In the mid-1990s, Merck & Co. was at a crossroads. A number of its best-selling drugs would no longer be protected by patents within a relatively short period, and Merck had not provided a new set of blockbuster drugs to take their place. The company focused on one growth area—drugs used as painkillers. It had developed Vioxx as the main drug in this category, but it needed to make sure doctors and patients would see the benefits of this Cox-2 drug versus traditional pain relievers. Cox-2 is part of the family of enzymes within the body called cyclooxygenase, or Cox. The body has two types of Cox enzymes: Cox-1 enzymes protect the stomach lining from acids. Cox-2 enzymes cause pain and inflammation. Over-the-counter (OTC) painkillers such as aspirin, ibuprofen (in products such as Motrin and Advil), and naproxen (in products such as Aleve)

block both Cox-1 and Cox-2 enzymes. Vioxx and other Cox-2 inhibitors block only the Cox-2 enzyme. As a result, Cox-2 inhibitors should not have an adverse effect on the patient’s stomach while relieving pain and inflammation. One theory about the dangers of Cox-2 drugs is that Cox-1 enzymes may help the body clot blood while Cox-2 enzymes help the body reduce blood clots.

Merck wanted to ensure the Vioxx was proved to be gentler on the stomach than OTC medications. More than 16,000 Americans die each year from gastrointestinal bleeding from the cheaper OTC medicines, and Merck wanted to prove that Vioxx was better than the OTC medicines.

Getting Ready to Launch

In a November 21, 1996, memo, Merck officials warned that if the patients didn’t take aspirin to relieve potential blood clotting along with Vioxx, there would be a higher rate of cardiovascular problems. Dr. Alise Reicin, who worked in the clinical research department at Merck, stated that giving an aspirin with Vioxx would create a “no-win” situation because the aspirin would increase the potential stomach problems, which Merck was claiming would not occur if the patient had taken Vioxx. Reicin advised that patients with a high risk of cardiovascular problems should not be included in the study so the difference in cardiovascular problems between the Vioxx and non-Vioxx patients would not be evident. In 1999, Merck started the Vioxx Gastrointestinal Outcomes Research study (VIGOR) clinical trial to collect data to prove that Vioxx was better for the patients’ stomach than naproxen.

On May 29, 1999, Merck launched Vioxx after receiving approval from the Food and Drug Administration (FDA). Vioxx was introduced in 80 countries in 1999. In March 2000, the results of the VIGOR study were completed. The study demonstrated that Vioxx users had fewer stomach problems than did those patients who had used naproxen but that Vioxx users had significantly higher numbers of blood clot–related problems. Furthermore, Vioxx users had four to five times higher rates of heart attacks than the naproxen group did.

The Trouble Begins

On March 9, 2000, Merck’s research head, Edward Scolnick, emailed his colleagues at Merck and warned them, based on the results of the VIGOR study, that Vioxx created a higher risk of a cardiovascular event. He called the side effects a shame but stated that there are always hazards with using drugs. Scolnick also asked that additional data be developed to show that this result occurred in all Cox-2 inhibitors, not just Vioxx.

Merck sent out a press release describing the results of the VIGOR study. In contrast to the concerns raised by Scolnick and others at Merck, the press release was titled “Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx.” In the press release, Merck did acknowledge the results of the study but also highlighted other clinical trials and other data collected that had shown “no difference” in the rates of cardiovascular events for patients using Vioxx and a placebo or OTC pain relievers. Merck explained that the antiplatelet properties of naproxen might have helped the patients who took it.3 In November 2000, the New England Journal of Medicine published the results of a VIGOR study. The article was written by academic researchers who had received research grants or consulting contracts from Merck. The paper touted the potential benefits of Vioxx for stomach problems and heart attacks. The authors did not provide any information about the higher risk of serious cardiovascular complications from using Vioxx, such as strokes and blood clots. Based on the data in the study, the authors had concluded that Vioxx did not show a significant rise in heart attacks among patients who were not at high risk for heart attacks before they started taking Vioxx.4 This study demonstrated that Vioxx patients were four times more likely to have a heart attack or stroke (0.4% to 0.1%) than were those patients who took the OTC drug naproxen.

However, the focus on the paper was Vioxx’s benefits. Merck argued that the results of the study could have been based on the protective effects of naproxen, rather than on the dangers of Vioxx.5 In February 2001, Merck won a significant decision from the FDA when the FDA allowed Merck to claim that Vioxx is safer for patients’ stomachs than previous painkillers, giving Vioxx a significant competitive advantage over its chief rival, Celebrex, made by Pfizer. The FDA wanted to have the dangers of cardiovascular problems displayed prominently on the Vioxx label, but Merck refused, arguing that it wanted to promote the positive aspects of the drug. They compromised, resulting in a label showing the positive impact on stomach problems first, then the information about the risks of heart attacks and strokes. The new labeling was released in April 2002.

External Red Flags Start to Fly

In August 2001, the results of a Vioxx study done by the Cleveland Clinic were published in the Journal of the American Medical Association. Researchers concluded that a cautionary flag needed to be raised concerning the increased risk of cardiovascular events occurring in patients who use Vioxx. The authors stated that all Cox-2 inhibitors may increase the risk, but Vioxx appeared to be riskier than the other drugs in the marketplace. Merck met with the authors to argue that Merck did not believe that there was a problem with the drug and asked the journal to allow Merck to present a rebuttal to their findings. The journal refused Merck’s request.6 On September 17, 2001, the FDA sent a letter to Merck’s CEO, Raymond Gilmartin, warning Merck that it should stop marketing Vioxx as a drug with a minimal threat of cardiovascular problems when comparing Vioxx with naproxen. The FDA stated explicitly that Merck’s promotional campaign discounted the fact that patients who had used Vioxx were observed to have four to five times higher risk of a heart attack than those patients in the other sample, which it claimed was a critical fact. The FDA also criticized Merck for claiming that the reason Vioxx patients had more heart attacks was because of the protective properties that were found in naproxen. The FDA claimed that Merck had no proof that naproxen had any protective properties for the patients’ hearts. In addition, the FDA claimed that Merck was misleading the public by titling the press release of the VIGOR study “Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx.”

How to Address the Concerns

An internal Merck marketing document for sales representatives told the reps to “dodge” any potentially tough questions that were asked by doctors about the side effects of Vioxx. This advice was part of the “obstacle handling guide” given to help the sales reps continue to convince doctors to prescribe Vioxx. When a doctor asked specifically about concerns related to heart problems, the sales rep was instructed to tell the doctor that Vioxx would not reduce the level of cardiovascular problems and that Vioxx would not be considered a substitute for aspirin. The sales reps were given a 16-page “Dodge Ball Vioxx” document that went through a step-by-step process teaching reps how to respond to questions from doctors about Vioxx. The final four pages of the document had the single word DODGE on each page.

In addition, Merck attempted to control academics who started to question the benefits of Vioxx. Stanford University’s Dr. Gurkipal Singh was a leading expert in Cox-2 research and was presenting lectures that were funded by Merck and other companies. Singh asked Merck for additional information pertaining to cardiovascular issues, and Merck refused to provide any. Singh added a slide to his PowerPoint presentations—a picture of a man hiding underneath a blanket—to represent the missing data that Merck would not supply.

Merck canceled Singh’s subsequent lectures, and the company also complained to Stanford University Medical School that Singh was anti-Merck and anti-Vioxx and was acting irresponsibly. Merck warned Stanford that if Singh’s actions continued, there would be consequences for the doctor and for Stanford. Stanford replied that Merck had crossed the line and that other top-tier medical schools had also complained about Merck’s threatening behaviors toward researchers who had studied Vioxx. Merck CEO Gilmartin responded that Merck had a strong commitment to have strong ethical standards with its dealings with all doctors and healthcare providers.....

Questions

1. What are the ethical implications of the “Dodge Ball Vioxx” document given to sales representatives?

2. Do you think this is a case of putting profits first? Explain.

3. It took Merck 5 years to remove Vioxx from the market. Why?