Acute: A term used to describe conditions that are short-lived and usually sudden or unexpected. This term is used in contrast to chronic, which refers to conditions that worsen over time.

Anaphylaxis: A severe allergic reaction that can cause hives and swelling of the throat, neck, and other exposed areas. In severe cases, anaphylaxis can cause the body to go into anaphylactic shock, which involves a sudden drop in blood pressure and a swelling of the airways. It can be fatal if not treated within minutes; emergency measures may include CPR and adrenaline injections.

Autoimmune Disease: Any disease of the immune system in which the immune system attacks tissues and/or materials that are not normally harmful to or are a part of the body. The immune system normally protects the body from infection and helps to promote healing, but in patients with autoimmune disease, the immune system becomes overactive and attacks non-infected materials, or even entire areas of the body. For example, in the case of Rheumatoid Arthritis, the immune system attacks the lining of the joints, causing pain and inflammation.

Ankylosing Spondylitis (AS): A degenerative form of arthritis primarily affecting the spine. AS is an autoimmune disease (see above definition) and is believed to be caused by a genetic predisposition.

Arthritis: A class of diseases involving pain and inflammation of the joints, caused by one of several factors affecting the cartilage that cushions the joints.

Black Box Warning: A printed warning included on the packaging of a drug, which is enclosed in a black box to distinguish it from other packaging information and to draw the user’s attention. In the case of Vioxx, in 2002, a black box warning was added describing the risk of cardiovascular complications associated with the drug. Celebrex, which is still on the market, carries essentially the same black box warning concerning cardiovascular complications.

Chronic: Term describing any condition that recurs continually or repeatedly, or that worsens over time. This term is used in contrast to acute, which refers to short-lived or single-instance conditions.

Codeine: The most commonly used opiate drug. Codeine is found in analgesics (pain killers), cough medicines, and anti-diarrheal medications. Opiates are derivatives of the poppy plant.

DMARD: Disease-Modifying Anti-Rheumatic Drug. DMARDs are used to slow the progression of diseases like Rheumatoid Arthritis, which are directly caused by a malfunction of the immune system. These drugs attempt to prevent the immune system response from worsening the disease, and are often used in conjunction with pain killers, which merely treat the disease symptoms.

Inactive Ingredients: All of the ingredients of a medication besides the “active” ingredient. In the case of Vioxx, “rofecoxib” is the active ingredient. Inactive ingredients may include things like coloring, flavoring, and texture stabilizers. These ingredients may vary between different manufacturers of the same drug; however, the active ingredient must be the same.

Juvenile Rheumatoid Arthritis (JRA): Now called Juvenile Idiopathic Arthritis (JIA), JRA formerly referred to any form of inflammation of joint tissue that appears in childhood, and may be chronic or acute.

Lipid: Any fat-soluble molecule found in the body. Lipids come in various forms and have multiple physical functions, including energy storage, assisting in neural (nerve-related) communication within the body, and even making up part of the structure of cell membranes.

Method of Administration: This term refers to the format of a drug. Methods of administration can be capsules, tablets, liquid, injection, etc.

Naproxen: A non-selective NSAID that has been used in various clinical trials as a base of comparison to test both the safety and efficacy of selective COX-2 inhibitors, including Vioxx.

NSAID: Non-Steroidal Anti-Inflammatory Drug. NSAIDs treat pain by reducing swelling, or inflammation, without the use of steroids.

Osteoarthritis: A type of arthritis in which overuse or normal wear-and-tear of the joints causes the cartilage, which normally cushions the movement of the joints, to become damaged and worn. The body responds with inflammation, which in turn causes pain. Osteoarthritis is considered a degenerative condition because it usually worsens with the passage of time.

Prostanoids: A subclass of fatty acid molecules, found in every body system, which interact with the enzyme cyclooxygenase (COX) to cause inflammation of tissues. Prostanoids come in three forms: prostaglandins, which are associated with pain and inflammation; thromboxanes, which assist in forming necessary blood clots; and prostacyclins, which are involved with platelet production and also assist the blood in clotting.

Rheumatoid Arthritis (RA): A type of arthritis in which the immune system attacks the cartilage that cushions the joints from the friction of movement. In some cases, the immune system also attacks other organs. The symptoms of RA can be treated with NSAIDs, but the disease itself is an autoimmune disorder and must be treated with a class of drugs called DMARDs.

When Vioxx was withdrawn from the worldwide market in 2004, patients had no choice but to stop taking the medication. The only other COX-2 inhibitors on the market were Celebrex and Bextra, both manufactured by Pfizer. Patients who did not wish to continue taking COX-2 inhibitors were given the option of trying a non-selective NSAID.Below, you will find information about the medication alternatives of former Vioxx patients, including other COX-2 inhibitors and non-selective NSAIDs.

Cox-2 Inhibitors

Celebrex

Celebrex (generic name celecoxib), manufactured by Pfizer, was the first COX-2 inhibitor approved by the FDA. Celebrex was released in 1999, mere months ahead of Merck’s competing drug, Vioxx. The two drug giants used their strongest marketing efforts to snatch up the new customer base of arthritis sufferers, who numbered in the millions and had been offered no notably effective medications up to that point. Celebrex is also approved by the FDA for the treatment of Ankylosing Spondylitis (spinal arthritis), dysmenorrhea (severe menstrual pain), Familial Adenomatous Polyposis (precancerous colorectal polyps), and acute pain.

Bextra

Bextra (generic name valdecoxib), also manufactured by Pfizer, was withdrawn from the US market in 2005. Shortly after the withdrawal of Vioxx, the safety of the entire class of COX-2 inhibitors was called into question. The FDA determined that the benefits of Celebrex outweighed its risks, and it was allowed to remain on the market. In the case of Bextra, however, the elevated cardiovascular risks, and a rare incidence of a potentially fatal skin reaction, caused the FDA to recommend its withdrawal.

Arcoxia

Arcoxia (generic name etoricoxib) was intended to be the new COX-2 inhibitor by Merck, but in April of 2007, Merck’s request for FDA approval of Arcoxia was denied. The FDA has requested further safety and efficacy data in support of Arcoxia be provided before it will approve the drug. Arcoxia is currently approved in more than 40 countries, but not in the US.

Prexige

Prexige (generic name lumiracoxib), manufactured by Novartis, was first approved for use in the European Union in November of 2006, and it was quickly approved in several other countries around the globe. By August of 2007, Prexige was withdrawn in Australia. In September of 2007, the FDA denied approval of Prexige in the US pending further safety data. In October of 2007, Prexige was withdrawn in Canada, and in November, it was withdrawn from several countries in the European Union.

Although Prexige is a selective COX-2 inhibitor, it works slightly differently from other COX-2 inhibitors like Celebrex or Vioxx. The chemical makeup of Prexige causes it to bond to a different area on the COX-2 enzyme. The basic effect of suppressing the COX-2 enzyme is the same, but Prexige was withdrawn because of a high incidence of severe liver damage, rather than cardiovascular complications as in the cases of Vioxx and Celebrex.

Licofelone

Licofelone (also called ML3000) is a new kind of NSAID called a COX/LOX inhibitor. While COX inhibitors react with the enzyme cyclooxygenase, LOX inhibitors react with the enzyme lipoxygenase. Both enzymes are involved in the production of prostaglandins, which are the pain- and inflammation-causing agents targeted by this entire drug class. Licofelone was developed by a German pharmaceutical company called Merckle GmbH for the treatment of osteoarthritis. Licofelone is still in testing stages and has not yet been submitted for approval. It is designed to have even fewer gastrointestinal (GI) side effects than other selective COX-2 inhibitors. In clinical trials, Licofelone has shown fewer GI complications compared to naproxen in osteoarthritis patients.

Non-selective NSAIDs

Non-selective NSAIDs are another option for former Vioxx patients. NSAIDs have been around much longer than COX-2 inhibitors, and have never been shown to cause the same severity of complications. Unlike selective COX-2 inhibitors, like Vioxx, non-selective NSAIDs inhibit both the COX-1 and COX-2 enzymes. The COX-2 enzyme is responsible for pain and inflammation, while the COX-1 enzyme helps to protect our stomach and intestinal lining from corrosion. By inhibiting both enzymes almost equally, NSAIDs offer pain relief accompanied by a higher risk of gastrointestinal side effects, including ulcers. Ulcerations of the stomach and intestines can lead to internal bleeding, and in extreme cases, death. The risk of these serious side effects is relatively small, but many people experience some gastrointestinal complications with prolonged or high-dosage NSAID use.

Several NSAIDs are available over-the-counter, including aspirin and ibuprofen, which are sold under various brand names. Prescription NSAIDs currently approved in the US include:

• Diclofenac
• Diflunisal
• Etodolac
• Indomethacin
• Ketoprofen
• Ketorolac
• Nabumetone
• Naproxen
• Oxaprozin
• Piroxicam
• Salsalate
• Sulindac
• Tolmetin

These medications may be prescribed for various pain or inflammation-related conditions, as determined by your doctor. Because individuals react differently to drugs, it is not unusual for your doctor to try different NSAIDs until you find the one most effective for your condition and body chemistry.

As explained below, generic drugs are identical to their name-brand counterparts in everything but appearance and inactive ingredients. The information on this web site applies to name-brand Vioxx as well as its generic version, rofecoxib. If you took rofecoxib, or generic Vioxx, your rights and responsibilities, as well as your entitlement to safe, high-quality medication, are the same as those of someone who took the name-brand drug.

Drug Patent Process

When a new drug is first created, the manufacturer holds the patent so that no other drug company may produce the drug. This patent begins with the very first preclinical trials and lasts for 20 years. By the time a drug is available to the public, the patent usually has 7-12 years remaining, during which time a generic version is not available. The justification for this extended patent period is that the original manufacturer of a drug invests the lion’s share of the research money. The exclusive rights to the drug’s profits pay the company back for that initial investment.

Once the original patent on a drug has expired, other manufacturers are free to produce a generic form of the drug. Often, the original manufacturer of a drug will produce a generic version of its own drug, while also continuing to produce the name-brand version.

FDA Guidelines for Generic Drugs

According to FDA guidelines, a generic drug must be equivalent to its brand name version in active ingredients (inactive ingredients may vary), dosage, method of administration, side effects, and safety. While generic drugs vary in appearance from their name-brand cousins, in every other way, they should be considered the same. In other words, any information provided on a name-brand drug also applies to its generic counterpart, and vice versa.

The FDA inspects American drug manufacturers on a rotating basis to ensure that their production meets safety and quality standards. The FDA does not, however, inspect prescription drug manufacturers located outside of the US.

All drugs come with some package warnings, which include contraindications (outlining who should not take the drug). Contraindications take into account pre-existing conditions as well as other medications a patient is currently taking.

Vioxx was Not Recommended for Patients Who:

• Had a history of gastrointestinal bleeding or ulcers. These patients were shown to have a 10-fold increased risk of developing an ulceration of the stomach or intestines while using Vioxx.
• Were pregnant, nursing, smoked, or drank heavily.
• Suffered from renal insufficiency, and additionally the drug was not well absorbed by these patients. (See Vioxx Dosage Information for more about Vioxx absorption rates.)
• Had a known allergy to rofecoxib, aspirin, sulfur, or any NSAID drugs. In rare cases, severe allergic reactions occurred, including hives, swelling, and even symptoms of anaphylaxis.

Vioxx was Contraindicated for Patients Taking the Following:

• Hepatitis A or B medications
• HIV drugs or certain antivirals and antiretrovirals used in HIV patients
• Immunosuppressive medications, often used in transplant patients
• Other NSAIDs or low-dose aspirin therapy
• Certain muscle relaxers, including those used for Multiple Sclerosis or severe muscle spasms

There were literally hundreds of medications that were listed as having potential interactions with Vioxx, most of which fell into the above groups.

Vioxx was available in both oral suspension and tablet formats. The oral suspension was off-white/yellow with strawberry flavoring. Vioxx tablets came in 12.5 mg, 25 mg, or 50 mg sizes, and could be taken with or without food.

Description of Vioxx Tablets

• 12.5 mg: round, off-white, engraved with MRK 74 on one side, VIOXX on the other.
• 25 mg: round, yellow, engraved with MRK 110 on one side, VIOXX on the other.
• 50 mg: round, orange, engraved with MRK 114 on one side, VIOXX on the other.

Commonly Prescribed Vioxx Dosages

For arthritis, a chronic condition, Vioxx had a recommended daily dose of no more than 25 mg. In some cases, dosages were adjusted for a particular patient’s needs, but Vioxx came with a general dosage guide as follows:

• Rheumatoid Arthritis: 25 mg once daily (same for treatment of Juvenile Rheumatoid Arthritis in patients aged 2 and up).
• Osteoarthritis: 12.5 or 25 mg once daily.
• Acute pain or dysmenorrhea: 50 mg once daily, for up to 5 days.
• Migraine Headaches: 25 or 50 mg once daily, up to 5 days per month.

Factors Affecting Vioxx Dosages

The patient’s body mass, size, weight, age, and diet may have a bearing on a doctor’s dosage adjustment of any medication. Merck (manufacturer of Vioxx) recommended that Vioxx be taken in the lowest possible effective dosages, particularly when used for long-term treatment. In other words, the chronicity and severity of the condition also had a bearing on what dosage of Vioxx patients were prescribed.

Vioxx Absorption Rates

The body’s absorption of a drug is represented graphically by a roughly bell-shaped curve, which shows the concentration of a drug in the bloodstream in relation to time, as shown below:

The drug’s concentration gradually increases as the body absorbs it; then the concentration peaks, and then gradually declines as the medication wears off. The term used to denote the total amount of a medication absorbed by an individual is the AUC, or Area Under the Curve.

Variations in AUC are observed when individual patients show different levels of the drug in their bloodstreams after the same amount of time has elapsed. An increased AUC means that a patient, in total, absorbs a higher than average amount of a drug. In this case, dosage may be lowered to compensate. Conversely, if a patient shows a decreased AUC, dosage may be raised.

The following AUC variations were observed in Vioxx clinical trials:

• 34% increase in AUC in elderly patients compared with young patients.
• 10-15% increase in AUC in people of African-American or Hispanic descent.
• Up to 30% decrease in AUC in patients with certain types of Hepatitis.

In the late 1990s, pharmaceutical companies released a new class of drugs called “super aspirins.” These drugs — Bextra, Vioxx, and Celebrex — were touted as the miracle treatment for arthritis, a disease affecting an estimated 28 million Americans.

The idea behind the super aspirins was that they would act as strong pain relievers by reducing the inflammation associated with arthritis. The major promised benefit of these drugs was that they would treat pain without the risk of peptic ulcers associated with traditional NSAIDs like aspirin.

In addition to the conditions detailed below, Vioxx was prescribed for acute pain conditions in adults. In March of 2004, it gained FDA approval for the treatment of migraine headaches. Although the use of Vioxx for one year or longer was later proven to carry significant cardiovascular risk, these short-term uses never demonstrated the same level of cardiovascular risk.

Vioxx and Arthritis

Arthritis is a chronic disease commonly associated with old age or overuse of joints, and in some cases an immune deficiency. In an arthritic patient, the cartilage protecting a joint becomes worn, and the body responds with inflammation, which in turn causes pain. Osteoarthritis is a type of arthritis in which overuse or repetitive movements cause the cartilage to become worn. Rheumatoid arthritis, on the other hand, is caused by the immune system attacking the cartilage protecting a joint. Ankylosing Spondylitis is another form of arthritis that affects the spine. Vioxx was prescribed for all of these types of arthritis.

COX-2 inhibitors, like Vioxx, treat pain by targeting a chemical in the body that causes inflammation. COX-2 inhibitors are used in low doses to treat pain, and in higher doses to treat inflammation. Unfortunately, high doses of Vioxx were shown to cause a much higher incidence of cardiovascular complications, for which the primary age group suffering from arthritis was already at increased risk.

In September of 2004, only weeks before Vioxx was withdrawn from the worldwide market, it was approved by the FDA for the treatment of Juvenile Rheumatoid Arthritis (JRA).

Vioxx and Dysmenorrhea (Painful Menstruation)

Vioxx was approved for use “as needed” in patients with dysmenorrhea. Dysmenorrhea is a condition characterized by severe pain in the uterus during menstruation, sometimes accompanied by heavy bleeding. Dysmenorrhea is associated with the release of prostaglandins in the uterus, which is why the condition responds to NSAIDs. Dysmenorrhea usually affects women under the age of 30, and is often accompanied by other factors such as early menarche (first menstruation), PMS, and other menstrual problems.

Vioxx and Colorectal Adenomatous Polyps

Clinical trials measured the effectiveness of COX-2 inhibitors in preventing the regrowth of colorectal adenomatous polyps, benign polyps found in the colon and rectum that often lead to cancer of those organs. In the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, Vioxx was tested on more than 1,000 patients with a history of colorectal adenomas. Although Vioxx was found to be effective in treating the polyps, the study was terminated early because of a high incidence of heart attacks in the Vioxx study group.

The information contained in the Vioxx Advisor applies to all forms of the drug rofecoxib, which was manufactured under the names Vioxx, Ceoxx, and Ceeoxx. According to the FDA, generic drugs are identical to their name-brand versions in dosage, method of administration, effectiveness, safety, and active ingredient.

What is Vioxx?

Vioxx (manufactured as Ceoxx outside the US) is the brand name of the pain treatment drug rofecoxib, and was released by Merck & Co., Inc. in 1999. Vioxx was prescribed and marketed as a “super-aspirin” for patients suffering from osteoarthritis and other chronic and acute pain conditions. Vioxx was one of a class of drugs called NSAIDs, or Non-Steroidal Anti-Inflammatory Drugs.

Vioxx was designed to provide pain relief with a lower risk of peptic ulcer than is associated with traditional NSAIDs such as aspirin. After it was discovered that Vioxx was associated with severe cardiovascular complications, the medication was withdrawn from the worldwide market in 2004.

Chemistry of Vioxx

Chemical Formula of Vioxx: C₁₇H₁₄O₄S

Nomenclature: 4-(4-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone

Note: Vioxx contains sulfur (represented by the “S” in the chemical formula above), a common allergen contained in sulfonamides. Because Vioxx is not technically considered a sulfonamide drug, many patients with sulfur sensitivity suffered allergic reactions after being prescribed Vioxx for pain.

Definition of NSAIDs

NSAID is the common name of a class of drugs called Non-Steroidal Anti-Inflammatory Drugs. NSAIDs are prescribed for pain, fever, and swelling. All NSAIDs alleviate pain by reducing inflammation. Specifically, NSAIDs work by inhibiting the body’s formation of a chemical called prostaglandin, which is found in the blood, stomach, and kidneys. Prostaglandin has multiple functions within the body, and there are different types of prostaglandin.

Vioxx is a Selective COX-2 Inhibitor

Within the class of drugs known as NSAIDs, Vioxx is a specific type of NSAID called a COX-2 inhibitor. Traditional NSAIDs are associated with a high incidence of gastrointestinal and/or digestive side effects, including potentially-fatal peptic ulcers, whereas the subclass of NSAIDs known as COX-2 inhibitors are associated with an increased risk of heart attacks and strokes. For chronic pain sufferers, like those coping with osteoarthritis, the struggle to find a safe and effective pain medication without side effects is ongoing.

How NSAIDs Work

NSAIDs treat pain by preventing the body’s production of a chemical called prostaglandin. Prostaglandin is a lipid that is found in the blood vessels, kidneys, stomach, and most other organs. Prostaglandin has multiple effects within the body, and is sometimes sub-classified into “good” and “bad” prostaglandin. Prostaglandin is formed in the body by the reaction of fatty acids with the enzyme cyclooxygenase (COX), and it is this enzyme that is directly targeted by Vioxx.

COX Inhibitors

Vioxx is called a selective COX-2 inhibitor because it specifically targets one form of the COX enzyme, COX-2. COX-2 is responsible for the production of “bad prostaglandin,” which causes pain and inflammation, while the COX-1 enzyme is responsible for the production of “good prostaglandin,” which creates a protective mucous lining in the stomach and intestines.

Traditional NSAIDs are considered non-selective COX inhibitors because they target the COX-1 and COX-2 enzymes almost equally. While non-selective COX inhibitors do prevent the formation of bad prostaglandin associated with pain and inflammation, they also prevent the formation of good prostaglandin, which has protective effects. This is why non-selective NSAIDs are normally associated with gastrointestinal side effects such as peptic ulcers.

How Super Aspirins Differed from the Alternatives

Steroidal Anti-Inflammatory Drugs

Steroids are used to treat a variety of conditions, including inflammation, severe allergies, and difficulty regulating immune or digestive system functions. NSAIDs, by definition, do not contain steroids. The numerous associated side effects make steroids undesirable and dangerous for extended use, and they are rarely used to treat chronic conditions.

Traditional Pain Killers

Many traditional over-the-counter pain killers are NSAIDs. Aspirin and ibuprofen-based drugs like Motrin and Advil are non-selective NSAIDs, which means they treat pain by inhibiting the body’s production of prostaglandin.

Acetaminophen-based drugs, like Tylenol, are used for pain and fever, but they do not treat inflammation so they are not NSAIDs. These drugs treat pain by affecting prostaglandin production, but they do not specifically inhibit the COX enzyme. The mechanism of action for these types of drugs is not completely understood.

VIGOR Study (Vioxx GI Outcomes Research)

The VIGOR study began in January 1999 and concluded in March 2000. The study was designed to measure the safety of Vioxx vs. naproxen in arthritis patients, but it did not test the efficacy of Vioxx in treating arthritis.

As early as 4-6 weeks into the trial, the Vioxx group began showing a higher rate of fatal cardiovascular events including heart attack and stroke. By December of 1999, there were twice as many deaths in the Vioxx group. The Data Safety Monitoring Board (DSMB) overseeing the VIGOR study was notified about the deaths, but the data was not immediately interpreted as evidence of the risks of Vioxx. It was hypothesized that the difference in fatalities might have been attributable to the protective anti-platelet effects of naproxen, instead of indicating a complication of Vioxx.

However, in 2006, an investigative report by National Public Radio revealed that the percentage of deaths was steadily rising in the Vioxx group, while remaining almost constant in the naproxen group, which indicated an increased danger with extended use of Vioxx. Additionally, there is no evidence that naproxen’s anti-platelet effects were significant enough to have caused the discrepancy in the VIGOR study.

Perhaps the most ironic finding of the VIGOR study was that the incidence of peptic ulcers was the same in both the Vioxx and naproxen groups. Thus, VIGOR proved that Vioxx had no benefit over traditional pain killers in preventing ulcers.

The results of VIGOR were submitted to the FDA in 2001, and consequently in 2002 a black box warning was ordered for Vioxx packaging, informing consumers of the possible risk of heart attack, stroke, and fatal blood clots.

APPROVe Study (Adenomatous Polyp PRevention On Vioxx)

The APPROVe trial began in 2001 as a 3-year study of the effectiveness of Vioxx vs. placebo in preventing the regrowth of colon and rectal polyps in 2,586 patients with a history of colorectal adenomatous polyps (pre-cancerous masses in the colon and rectum). The study was terminated in September 2004 because of a drastic increase in heart attacks in the Vioxx group. It was due to this study that Merck made the long-standing claim that the risks of Vioxx did not appear until after 18 months of treatment. Merck maintained the 18-month theory until 2008, when the results of several Vioxx studies were scrutinized and it was discovered that as many as 25% of the heart attacks in Vioxx trials occurred within the first month of treatment.

As a direct result of the APPROVe study, Vioxx was withdrawn from the market. The APPROVe study publicized the cardiovascular risks of Vioxx, and it marked the beginning of a string of lawsuits that have cost Merck billions. Because of the drug’s withdrawal, Merck’s handling of Vioxx was placed under intense scrutiny. It was later discovered that the APPROVe study results revealed that taking Vioxx carried even more risk than previously thought.

In 2006, a New England Journal of Medicine article revealed that the APPROVe study results, specifically the number of Vioxx-related deaths during and after the study period, were improperly calculated in order to make the drug appear safer. Some numbers appeared not to have been reported at all.

Merck claimed that numbers were “transposed.” However, later inquiries showed that the numerical discrepancy in the results of the APPROVe trial resulted from the fact that, in the “off-drug period” immediately following the discontinuation of the study, deaths in the placebo group were counted for a year, but deaths in the Vioxx group were counted for only 14 days. During that unreported period, the proportion of deaths in the Vioxx group was much greater than in the control group.

In addition to several audits of Merck’s study results for APPROVe, Merck was investigated for their handling of Vioxx from a “sponsorship” perspective. Merck was accused of utilizing professional ghostwriters to author clinical studies, with the idea of making the results sound more favorable.

At every turn, Merck made decisions and oversights that came back to haunt the drug giant later. The entire medical community scrambled to analyze the Vioxx disaster and answer the big questions: how did it happen, and could it happen again?

Several editorials were published accusing Merck, and the drug industry at large, of corruption and profiteering at the cost of public health. In 2006, Merck made an official statement admitting that it had misinterpreted the results of the APPROVe study, and admitting that the cardiovascular risks of Vioxx appeared to be the same before and after the 18-month benchmark. This statement was expected to have disastrous effects for Merck in its legal battles over Vioxx because now patients who had taken Vioxx for a short time were more likely to file successful lawsuits.

ADVANTAGE Trial (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness)

ADVANTAGE was a 12-week trial in 2000 designed to measure Vioxx safety. The results of the 6,000-patient ADVANTAGE study were not publicized until 2005, when all Merck-sponsored clinical trials were under intense scrutiny. In its 2001 report to the FDA on the ADVANTAGE trial, Merck reported a total of eight cardiovascular events. But in 2005, it was discovered that one death had been omitted from the results, bringing the total number of events to 9 — 8 of which were in the Vioxx group. It was later speculated that these results were not made public earlier because they did not support Merck’s claim that Vioxx risks only appeared after 18 months of continuous treatment.

VICTOR Trial (Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime)

Beginning in 2002, the VICTOR trial was designed to measure the effectiveness of Vioxx vs. placebo in preventing the regrowth of colorectal tumors, in patients who had previously undergone surgery to remove colorectal tumors. The study was terminated prematurely in 2004 because of the worldwide Vioxx withdrawal, and the partial results were never published.

In 2007, an article in The Wall Street Journal included a description of the unpublished VICTOR study. According to Merck’s own records, there were 23 cardiovascular events during the study, 16 of which were in the Vioxx group. Of those 16, 12 occurred during the first 12 months of treatment. These findings came as another blow to Merck’s claim that Vioxx posed no cardiovascular risk until after 18 months of treatment. In response to the publication of these results, Merck announced that they would not make an official statement until the data was re-examined more closely.