Marco Acevedo, Andrew Adams, Leah Ali, Safi Ayinde, Loren Ball Ethics Forum: VIOXX Marco Acevedo, Andrew Adams, Leah Ali, Safi Ayinde, Loren Ball Dr. Jeffrey Evanseck June 18, 2013

What is VIOXX? VIOXX is a non-steroidal anti-inflammatory drug (NSAID) that acts as a COX-II inhibitor VIOXX was designed for the relief/treatment of: Osteoarthritis, acute pain in adults, menstrual symptoms, and rheumatoid arthritis It was created by Merck & Co.

Arthritis Types Osteoarthritis: Cause still unknown Currently no cure Most common form of arthritis Chronic condition characterized by the breakdown of the joint cartilage causing pain and stiffness in affected joints Cause still unknown Possible risk factors: increased age, obesity, injury or overuse (Athletes/ jobs with repetitive motion – landscaping or typing), genetics, muscle weakness Currently no cure

Arthritis Types Rheumatoid Arthritis: Is a form of inflammatory, auto-immune based arthritis, leading to a build up of fluid in the joints causing pain and stiffness Symmetrical Nearly 3 times more common in women then men Begins between the ages of 30 and 60 in women Cause is unknown Currently no cure NSAIDs are used to relive symptoms and reduce inflammation.

COX inhibitors Prostaglandins are made by the COX-I and COX-II enzymes Prostaglandins produced via the COX-II enzyme cause pain/swelling/inflammation. Prostaglandins produced via the COX-I enzyme protect the inner lining of the stomach. Traditional NSAIDs block both the COX-I and COX-II enzymes reducing inflammation, but reducing the protection of the stomach lining. Examples: Aspirin, Ibuprofen, Naproxen, Piroxicam, and Nabumetone COX-II inhibitors are NSAIDs that selectively block only the COX-II enzyme Examples: Celebrex, VIOXX(unavailable in the US), and Bextra (unavailable in the US)

Financial Background: Merck was losing patent protection on five of its top selling drugs in 1999 Vasotec, Pepcid, Mevacor, Priloxed, and Prinivil Estimated Development costs - $400 million VIOXX made company $2.5 billion in 2001 alone on average made $2.5 billion per year the drug was on the market best selling drug Merck had produced

VIOXX Timeline: November 1998- Merck requests FDA approval after testing on 5,400 subjects Jan 1999- Merck launches VIGOR (VIOXX gastrointestinal outcomes research) study. Has 8,000 participants with half taking VIOXX and half taking naproxen. Hope is to show that VIOXX is better for digestive system May 1999- VIOXX is approved by the FDA Oct.-November 1999- VIGOR study shows improved gastrointestinal function for the VIOXX but shows small stat that signals for cardiac concern Dec. 1999- VIGOR panel is told that VIOXX doubles cardiac issues compared to the naproxen. Decide to keep product on market and keep study going to decide if VIOXX is the cause or if naproxen is preventing March 2000- Merck is given the VIGOR trial results Merck’s research chief writes email suggesting that if the cardiovascular risks of VIOXX are to be published, it is to indicate that the issue is caused by all cox-II inhibitors

VIOXX Timeline: May 2000- Merck submits paper to New England Journal of Medicine not included 3 of the heart attacks that Vioxx patients had July and Nov. 2000- Submits two different corrections to articles, none include the 3 heart attacks Oct. 2000- Merck informs FDA of 3 heart attacks Nov. 2000- VIGOR results published in NEJM with no mention of adverse cardiovascular effects Aug. 2001- outside analysis of VIGOR report suggest doubt that naproxen protects heart Sept. 2004- APPROVe study on colon-polyp prevention suggests increase in heart attacks after 18 months. Vioxx withdrawn from market by Merck March 2006- VIGOR authors state that they did not leave any data our of NEJM as following the studies “prespecified cutoff date”, cutoff date was much earlier than it was for the tests on gastrointestinal problems

Ethical Dilemma: Was Merck’s marketing in which they downplayed the potential cardiovascular issues of VIOXX ethical? Is the common practice of setting data collection windows ethical? Is the exclusion of data occurring past the collection window ethical?

FDA Approval: November 1998: Merck asks the FDA for approval of VIOXX, having tested the drug on 5,400 subjects in eight studies. “Study 090” not published. 1998: Medical researchers at the University of Pennsylvania reported findings that COX-II inhibitors, might interfere with enzymes thought to play key roles in warding off cardiovascular disease. January 1999: Merck launches the VIOXX Gastrointestinal Outcomes Research study (VIGOR). April 1999: VIOXX was taken before the Arthritis Advisory Committee. May 1999: The FDA approves VIOXX, making the drug available by prescription in the United States.

VIGOR Study: The focus was on gastrointestinal side effects. There were 8,076 rheumatoid arthritis patients in 22 countries and 301 centers. It lasted about 9 months. The conclusion of the study is that there is significant gastrointestinal events: Rofecoxib (VIOXX) has a superior gastrointestinal safety profile compared to non-selective NSAIDs. This spawned questions to cardiovascular health/issues with VIOXX.

VIGOR Study: Adverse experiences that were hypertension-related was 0.7% for Rofecoxib (VIOXX) and 0.1% for naproxen. Adverse experiences that were related to congestive heart failure was 0.5% for VIOXX and 0.2% for naproxen. VIOXX had more confirmed cardiovascular events than naproxen. Only four patients taking VIOXX reported a hypertension adverse experience prior to a thrombotic adverse experience. 1 experienced a myocardial infarction. Part of their hypothesis was that their selective COX-II inhibitor (VIOXX) would not inhibit effects on platelets. Part of their conclusions were: COX-II inhibitors do not reduce platelet thromboxane production but reduce systemic prostacyclin synthesis. Solid understanding of GI but the collection and interpretation of CV data was questionable

Post-VIGOR Study: In 2000, they tested an Alzheimer's group. The results showed that the cardiovascular events between the treated group and placebo group were similar. In their cardiovascular safety summary: The risk of cardiovascular events is similar to placebo. Naproxen’s decreased cardiovascular events is consistent with antiplatelet effects. The cardiovascular results are consistent with the COX-II selectivity of VIOXX and its lacking antiplatelet activity. The true CV consequences became clear at this point.

FDA’s Position: FDA ultimately sends a warning letter to Merck regarding their marketing Claimed that they were trying to downplay the risks of heart attack revealed by the VIGOR study The FDA claim there is insufficient data to prove that Naproxen provides a protective effect hypothesis Require a blackbox warning be placed on VIOXX They do not order VIOXX pulled from the market

New England Journal of Medicine: VIGOR study published in NEJM in 2000 Following dispute over unpublished data and removal of VIOXX from the market an “expression of concern” was published by the journal Focused on non-included cardiovascular events that occurred after a predetermined cutoff date In March 2006, VIGOR authors respond defending their study methodology

Payouts: Lawsuit settlements- $4.85 billion Criminal fine of illegally introducing drug to interstate commerce- $321 million Federal government compensation - $426 million State government compensation- $202 million

Current State of VIOXX and COX-II Inhibitors: VIOXX was voluntarily removed from the market in 2004 Celebrex is the only COX-II inhibitor available in the US Many are still available in other regions around the world FDA currently requires “black box” labeling on COX-II inhibitors

Recommendations: FDA modify methods by which scientific research studies incorporate and interpret data Merck should have taken a more neutral stance on the effects of the drug do more studies to have more clarity be careful to not put too much of a positive spin on something they don’t know about Worst case scenario versus best case

References: Abrams, T. W. (2001). Warning letter to merck & co., inc. regarding marketing of vioxx FDA. Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargas, R., Davis, B., . . . Schnitzer, T. J. (2000). Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med, 343(21), 1520-1528. doi:10.1056/NEJM200011233432103 Curfman, G. D., Morrissey, S., & Drazen, J. M. (2006). Expression of concern reaffirmed. N Engl J Med, 354(11), 1193-1193. doi:10.1056/NEJMe068054 Response to expression of concern regarding VIGOR study. (2006). N Engl J Med, 354(11), 1196-1199. doi:10.1056/NEJMc066096 Goldman/Merck Research Laboratories, Bonnie, M.D. VIOXX Gastrointestinal Outcomes Research Trial. Rep. www.fda.gov, Web. 11 June 2013 < Culp, D.R.; Berry, I.; Journal of Civil Rights and Economic Development, Vol. 22, Iss. 1 [2007], Art. 1. Wilson, D.; Merck to Pay $950 Million Over Vioxx. New York Times. [Online] 2011, http://www.nytimes.com/2011/11/23/business/merck-agrees-to-pay-950-million-in-vioxx-case.html?ref=vioxxdrug&_r=0.

References: Bartleby, J. (2006, March 23). Aspirin, ibuprofen, naproxen, acetaminophen: The difference between over-the-counter pain relievers. Retrieved from http://voices.yahoo.com/aspirin-ibuprofen-naproxen-acetaminophen-difference-28909.html Information for healthcare professionals: Celecoxib (marketed as celebrex). (2005, April 7). Retrieved from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm Ogbru, O. (n.d.). Cox-2 inhibitors. Retrieved from http://www.medicinenet.com/cox-2_inhibitors/article.htm Osteoarthritis. (n.d.). Retrieved from http://www.arthritis.org/conditions-treatments/disease-center/osteoarthritis/ Prakash, S., & Valentine, V. (2007, November 10). Timeline: The rise and fall of vioxx. Retrieved from http://www.npr.org/templates/story/story.php?storyId=5470430 Report: Vioxx linked to thousands of deaths. (2004, October 6). Retrieved from http://www.nbcnews.com/id/6192603/ns/health-arthritis/t/report-vioxx-linked-thousands-deaths/

References: Rheumatoid arthritis. (n.d.). Retrieved from http://www.arthritis.org/conditions-treatments/disease-center/rheumatoid-arthritis/ Rubin, R. (2004, October 12). How did vioxx debacle happen?. Retrieved from http://usatoday30.usatoday.com/new/health/2004-10-12-vioxx-cover_x.htm Kweder, Sandra. Testimony of Deputy Director, Office of New Drugs
Center for Drug Evaluation and Research on Vioxx and Drug Safety. U.S. Senate Committee on Finance. U.S. Food and Drug Administration. Prakash, S.; Valentine, V., TImeline: The Rise and Fall of Vioxx, NPR. [Online] 2007. http://www.npr.org/templates/story/story.php?storyId=5470430

Naproxen vs. Aspirin vs. Ibuprofen

Naproxen vs. Aspirin vs. Ibuprofen Aspirin: Pain and inflammation reliever, most common over-the-counter pain reliever rough on the digestive tract bad for people with hemophilia (because it’s an anticoagulant), not always safe for children (linked to Reye’s syndrome) Ibuprofen: In lower doses, seems to irritate the esophagus and stomach lining less than aspirin and naproxen Naproxen: Used for headaches, but especially effective as an anti-inflammatory agent Similar doses of this as compared to other NSAIDs seem to show Naproxen