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:
o Osteoarthritis, acute pain in adults, menstrual symptoms, and
rheumatoid arthritis
• It was created by Merck & Co.
Arthritis Types
• Osteoarthritis:
o Most common form of arthritis
o Chronic condition characterized by the
breakdown of the joint cartilage causing pain
and stiffness in affected joints
• Cause still unknown
o 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:
o Is a form of inflammatory, auto-immune
based arthritis, leading to a build up of fluid in
the joints causing pain and stiffness
o Symmetrical
o Nearly 3 times more common in women then
men
• Begins between the ages of 30 and 60 in women
o Cause is unknown
o 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
o Prostaglandins produced via the COX-II enzyme
cause pain/swelling/inflammation.
o 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.
o Examples: Aspirin, Ibuprofen, Naproxen, Piroxicam, and
Nabumetone
• COX-II inhibitors are NSAIDs that selectively block only
the COX-II enzyme
o 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
o Vasotec, Pepcid, Mevacor, Priloxed, and Prinivil
• Estimated Development costs - $400 million
• VIOXX made company $2.5 billion in 2001
alone
o on average made $2.5 billion per year the drug was on the
market
o 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
o 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?
o 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:
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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
o 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
o 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
o 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
o do more studies to have more clarity
o be careful to not put too much of a positive spin
on something they don’t know about
o Worst case scenario versus best case
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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-topay-950-million-in-vioxx-case.html?ref=vioxxdrug&_r=0.
References:
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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-naproxenacetaminophen-difference-28909.html
Information for healthcare professionals: Celecoxib (marketed as
celebrex). (2005, April 7). Retrieved from
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation
forPatientsandProviders/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/conditionstreatments/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/reportvioxx-linked-thousands-deaths/
References:
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Rheumatoid arthritis. (n.d.). Retrieved from
http://www.arthritis.org/conditions-treatments/diseasecenter/rheumatoid-arthritis/
Rubin, R. (2004, October 12). How did vioxx debacle happen?.
Retrieved from http://usatoday30.usatoday.com/new/health/200410-12-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