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Vioxx_sales.inddWhen Drug Sales and Science Collide*
Elizabeth McCain, Biology, Muhlenberg College, Allentown, PA
Karin Grimnes, Biology, Alma College, Alma, MI
Cindy Trussell, Natural Sciences, Kodiak College—UAA, Kodiak, AK
Part I—February 2001
One early morning a young husband and wife, Jeﬀ and Leslie, were briskly walking around their neighborhood in Chapel Hill, North Carolina, before they headed oﬀ to work.
“I can’t believe how much better my stomach and arthritic knees have felt since I started taking Vioxx®,” Leslie said as they ﬁ nished their ﬁ rst mile.
“It’s amazing how well it has worked, and without that awful upset stomach,” said Jeﬀ .
Jeﬀ , too, had been reﬂ ecting on how much more energetic and upbeat Leslie had been lately, pleased that “his” company’s new drug was working so well for her. Jeﬀ had just been hired by Merck as a pharmaceutical representative (salesperson) and couldn’t believe how lucky he was to have been placed on the Vioxx (chemical name, rofecoxib) account. It had been less than two years since Vioxx had been approved by the FDA and it was now considered Merck’s latest wonder drug.
Vioxx is known as a speciﬁ c non-steroidal anti-inﬂ ammatory drug (NSAID), which has the ability to reduce pain but without the more severe gastrointestinal side eﬀ ects attributed to the non-speciﬁ c NSAIDs like ibuprofen, diclofenac, nabumetone, and naproxen (brand name Aleve®). So, over a year ago, when Leslie was taking naproxen, her doctor was not surprised that Leslie had chronic stomach upset, although her arthritic symptoms had been signiﬁ cantly reduced.
When Jeﬀ got to work that morning, he continued to sort through what he was given on his ﬁ rst day, looking for any informational material he could provide to his clients. One marketing pamphlet, called “Th drug representatives could show the card to (but not leave it with) doctors who asked questions speciﬁ cally about Vioxx and its possible association with myocardial infarctions (MIs or heart attacks), CVAs (strokes or cerebral hemorrhages), or TIAs (mini-strokes). Jeﬀ wasn’t aware that Vioxx had any cardiac or circulatory side eﬀ ects and read the information (see next page) with interest, thinking of Leslie even though she currently had no other medical conditions beside arthritis.
is case study was inspired by actual events that took place in February, , concerning Merck & Co., Inc. and Vioxx which have been widely reported in mainstream media and scientiﬁ c literature. However, the precise scenario presented here is a work of ﬁ ction and solely the creation of the authors. Fictional elements include the characters Jeﬀ , Leslie, and Dr. Sara, as well as their statements, thoughts, and actions. Th ese characters and the resulting storyline have been introduced merely as a pedagogical aid to students as they examine excerpts from actual documents and data identiﬁ ed throughout the case. Every eﬀ ort was made to portray the scientiﬁ c issues precisely and accurately. Vioxx is a registered trademark of Merck & Co., Inc. Aleve is a registered trademark of Bayer Corporation. Title image credit: photo Ken Hurst/Fotolia.com.
“When Drug Sales and Science Collide” by McCain, Grimnes & Trussell CARDIOVASCULAR EVENT PROFILE
Cardiovascular thromboembolic adverse events in OA clinical trials†,1
e overall incidence of cardiovascular thromboembolic adverse events was assessed. Th included events pertaining to cardiac (i.e., MI, angina), central nervous (i.e., CVA, TIA), and peripheral vascular (i.e., arterial embolism) systems.
• Due to the variable duration of treatment in the studies, results are expressed as events per romboembolic Adverse Events per Patient-Years **MI, cerebrovascular accident (CVA), transient ischemic attack (TIA), and angina e incidence of events was similar among the groups.
*Recommended dosing in OA: Th
e recommended dose of VIOXX is . mg once daily. Some patients may receive beneﬁ t by increasing the dose to mg once daily. Th e above is an excerpt from a tri-fold marketing pamphlet called the “Th Questions
. What is the advantage of Vioxx, in terms of side eﬀ ects, over the naproxen Leslie was previously taking? . Deﬁ ne and describe the purpose of a placebo and a control group in an experimental design.
. What types of medical conditions are included as a cardiovascular thromboembolic adverse (CTA) event? . According to the table of data, how does the incidence of CTA events with Vioxx compare to the other . What do you know about the source of these data? . Based on these data, what should Jeﬀ tell his wife when he goes home? “When Drug Sales and Science Collide” by McCain, Grimnes & Trussell Part II—The VIGOR Study
at afternoon, Jeﬀ made his ﬁ rst visit to Dr. Sara’s clinic to drop oﬀ Vioxx pens and bring lunch from the Dr. Sara said, “I’m glad that you’re here. I’ve been so pleased with Vioxx for my arthritis patients. I ﬁ nally got a chance to look at the Merck-funded publication by the VIGOR study group. Th what I’ve seen in my patients! So many fewer are complaining of stomach upset or have had ulcers since I e doctor pulled out the November New England Journal of Medicine article entitled “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis” and pointed to Figure . As Jeﬀ looked it over, he wasn’t surprised that the graph conﬁ rmed what he had already learned about Vioxx (rofecoxib) in his short time at Merck.
Figure 1. Cumulative Incidence of the Primary End Point of a Conﬁ rmed Upper Gastrointestinal Event among All Randomized Patients.
Source: Bombardier, C., L. Laine, A. Reicin, et al. . Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. :–. Copyright Questions
. What information is on the y-axis? Express this in your own words, being sure to deﬁ ne “Cumulative . What information is on the x-axis? Express this in your own words.
. What do you think is a “gastrointestinal event?” . Suggest why these gastrointestinal event data would make Dr. Sara pleased with Vioxx.
“When Drug Sales and Science Collide” by McCain, Grimnes & Trussell Part III— An Inconsistency?
Dr. Sara continued: “I have one concern, though. I wasn’t aware that there was a risk of heart attack for my patients on Vioxx. Look here on the fourth page of the article: ‘Myocardial infarctions were less common in the naproxen group than in the rofecoxib group (. percent vs. . percent …).’ Th Jeﬀ was perplexed by what Dr. Sara had just said. He recalled the Cardiovascular Card he had read that morning suggesting that heart attacks and strokes were no more frequent in patients on Vioxx than those taking a placebo or non-speciﬁ c NSAIDs.
. Reexamine the table of data on the Cardiovascular Card. Can you determine the incidence of myocardial infarctions (heart attacks) with Vioxx or any of the treatments? Explain your answer.
e Cardiovascular Card was printed several months before the VIGOR study was published but after the study was complete. What are some possible explanations for why Merck did not directly refer to the . In the VIGOR study, with a total of about , participants, .% ( out of ~, subjects) on naproxen experienced myocardial infarctions compared to .% ( out of ~, subjects) on rofecoxib or Vioxx. Explain whether or not you think this is a meaningful diﬀ erence.
. It has been estimated that million people worldwide took Vioxx before it was removed from the market. Predict how many of these Vioxx patients could have experienced myocardial infarctions. Does this calculation change your interpretation of whether or not this is a meaningful diﬀ erence? . One piece of information the VIGOR study does not provide is the heart attack rate of a control group in a population similar to the one that was in this study (+ years of age, not morbidly obese, no history of cancer, strokes or heart attacks within past , , or years respectively, and no history of gastrointestinal surgery or inﬂ ammatory bowel disease, to name a few). How does this make it challenging for Jeﬀ to interpret the meaning of the numbers? “When Drug Sales and Science Collide” by McCain, Grimnes & Trussell Part IV—The Internal Bulletin
Dr. Sara then said, “I also heard that Merck reported to the FDA that additional myocardial infarctions (heart attacks) occurred within weeks after the study termination date. How does this change the risk of Jeﬀ was suddenly very concerned that he hadn’t heard of these data. “Let me look into it and I’ll get back to ce, he found a memo in his inbox. As Jeﬀ started to read the bulletin, his heart sank. “How can I work with my physician clients if I can’t talk with them about published data?” As he read the ﬁ nal paragraph more closely, he realized things were more serious than he had thought.
FDA Arthritis Advisory Committee Meeting for VIOXX® All ﬁ eld personnel with responsibility for VIOXX® DO NOT INITIATE DISCUSSIONS ON THE FDA ARTHRITIS ADVISORY COMMITTEE
(ADVISORY COMMITTEE) REVIEW OF THE RESULTS OF THE VIOXX® GI OUTCOMES
RESEARCH (VIGOR) STUDY. YOU MAY RESPOND TO CUSTOMER INQUIRIES ONLY AS
is information is provided for your background information only and is not to be used in
discussions with physicians.
Although the VIGOR study was a GI outcomes study and was not designed to show diﬀ erences in cardiovascular eﬀ ects, signiﬁ cantly fewer heart attacks were observed in patiens taking naproxen (. percent) compared to the group taking Vioxx mg (. percent) in this study. Th diﬀ erence in cardiovascular mortality between the groups treated with Vioxx or naproxen.
Excerpts from Bulletin for Vioxx February , . Full document available at: “When Drug Sales and Science Collide” by McCain, Grimnes & Trussell Questions
. Why do you think Jeﬀ , as a “ﬁ eld personnel with responsibility for Vioxx,” is prohibited from discussing the results of the VIGOR study, the same results published in the New England Journal of Medicine, or the new data provided at the bottom of the memo? . How is the percentage of heart attacks cited in this memo diﬀ erent from the published VIGOR study in the New England Journal of Medicine that Dr. Sara showed him? Give a possible explanation for the percent change in heart attacks between the memo and the published paper. Consider what Dr. Sara told . Assuming million people have taken Vioxx, calculate how many more people would suﬀ er from heart attacks while on Vioxx with the percentage presented in the bulletin. Do you think this number represents a real risk to the public? Explain your answer.
. What do you think of the data cited in the very last sentence? How could this be possible, considering the rates of nonfatal heart attacks? Is the risk of Vioxx that serious if the rate of cardiovascular mortality is no greater while on Vioxx than while on naproxen? “When Drug Sales and Science Collide” by McCain, Grimnes & Trussell Part V—Conclusion
. Considering the restrictions outlined in the Merck bulletin, express your opinion about whether or not Jeﬀ should share the information with Dr. Sara about the increased risk of heart attacks you have just calculated. What things might Jeﬀ need to consider? . Do you think Jeﬀ should consider quitting his job at Merck? What is your reasoning? . Discuss what should happen next with Vioxx. Choose the perspective of Jeﬀ , Dr. Sara, or Merck and Fast Forward
FDA asks Merck to include a warning about cardiovascular risks on the Vioxx Merck income estimates for Vioxx at $. billion dollars.
Additional cardiovascular events appear in the APPROVe study.
Merck voluntarily pulls Vioxx from the market amid increasing safety concerns.
Arthritis Advisory Committee and the Drug Safety and Risk Committee of the FDA vote in support of marketing Vioxx in the US ( yes, no votes) with proper labeling and contraindications for patients with heart problems.
First Vioxx lawsuit trial begins in Texas and ends with the jurors awarding $. million dollars to the widow of a man who suﬀ ered a fatal heart attack in Merck admits to error in the data analysis of the APPROVe study (also published in the New England Journal of Medicine). Risk of damage to the heart begins Current lawsuit total stands at over , ﬁ led.
Case copyright by theriginally published // at “When Drug Sales and Science Collide” by McCain, Grimnes & Trussell
Contents of the Nursing Kits NUR-101 Navy Blue Bag (Kit K1219A) Foley Cath Tray Cotton Ball/Hydroge 2 Required Gloves Surgeon LTX Free PF 7.5 4 Required Glasses Safety 1 Required Bag Plastic Drawstring 1 Required Thermometer Kit W/20 Sheaths 1 Required ISO Kit: Latex Free 1 Required Tote Navy Large 1 Required Irrigation Tray Piston S