box" warnings - the government's strongest warning short of a ban - about increasing the risk of suicidal behavior in children. Pfizer has vigorously fought cases claiming antidepressants cause violent or suicidal behavior. Eli Lilly, the maker of Prozac, has also vigorously argued that the drug leads to suicidal behavior.

Recommended article: Role of Celebrex advertising

Vioxx side effects reconfirmed

Another study published in the Annals of Medicine this month by Linda E. Lévesque, BScPhm, MSc; James M. Brophy, MD, PhD; and Bin Zhang, MSc will further add to the confusion whether Celebrex is indeed a safe drug. (Related article: Celebrex safety update from Pfizer)

In the study entitled "The Risk for Myocardial Infarction with Cyclooxygenase-2 Inhibitors: A Population Study of Elderly Adults", these scientists at the McGill University in Canada assessed the influence of various NSAIDs on the risk for a first myocardial infarction (MI). The study reconfirmed the serious adverse side effects of Vioxx, which was recalled by Merck in September of last year, but clearly leave open the question of safety of Celebrex. (Related article: History of Vioxx and its recall by Merck)

Their study provides evidence of an increased risk for myocardial infarction, nonfatal and fatal, with current use of rofecoxib (Vioxx), even in individuals with no history of myocardial infarction. The concomitant use of aspirin in persons using low-dose rofecoxib (Vioxx) appears to mitigate this risk. Although the observational nature of their study limits the ability to assign causality, the totality of the current evidence confirms the increased cardiovascular risk associated with rofecoxib (Vioxx) and the sagacity of its withdrawal. (Related article: FDA should have never approved Vioxx)

The scientists are, however, cautioning against drawing any conclusions about Cox-2 inhibitors drugs in general, and more specifically, Celebrex. They write, "Of equal importance, we provide evidence against a broad class effect for COX-2-mediated cardiotoxicity when used at usual doses." That does not mean that other Cox-2 drugs are safe and there is no reason to worry. They recommend more careful prescription of these drugs, "Nevertheless, given the widespread use of these agents and the increased risk seen in a recent cancer trial of high-dose celecoxib (Celebrex), further research should be undertaken. Until evidence to the contrary is available, new agents with COX-2 inhibitory potency similar to or greater than that of rofecoxib (Vioxx) should be used only with extreme caution, even in populations at relatively low risk for cardiovascular events." (Related article: Celebrex increases risks of heart attacks)

While the researchers admit that considerable uncertainty remains regarding the clinical profile of persons at risk for COX-2-mediated cardiovascular events and whether celecoxib (Celebrex), as well as other COX-2 selective agents, poses a similar risk. No increased risks were observed with celecoxib or the other NSAIDs, they find. This is exactly what Pfizer has been saying all along though there are other studies that prove otherwise. (Related articles: Pfizer stands by the safety of Celbrex and Consumer Group charges that Pfizer hid safety data on Celebrex)

So what does it mean? Simply that there is no definitive proof either way about Celebrex. The FDA experts will meet in less than two weeks to discuss what to do next with Cox-2 drugs like Celebrex and Bextra. The European Medicines Agency is already reviewing these drugs and will closely watch what the FDA decides in the United States.

Recommended article: Celebrex class action lawsuits explode