Professionalism/Vioxx: Merck and the FDA

Merck & Co, one of the largest pharmaceutical companies in the world, launched Vioxx on May 21, 1999 to 47 countries. Vioxx, generically known as rofecoxib, became one of the most widely used pain killers for treating arthritis. Vioxx is a nonsteroidal anti-inflammatory drug (NSAIDs), used to reduce pain, inflammation, and stiffness caused by osteoarthritis and certain types of rheumatoid arthritis. It is also used to manage acute pain and dysmenorrhea. Common side effects included upper–respiratory infection, diarrhea, nausea, and high blood pressure.

The NSAIDs, which block both COX-1 (Cyclooxygenase) and COX-2 enzymes, are the primary drug types for pain relief. COX-1 maintains the stomach lining and digestive tract, while COX-2 enzyme is mainly associated with pain and inflammation by mediating synthesis of prostaglandins. However, Vioxx was a selective NSAIDs, which inhibited only COX-2 enzymes. Since COX-1 and COX-2 enzymes are a checks and balances system, their relationship is inversely proportional. Serious side effects occur when there is imbalance, such as a heart attack when COX-2 enzyme is suppressed. Although Vioxx showed clinical evidence of its superior gastrointestinal safety, it also caused many serious cardiovascular complications. Possible cardiovascular complications are heart attack and strokes, blood clots, and kidney failure. Following the termination of a long-term Vioxx study called APPROVe (Adenomatous Polyp Prevention on VIOXX), Merck concluded that Vioxx increased the risk of cardiovascular events if taken for 18 months or longer. Shortly after ending APPROVe, Merck voluntarily withdrew Vioxx from the market on September 30th, 2004. The FDA has estimated that the number of death caused by Vioxx-induced cardiovascular events is approximately 28,000 in US and over 150,000 worldwide. To adequately examine the underlying ethical issues, this chapter will focus on the FDA and its role in the Vioxx scandal.

Food and Drug Administration
The Food and Drug Administration (FDA) is a government agency responsible for protecting the public health by regulating goods, dietary supplements, drugs, cosmetics, medical devices, biologics, and blood products in the United States. The FDA is comprised of various offices and center branches under the Office of the Commissioner. Their legal authorities include most of federal laws as part of the Food, Drug and Cosmetic Act. Drugs are regulated by the Center for Drug Evaluation and Research (CDER), which requires different qualifications for three main types of drug products, new drugs, generic drugs, and over-the-counter drugs. Within the CDER, the Office of New Drugs approves new drugs while the Office of Drug Safety monitors drugs once they are approved.

The FDA failed its obligation to protect the public by exposing consumers to Vioxx and allowing the drug to stay on the market from 2000 – 2004. Although Merck was intentionally misrepresenting data, the FDA had multiple opportunities to recall Vioxx. At each major event throughout Vioxx’s timeline, the FDA's primary concern was protecting itself (and sometimes Merck) while disregarding the safety of the consumers.

Vioxx Gastrointestinal Outcome studies (VIGOR) – June 29, 2000
This studied confirmed that Vioxx reduced the number of gastrointestinal (GI) complications; however, according to the FDA, it was the first study that showed an increase in cardiovascular (CV) complications. On February 8, 2001 (8 months later), the FDA’s Arthritis Advisory Committee met to discuss the findings of VIGOR. This committee concluded that Vioxx labeling must include the results of this study. The committee “recommended to include balanced information regarding safety results of Vioxx and de-emphasize the GI safety advantage in [the] Vioxx label”. Merck was unwilling to de-emphasize the GI advantages and it was not until April 11, 2002 (nearly 22 months after VIGOR) that the labeling was changed to include information of clinical studies, precautions, drug interaction, and dosage and administration sections. The label first presented the positive GI safety of the drug then the negative CV risks.

In addition the FDA’s inability to implement and enforce Vioxx label changes in a timely manner, Merck severely misled the public by issuing a press release titled, “Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx,” on May 22, 2001, almost a year after VIGOR. This press release stated that, “Clinical trials with Vioxx…have shown no difference in the incidence of cardiovascular events,”. This statement directly contradicts the results of VIGOR.

Kaiser Permanente Study – August 11, 2004
After the VIGOR results were submitted to the FDA, they began their own investigation, in August 2001 and ended in 2004, regarding CV safety while using Vioxx. This investigation was collaborative with Kaiser Permanent and was led by FDA’s Dr. David Graham, named the Office of Drug Safety (ODS) project officer. On August 11, 2004, Graham emailed his supervisor at ODS and reported the following, “We concluded that high-dose Vioxx significantly increased the risk of heart attacks and sudden death and that the high doses of the drug should not be prescribed or used by patients. This is exactly the finding of VIGOR: high dose increases the risk of heart attack”. Graham stated that after he provided his findings to the FDA, “[it] triggered an explosive response from the Office of New Drugs, which approved Vioxx in the first place and was responsible for regulating it postmarketing. One drug safety manager… noted that Merck needed to know our study results. I guess that Merck needed to know the results, but the public didn't”. Graham had also expressed interest in submitting the findings to many prominent scientific journals; however, his management immediately denied the request.

Although Graham had not received permission, he submitted an abstract to the Lancet. Acting FDA Commissioner, Dr. Lester Crawford issued a statement that Graham’s findings had not gone, “through the long-established peer review and clearance,” which prompted the FDA to, “[contact] the journal's editor, out of respect for the scientific peer-review process”. However, it was clear that the FDA was only trying to cover its tracks. After careful investigation by Tom Devine, legal director of the Government Accountability Project, he found that, “the FDA flunked every test of credibility while Graham passed all of them”. Instead, Devine believed the FDA was employing a “smokescreen syndrome” to divert focus to the messenger and away from the message.

Adenomatous Polyp PRevention On Vioxx (APPROVe) – September 27, 2004
This study was a long term investigation to evaluate the effectiveness of Vioxx for treating colon polyps. However, on September 27, 2004, this study was immediately stopped when data indicated a significant increase in the amount of CV events. On September 28, 2004, Merck held a meeting with senior management of FDA to discuss these results and “announced the product withdrawal of Vioxx from the market”. Two days later, on September 30, 2004, this withdrawal was publicly announced.

FDA Presents Initiatives to Strengthen Drug Safety – November 18, 2004
On November 18, 2004, Dr. Sandra Kweder issued a statement before the Senate Committee on Finance summarizing the Vioxx incident. At the end, Kweder offered a five step plan that was to be implemented. First, the CDER would fund a study to evaluate the FDA’s drug safety system by the Institute of Medicine (IOM). Second, the FDA would implement a program that allows individuals’ professional opinions to be heard. Third, a Director of the Office of Drug Safety, a position that was currently unoccupied, would be appointed by the FDA. Fourth, the FDA would hold seminars to discuss “drug safety and risk management issues”. Lastly, the FDA would, “publish final versions of three guidances that the agency developed to help pharmaceutical firms manage risks involving drugs and biological products”.

Conclusion
Many point to the Vioxx Scandal as proof that the FDA is currently an under-regulated industry, but such haphazard conclusions should not be reached so hastily. This would likely be an instance of confirmation bias without further evidence. There are arguments of under-regulation and over-regulation within the FDA. It is important to note that the prescription drug companies often favor over-regulation due to the distinct economic advantages.

Under-Regulation
Both Vioxx and Rezulin are high profile cases of drugs that the FDA have approved but later withdrawn due to substantial health risks. The public champions cases such as Frances Oldham Kelsey who refused the authorization of thalidomide which turned out to be a strong teratogenic substance that caused babies to be born limbless. Many point to the thalidomide incident to the modern day approval of Vioxx as a change in the culture of the FDA that needs to be better-regulated.

The FDA is strongly influenced by pharmaceutical industries. In 2005, 70% of FDA panels writing clinical guidelines contained at least one member on the panel who had financial links to the drug companies whose drugs were being covered by those guidelines. The FDA passed a policy on March 21, 2007 that prohibited experts from serving on the advisory committees if they are financially linked to a company whose product is being questioned.

Over-Regulation
On the other-hand, over-regulation can also hurt not only drug companies, but also consumers. The drug-approval process can delay the time between the drugs development and the time it reaches the market. This delay could prevent many life-saving drugs from entering the market in time to save lives. These harms of over-regulation often go unobserved because a wrongful ban or an over-extended delay in a drug approval maintains the status-quo to the public eye. These harms of over-regulation are further magnified when they are not properly weighed against highly publicized scandals such as Vioxx. These delays also force people to seek drugs elsewhere such as through the black market or in other countries, which introduces many other risks.

Over-regulation can also increase the price of drugs. High levels of regulation increases the cost of the development of the drug, which would raise prices. Long delays in drug-approval also lower competition within the drugs available to consumers, leading to an increase in price. In 2011, the drug Makena increased their price from about $10 to $1,500 after the FDA began regulating its market. After public outcry and complaints, the FDA lowered certain regulations within the market and the price of Makena was reduced. This is clearly an instance where over-regulation benefits drug companies.