BTEC 635 Major Project: Vioxx Drug Approval and Withdrawal Review

This literature review examines the history of Vioxx (rofecoxib), a non-steroidal anti-inflammatory drug initially approved by the FDA and subsequently withdrawn from the market due to significant cardiovascular risks. The review delves into the drug's development by Merck & Co., its intended uses for conditions like osteoarthritis and rheumatoid arthritis, and the pivotal events leading to its withdrawal in 2004. It highlights key findings from studies and reports, including the USFDA's David Graham's memorandum indicating increased acute myocardial infarctions (AMIs), and the postmarketing database examination revealing adverse events such as hemorrhage, edema, and thrombosis. The review also explores the reasons behind the withdrawal, including the influence of clinical results from Merck & Co. and the VIGOR study, which demonstrated elevated risks of stroke and heart attacks in Vioxx users. Furthermore, the review discusses the controversies surrounding the drug's safety, the criticisms of the mathematical models, and the conclusions of the Martin report. Ultimately, the review provides a comprehensive understanding of the factors that led to Vioxx's initial approval and its eventual removal from the market, along with the lessons learned by the pharmaceutical company.

Running head: LITERATURE REVIEW
Literature Review
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1LITERATURE REVIEW
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are the kind of medicines which help in
relieving and decreasing the pain experienced by people. Vioxx (rofecoxib) is a drug which falls
under the category of the non-steroidal anti-inflammatory drug. The drug Vioxx (rofecoxib) was
technologically advanced by the organization Merck & Co. in order to prevent osteoarthritis,
acute pain conditions, rheumatoid arthritis, dysmenorrhea and many more conditions. In the year
2004, USFDA’s associate director of science, David Graham released a memorandum
concerning the duration of 1999–2003. It showed that the use of rofecoxib (Vioxx) led to further
27,000 surplus acute myocardial infarctions (AMIs). On 27th September, executives of Merck
Research Laboratories, Dr. Kim and outside experts decided to withdraw the drug from the
market. It was found that the usage of rofecoxib led to several cases of hemorrhage, edema,
mortality, thrombosis and embolism. Thus, the researchers of the Merck & Co. decided to
remove the drug from the market place on 27th September 2004.

2LITERATURE REVIEW
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are the kind of medicines which help in
relieving and decreasing the pain experienced by a person. NSAIDs are also described under the
definition of the non-opioid analgesics. It means that it is a different type of painkiller or can be
said it is different than opioid drugs for instance morphine since it is utilized for more painful
instances (Enthoven, Roelofs, Deyo, Tulder & Koes, 2016). Vioxx (rofecoxib) is a drug which
falls under the category of the non-steroidal anti-inflammatory drug (U.S. Food and Drug
Administration, 2020).
When a new drug component is developed, it is given a chemical name (Heller,
McNaught, Pletnev, Stein & Tchekhovskoi, 2015). The drug Vioxx has also been given a
chemical name which is the 4-[4(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone. The
molecular weight of Vioxx is 314.36 and the empirical formula is C17H14O4S (U.S. Food and
Drug Administration, 2020).
The drug Vioxx (rofecoxib) was manufactured by the organization Merck & Co. in order
to prevent acute pain conditions, osteoarthritis, rheumatoid arthritis, dysmenorrhea and many
more conditions. In May 1999, the drug was approved and permitted by the US Food and Drug
Administration (FDA) and was sold in the market under the brand names Vioxx, Ceoxx, and
Ceeoxx. But later on September 2004, the drug was voluntarily withdrawn due to several issues
of heart attack risks and due to long-term and high dose of the drug, risk of stroke increases. The
following study will conduct a literature analysis to answer the research question –

3LITERATURE REVIEW
“Why was Vioxx (Generic name: Rofecoxib) initially approved and then withdrawn
from the US market?”
Literature Review
In the year 2004, USFDA’s associate director of science, David Graham released a
memorandum concerning the duration of 1999–2003. David Graham released the estimation of
the epidemiological evaluation regarding the use of rofecoxib (Vioxx). It showed that the use of
rofecoxib (Vioxx) led to further 27,000 surplus acute myocardial infarctions (AMIs) and sudden
cardiac deaths compared to that of the celecoxib (Celebrex). Instantaneously, the organization
Merck & Co. announced the pulling out of rofecoxib from the market place (Garrison Jr, Towse
& Bresnahan, 2007).
Bottone & Barry (2009) conducted a postmarketing database examination to understand
the frequency of cardiovascular and other serious adverse effects (SAEs) due to the used of the
rofecoxib (Vioxx). In order to perform the study, the researchers researched all the adverse
events involving the use of the rofecoxib (Vioxx) in the Adverse Event Reporting System
(AERS). The researchers found 31,024 cases of adverse events concerning the use of the
rofecoxib. When these cases were divided, it was seen that there were 3915 cases of hemorrhage,
3677 cases of edema, 1653 cases of mortality, 1917 cases of thrombosis and 233 cases of
embolism. Thus, the researchers concluded that the use of rofecoxib not only had cases of heart
attack and stroke but also caused hemorrhage, edema and other adverse events.
On 27th September, executives of Merck Research Laboratories, Dr. Kim and outside
experts decided to withdraw the drug from the market. On 30th September 2004, Raymond
Gilmartin, Merck’s CEO announced the withdrawing of the popular painkiller used for arthritis,

4LITERATURE REVIEW
Vioxx from the worldwide market. When the medicine was being withdrawn around 2 million
people were using Vioxx. Meanwhile the release of the drug in 1999, further 100 million
prescriptions for the Vioxx had already been released (O'Rourke, 2006). According to the report
of Rourke, the clinical results of the Merck & Co. showed that the availability of two additional
challenging Cox-2 inhibitors, Pfizer’s Celebrex and Bextra , were the major reasons that enabled
Merck’s final choice to pull Vioxx from the market.
In the study of Vioxx Gastrointestinal Outcomes Research (VIGOR) Merck found similar
type of results which they found earlier in their clinical results. Merck & Co. submitted the
results in 2000 to the FDA. In the study of Vioxx Gastrointestinal Outcomes Research, the
researchers involved 8000 patients (Krumholz, Ross, Presler & Egilman, 2007). The researchers
found an elevated increase in chance of stroke and heart attacks in the Vioxx users compared to
that of the naproxen users. Both the clinical results of Merck & Co. and the results produced by
the VIGOR forced the FDA to take strict actions against Merck organization and suggested them
to incorporate labeling amendments about the amplified risk of stroke and heart attacks in April
2002. The reasons that FDA had to consider a label amendment because of the devastating
number of information demonstrated the threats regarding the use of Vioxx have caused major
concern for Merck and Vioxx users (Krumholz, Ross, Presler & Egilman, 2007).
After the withdrawal, it was found out that FDA was conducting another research that
proved that the previous findings about its effect on cardiovascular health was true. One of the
analyst of FDA estimated according to his mathematical model that Vioxx might be the reason
for 88,000 to 139,000 numbers of heart attack and 30% to 40% of them might have led to death
when the medicine was circulating all over the market. There were criticisms for this
mathematical model because it was not concrete and should have been considered with caution

5LITERATURE REVIEW
(O'Rourke, J. S, 2006). The medical journal known as Lancet published a meta-analysis of the
previous researchers about the safety of rofecoxib by Juni et al on November 5, 2004. The
authors in this study concluded that Vioxx should have been removed from the market several
years back for the safety of cardiovascular risk. An editorial was published by Lancet that
implicated a controversy theory about Merck and FDA. It condemned the availability of this
medicine from 2000, which was allowed by Merck and FDA. The response for this allegation
was a rebuttal by Merck that was a meta-analysis by Juni et al, which showed that many studies
were omitted about no increased cardiovascular risk.
After a year to this incident, Merck sponsored a Martin report, which was to clear the
image about the company regarding the safety of Vioxx. It showed that the senior management
of Merck acted in a good faith and the reports about the clinical safety of the medicine was due
to the over enthusiastic behavior of the sales team and not due to any malicious practice. The
report displayed the timeline of the all the events that surrounded the withdrawal of this drug and
it also justified that Merck tried its best to conduct all the tests and trials in all honesty. They also
cleared it out that the discrepancies in the handling of the clinical tests about the safety of this
drug was due to manual error and not due to any sinister motive. The conclusion of this report
suggested that the marketing team of Merck exaggerated about the safety of Vioxx and the
essential information about the fatality of the drug was hidden through sales tactics (Dieppe et
al., 2004).
Conclusion
Thus, it can be concluded that even though the drug had a serious impact on the number
of patients causing them several issues, withdrawal and adverse effects caused by the drug also

6LITERATURE REVIEW
had an impact on the Merck & Co. organization. Withdrawal of the Vioxx gave several
important lessons to the company, making them aware, that the next time they develop a drug,
they should consider long-term view, even if there are pressures, it is necessary to believe in their
decisions and believe the employees.

7LITERATURE REVIEW
References
Bottone Jr, F. G., & Barry, W. T. (2009). Postmarketing surveillance of serious adverse events
associated with the use of rofecoxib from 1999–2002. Current medical research and
opinion, 25(6), 1535-1550.
Dieppe, P. A., Ebrahim, S., Martin, R. M., & Jüni, P. (2004). Lessons from the withdrawal of
rofecoxib.
Enthoven, W. T., Roelofs, P. D., Deyo, R. A., van Tulder, M. W., & Koes, B. W. (2016). Non‐
steroidal anti‐inflammatory drugs for chronic low back pain. Cochrane Database of
Systematic Reviews, (2).
Garrison Jr, L. P., Towse, A., & Bresnahan, B. W. (2007). Assessing a structured, quantitative
health outcomes approach to drug risk-benefit analysis. Health Affairs, 26(3), 684-695.
Heller, S. R., McNaught, A., Pletnev, I., Stein, S., & Tchekhovskoi, D. (2015). InChI, the
IUPAC international chemical identifier. Journal of cheminformatics, 7(1), 23.
Krumholz, H. M., Ross, J. S., Presler, A. H., & Egilman, D. S. (2007). What have we learnt from
Vioxx?. Bmj, 334(7585), 120-123.
O'Rourke, J. S. (2006). Merck & Co. Inc.: communication lessons from the withdrawal of
Vioxx. Journal of Business Strategy.
U.S. Food and Drug Administration. (2020). VIOXX® (rofecoxib tablets and oral suspension) -
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL

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