Vioxx Recall Timeline
What Merck Knew About Vioxx Side Effects
1. In a Nov. 21, 1996, memo by a Merck official, it shows the company wrestling with the issue of Vioxx's (Rofecoxib) involvement in increased cardiovascular events. Merck wanted to conduct a trial
to prove Vioxx was gentler on the stomach than older painkillers. But to show the difference most clearly, the Vioxx patients couldn't take any aspirin. In such a trial, "there is a substantial
chance that significantly higher rates" of cardiovascular problems would be seen in the Vioxx group, the memo said.
2. On February 25, 1997, an internal Merck e-mail warns that if a proposed Merck trial was carried out "you will get more thrombotic events" - more blood clots - "and kill [the] drug." In response,
Alise Reicin, now a Merck vice president for clinical research said in an e-mail that the company was in a "no-win situation." She went on to propose that people with high risk of cardiovascular
problems be kept out of the study so the difference in the rate of cardiovascular problems between the Vioxx patients and the others "would not be evident."
3. On November 23, 1998, Merck submitted its New Drug Application (NDA) to the U.S. Food and Drug Administration.
4. On April 20, 1999, the Advisory Committee on Arthritis Drugs (FDA) met to review Vioxx.
5. The FDA approved Vioxx on May 20, 1999 for the use for the management of acute pain in adults and for relief of the signs and symptoms of osteoarthritis. (The original safety database included
approximately 5,000 patients on Vioxx and did not, according to Merck, show an increased risk of heart attack or stroke).
6. On November 18, 1999, a meeting of the Data and Safety Monitoring Board (DSMB) concerning the Vioxx/VIGOR study (in which all voting members of the committee were to be independent from Merck),
took place where they discussed their concerns of the "excess deaths and cardiovascular adverse experiences" that was observed in the group using Vioxx as compared to the patients taking
Naproxen.
7. On March 9, 2000, Merck's research chief, Edward Scolnick, e-mailed colleagues that the cardiovascular events "are clearly there" and stated "it is a shame but it is a low incidence and it is
mechanism based as we worried it was." Worried about the affect on Vioxx, Dr. Scolnick wrote that he wanted other data available before the results were presented publicly, so "it is clear to the
world that this" was an effect of the entire Cox-2 class, not just Vioxx. But the company's public statements that same month, after Dr. Scolnick's e-mail, continued to reject the link between Vioxx
and increased intrinsic risk. Needless to say, Merck made no mention that the study found a "mechanism based" connection between Vioxx and the statistically significant increase in cardiovascular
events.
8. On March 17, 2000, Merck updated the label by adding reported in the "adverse events" section of the label certain "cardiovascular" reports.
9. In June of 2000 there was information presented at the European United League against Rheumatism, (Merck is a member and a corporate sponsor of this organization) that demonstrated a statistically
significant increase in hypertension and myocardial infarction.
10. The VIGOR study, submitted to the FDA in June 2000 (VIGOR - Vioxx® Gastrointestinal Outcomes Research which is the same study that gave rise to the memo of Dr. Targum, referred to below)
sponsored by Merck, was submitted to the FDA in June 2000. The study was primarily designed to look at the effects of Vioxx on side effects such as stomach ulcers and bleeding. This study showed that
patients taking Vioxx had fewer stomach ulcers and bleeding than patients taking another drug, Naproxen. However, this study revealed a statistically significant increase in the number of
cardiovascular events (over 100% increase), myocardial infarctions/heart attacks (approx. 400% increase) and strokes in patients who have taken Vioxx compared to those receiving Naproxen.
11. The VIGOR study was published in the November 2000 issue of the New England Journal of Medicine. Needless to say, the article didn't provide detailed information about other serious
cardiovascular complications such as strokes or blood clots.
12. On February 1, 2001, a memo was prepared by Dr. Shari L. Targum, an employee at the FDA, a Medical Officer, Division of Cardio-Renal Drug Products (and a graduate from Bronx High School of
Science and NYU School of Medicine), had, as one of her responsibilities, the review of the data concerning Vioxx. The memo documented the serious cardiac events and myocardial infarctions and
related deaths for participants in the study who were using Vioxx. These ADE's were being found in the early stages of the VIGOR study. In her memo, she indicates that as early as November 18, 1999,
at a meeting of the Data and Safety Monitoring Board (DSMB) concerning the Vioxx/VIGOR study (in which all voting members of the committee were to be independent from Merck), a discussion took place
concerning the "excess deaths and cardiovascular adverse experiences" in the group using Vioxx as compared to the patients taking Naproxen. (see # 5, above)
13. On February 8, 2001, at an FDA Arthritis Advisory Committee Meeting, the VIGOR study (sponsored by Merck) was discussed. The FDA Arthritis Advisory Committee met to discuss the side effects such
as stomach ulcers and bleeding that the VIGOR study was intended to study. The committee then turned their concern to the unexpected findings of cardiovascular risks and myocardial infarctions
associated with the use of Vioxx that was disclosed in the VIGOR study. It is important to note that the purpose of the VIGOR study was an attempt by Merck to do away with usual NSAID
gastrointestinal warnings on Vioxx. There were no cardiac endpoints assessed in the VIGOR study. As a result of this meeting, despite Merck's claim that Vioxx would have the same GI problems as
general NSAIDs, the Food & Drug Administration, required Merck to carry the same GI warnings as general NSAIDs. It had been a major marketing tool for Merck to claim that Vioxx does not cause the
same GI problems as do other NSAIDs. Merck eventually was required (April, 2002) to add some of the data as to cardiovascular events to their label.
14. In February, 2001, a letter was written by a Dr. James Fries, senior professor and medical doctor from Stamford University Medical School to Merck complaining about the intimidation by Merck's
investigators including the threatening of the loss of funding because of the school's discussion of cardio-vascular events associated with Vioxx.
15. In 2001, the concerns arising out of the VIGOR study were crystallized by Debabrata Mukherjee, Steven Nissen, and Eric Topol in JAMA in their review paper specifically highlighting the
cardiovascular side-effect profile of COX-2 inhibitors.
16. On May 22, 2001, despite the mounting evidence of the strong association of Vioxx to strokes and heart attacks, Merck issued a press release entitled "Merck Confirms Favorable Cardiovascular
Safety Profile of Vioxx", claiming Vioxx has a "… favorable cardiovascular safety profile"
17. On June 16, 2001 Merck issued another press release (released in Europe), entitled "Vioxx Similar to Placebo and Three (3) Widely Prescribed NSAID's Regarding Cardiovascular Events".
18. On July 11, 2001, Merck modified the package insert for Vioxx.
19. On August 22, 2001, a study published in Journal of the American Medical Association by Drs. Mukherjee, Nissen, and Topol, researchers from the Cleveland Clinic, indicated that Vioxx was linked
to a 200% increase in blood clots, heart attacks and strokes based on their review of previous clinical trials.
20. In September 2001, the American Heart Association, the National Stroke Association and the Arthritis Foundation asked Merck to test whether Vioxx increased the risk of heart attack and stroke.
After it reviewed all of its Vioxx studies, Merck claimed there was no evidence that, in comparison with other NSAIDs, the drug increased the risk of heart problems. Merck attributed the difference
to a heart-protective effect it said the other drug had.
21. Sometime in this time period, Merck published training materials to be used by their sales rep's, one was entitled "Dodge Ball Vioxx". Each of the 1st 12 pages lists a scenario that maybe posed
by a physicians questions or concerns. Each of the last four pages contain a single word in capital letters "DODGE!" clearly indicating that Merck was training its sales reps to "dodge" the tough
questions and concerns of the physicians regarding the cardiovascular risks that had started to make its way into publications.
22. On September 17, 2001 the FDA sent Merck a very seriously worded "Warning Letter". The FDA was obviously very upset with Merck for minimizing the potentially serious cardiovascular risks of Vioxx
disclosed by the VIGOR trial and for Merck's promoting Vioxx for unapproved uses. The letter demanding that Merck discontinue promoting Vioxx to doctors for unofficial uses, found after a review of
several of Merck's promotional conference calls and sales pitches, that the promotions by Merck "are false, lacking in fair balance, or otherwise in misleading in violation of the Federal Food, Drug,
and Cosmetic Act (the Act) and applicable regulations," wrote Thomas W. Abrams, the director of the FDA's division of Drug Marketing, Advertising and Communications. It also required Merck to send
letters about the deception to the medical community.
23. On April 11, 2002 the FDA instructed Merck to include in the package insert certain precautions based on results of the VIGOR studies regarding a higher cumulative rate of serious cardiovascular
thromboembolic adverse events (such as heart attacks, angina pectoris, and peripheral vascular events).
24. On April 11, 2002 Merck announced that it had added rheumatoid arthritis to the list of approved uses for Vioxx.
25. In August of 2002, Dr. Topol and Dr. Falk, a Cleveland Clinic gastroenterologist, published an editorial in The Lancet, encouraging further warnings and labeling regarding the cardiovascular
effects of Cox-2 drugs.
However, even following these warnings, and in the face of mounting evidence for the cardiovascular side-effects of Vioxx, aggressive direct-to-consumer marketing of this questionable drug continued
unabated.
26. On April 14, 2004, a study sponsored and conducted by Merck and Harvard Medical School and published in the journal Circulation, the researchers found an elevated risk of acute myocardial
infarction associated with Vioxx but not with Celebrex. The risk was statistically significant in persons taking greater than 25 mg of Vioxx, was elevated during the first 90 days of exposure but not
thereafter. These results were observed consistently in relation to several reference groups studied. What was especially noteworthy was that the elevation of relative risk was similar when Vioxx was
compared with patients not taking any NSAID (Non-steroidal anti-inflammatory drugs), naproxen (e.g. Naprosyn, Aleve) or ibuprofen (e.g. Advil, Nuprin, Motrin). Merck asked the researchers to delete
or tone down the part of the statement about this no-painkiller group, but the researchers refused, according to Daniel Solomon, a Brigham and Women's Hospital - Harvard professor who was the lead
author. "We made a decision that we should let the science rule the day," he says (WSJ, 11/01/04, page A1). Just before the paper was published in Circulation (the journal of the American Heart
Association), dated May 4, 2004, Merck removed the name of a key researcher, Carolyn C. Cunnuscio, from the study who was employed by Merck and who had worked on the study. Upon learning that Merck
had removed their employee's name from the Circulation article, the current JAMA editor, Catherine DeAngelis expressed her disappointment, and rounded-off her comments by saying "Aren't they seeking
truth?"
27. In a May 14, 2002 e-mail, Ann Trontell, FDA deputy drug safety director, warned colleagues that a Merck official had reminded her that "there had been an agreement that Merck would be informed
prior to any FDA publication about one of their drug products".
28. On August 12 2004, On Aug. 12, Anne Trontell wrote in an e-mail to another official that the study's recommendation was "unnecessary and particularly problematic" because FDA funded the study and
Graham (David Graham, an Associate Director for Science in FDA Drug Center's Office of Drug Safety and the FDA officer in charge of the report) also might be asked to present "alternative FDA
opinion" on the drug, She added that Merck should be notified about the study results before they became public "so they can be prepared for extensive media attention that this will likely provoke"
.
29. On August 13, 2004, John Jenkins, director of FDA's office of new drugs, wrote that Graham's conclusion uses "pretty strong language since, to my knowledge, FDA is not contemplating such a
warning or labeling." Jenkins suggested that the conclusion be changed to read, "[T]his and other studies suggest an increased risk of AMI (acute myocardial infarction, or heart attack) with Vioxx
use and should be considered by prescribers when making individual treatment decisions"
30. Shortly thereafter, Graham responded in an e-mail response to supervisors, "I've gone about as far as I can without compromising my deeply held conclusions about this safety question. I've also
shared with you the perspectives of my co-authors, and I think it's safe to say they share these same conclusions"
31. On August 25, 2004, at a medical/pharmaceutical conference in Bordeaux, France, at the annual meeting of The International Society for Pharmacoepidemiology, David Graham, an Associate Director
for Science in FDA Drug Center's Office of Drug Safety and the FDA officer in charge of the report, presented new data from a trial sponsored by the Food and Drug Administration indicate patients
administered Vioxx 25 mg or more per day have a risk of experiencing an acute myocardial infarction (AMI) or sudden cardiac death that is more than three times that of remote non-steroidal
anti-inflammatory drug users. Researchers analyzed data from a subset of Kaiser Permanente patients, aged 18 to 84 years, who were treated with a COX-2-selective or NSAID (Non-steroidal
anti-inflammatory drugs) between Jan. 1, 1999, and Dec. 31, 2001. Patients were enrolled in the study beginning with their first prescription and followed until the end of the study period,
withdrawal from the study, AMI or death. In the trial, approximately 1.4 million patients contributed 2.3 million person-years of observation time. The study population included 40,405 patients
administered Celebrex and 26,748 Vioxx recipients. Overall, there were 8,199 acute cardiac events, including 6,675 AMI cases and 1,524 cases of sudden cardiac death observed during the trial. Results
showed that treatment with Vioxx 25 mg/day or more conferred a 3.15-fold greater risk of AMI or sudden cardiac death (it's really higher but that's another story) compared with "remote use of any
NSAID." Such a risk was also observed with lower doses of Vioxx (less than 25 mg/d), but did not achieve statistical significance.
32. On September 8th, Vioxx received approval from the FDA for the relief of the signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) in children two years and older and who weigh at least 22
pounds.
33. What then finally tipped the balance in the risk-benefit equation leading to the September 30th, 2004 dramatic global withdrawal of Vioxx was the APPROVe study (Adenomatous Polyp Prevention
Vioxx®) which was a multi-centre, randomized, placebo-controlled, double-blind study investigating the effects of Vioxx on the recurrence of neoplastic large bowel polyps in 2600 patients with a
previous history of colorectal adenoma. The study participants were screened so that anyone with a history of heart disease was screened out. On September 14, 2004, the Data and Safety Monitoring
Board received the data that eventually lead to the September 30th withdrawal. The polyp study was stopped prematurely on the suggestion of the Data and Safety Monitoring Board and a Merck
statistician (James Neaton) after the investigators, who had access to all of the data, found that after 18 months treatment, patients taking Vioxx had twice the risk of a myocardial infarction
compared with those receiving placebo.
34. On September 17th, Neaton, the Merck statistician and the four safety committee members had a conference call with John Baron who was the principal investigator of the polyp study and some other
Merck officials. After the Merck officials and Baron left the call, the four safety committee members agreed that the study had to be stopped. Neaton then called John Baron and explained to him the
committee's decision. After reviewing the data that the decision was based on, Baron concurred.
35. Baron then took the next week to meet with the people at Merck including the steering committee, to explain to them the decision that both the committee and he arrived at, that is halting the
polyp trial.
36. On September 23rd, the full steering committee agreed to the halting of the polyp trial. Baron then advised Merck that same day that Vioxx presented an unacceptable risk of a cardiovascular
event.
37. Baron spent the next few days presenting the data and the conclusions to other experts in and outside of Merck.
38. Merck also spent the next few days reviewing all of the data from the polyp study.
39. On September 27th, the ranking officers at Merck decided that Vioxx needed to be withdrawn. However, the decision was made to take this decision to the board of directors.
40. Merck's board of directors met on September 28th. About this time, Merck notified the FDA that they needed to have an emergency meeting with them that afternoon informing them of Merck's decision
to withdraw the drug.
41. On September 29th, Merck informed there international affiliates of their decision and asked them to withhold informing the regulators in their jurisdiction until the information was made
public.
42. On September 30, 2004 at 9:00am Eastern Standard Time, Merck & Co., Inc., the manufacturer of Vioxx, announced a voluntary withdrawal of the arthritis and pain relief drug from the worldwide
drug market, after results from a major clinical trial sponsored by Merck that tracked 2,600 patients for almost 3 years, indicated that Vioxx users may have an increased risk of suffering a heart
attack, stroke, or other cardiovascular event. Merck's action was not ordered by the U.S. Food and Drug Administration (FDA), but was initiated by Merck based on its own findings from the clinical
trial.
43. Senate Finance Committee Chair Chuck Grassley (R-Iowa) started an investigation into the FDA. On October 7th, Grassley compared Graham's experience to that of Andrew Mosholder, another FDA
scientist whose research on the link between antidepressants and suicidality in children faced from superiors at the agency. "Dr. Graham described an environment where he was 'ostracized,' 'subjected
to veiled threats' and 'intimidation,'" Grassley said in a statement after committee investigators interviewed the researcher. He added, "Merck knew it had trouble on its hands and took action. At
the same time, instead of acting as a public watchdog, [FDA] was busy challenging its own expert and calling his work 'scientific rumor.'" The Senate Finance Committee is one of three congressional
committees examining FDA's actions. In addition, the Government Accountability Office has expanded its investigation of FDA's conduct in regard to Mosholder and the risks of antidepressants to
include its handling of Vioxx studies.
44. On November 2, 2004, the FDA posted an abridged version of study conducted by Dr. David J. Graham, associate director for science in the FDA's office of drug safety. The report, dated September
30, 2004 (the same day Merck withdrew Vioxx from the market) t builds upon research that he presented at a medical conference in France in late August (referred to above). "Rofecoxib [Vioxx]
increases the risk of serious coronary heart disease as defined by acute myocardial infarction [heart attack] and sudden cardiac death," Graham's report said. Rofecoxib is the scientific name for
Vioxx. Graham defined a high dose of Vioxx as more than 25 milligrams; a standard dose is equal to or less than 25 milligrams. The study, posted Tuesday, says the recently withdrawn Vioxx increased
by 3.7-fold the risk of "serious coronary heart disease" when compared to Pfizer's Celebrex. The study also says a standard dose of Vioxx increased the cardiovascular risk by 1.5 times over Celebrex.
"The population impact of rofecoxib's increased risk is great because of the widespread exposure to the drug," said Graham.
45. On November 5, 2004, a major study was published in The Lancet, a well regarded British medical journal. The researchers' pooled data from more than 25,000 patients who participated in 18
clinical trials and 11 observational studies all conducted before 2001. The results of this study demonstrated that patients taking Vioxx had 2.3 times the risk of heart attack as those prescribed
placebos or other NSAIDs. In addition, the researchers found an increased risk of myocardial infarction involving both short-term and long-term usage concluding that patients taking Vioxx for only a
few months were also at risk. The researchers specifically refuted Merck's position that there is no excess risk in the first 18 months of using Vioxx. In addition, the researchers also refuted
Merck's contention that cardio-vascular involvement was dose-dependent. As to Merck's contention that in their VIGOR Study, Naproxen was cardio-protective and, therefore, influenced the outcome,
these researchers found that if such evidence does exist, its effect is so small that it is not justified to claim Naproxen as a factor in the findings of the VIGOR Study. In concluding their
findings, the researchers stated that "If Merck's statement in their recent press release that 'given the availability of alternative therapies, and the questions raised by the data, we conclude that
a voluntary withdrawal is the responsible course to take.' was appropriate in September, 2004, then the same statement could and should have been made several years earlier, when the data summarized
here first became available. Instead, Merck continued to market the safety of Rofecoxib. This clearly demonstrated that Merck had, by the end of 2000, sufficient statistically significant information
that required the immediate withdrawal of Vioxx from its world-wide market.
46. Accompanying the study published in The Lancet on November 5, 2004 was an editorial that was even more damning than the study. Referring to the findings of the study, the editorial states "This
discovery points to astonishing failures in Merck's internal systems of post marketing surveillance, as well as to lethal weaknesses in the Food and Drug Administration's Regulatory Oversight . . .
The evidence showing that Vioxx caused significant adverse events was apparent well before data from the APPROVe trial triggered Merck's overdue intervention. This week's report by Peter Juni and
colleagues will add significant weight to on-going litigation by patients who believe they were harmed by this drug." The editorial went on to find "But, too often, the FDA saw and continues to see
the pharmaceutical industry as its customer - a source of funding for its activities - and not as a sector of society in need of strong regulation. Worse still, the FDA's Office of Drug Safety
co-exists in the same centre - the Centre for Drug Evaluation and Research (CDER) - as the Office of New Drugs, the part of the agency that works most closely with the industry to license new
medicines. Once a licensing approval has been made, it is naturally in CDER's own interest to stand by its original decision. CDER's reputation would be damaged if its licensing judgments were
constantly challenged by its own staff. This understandable, by dangerous tendency, to discourage dissent makes the Office of Drug Safety, which sits lower in the hierarchy of CDER than the Office of
New Drugs, weak and ineffective. The inherent precedence that licensing of new drugs takes over safety evaluation is a serious flaw in the FDA's complex regulatory structure. In a final blow to the
FDA's most recent release of the study by Dr. David Graham on November 2, 2004, the editorial states ". . . the FDA tried to shore up its tarnished reputation by posting on its website an early
version of a recently completed observational study into the safety of Vioxx. The report comes with a warning that it has 'not been fully evaluated by the FDA and may not reflect the official views
of the agency'. The FDA investigation estimated that over 27000 excess cases of acute myocardial infarction and sudden cardiac death occurred in the USA between 1999 and 2003. 'These cases' they
write, 'would have been avoided had celecoxib been used instead of Rofecoxib'. . . It is unclear why the FDA could not have waited for the fully evaluated report to have been scrutinized, revised,
and published according to the norms of scientific peer review. Bypassing independent peer review smacks of panic in the FDA, which is under intense reputational pressure. And, yet, its decision to
try to undermine the integrity of its work shows, that the agency's senior management is more concerned with external appearance than rigorous science". And finally, the editorial concludes "…
with Vioxx, Merck and the FDA acted out of ruthless short-sighted and irresponsible self-interest." This is the most condemning editorial in a well-respected medical journal that I have ever seen in
my entire two plus decades of the practice of law.
NOTE: It also turns out that Vioxx, despite the slick TV and magazine ads, has not been shown to be significantly more effective than the much cheaper non-prescription anti-inflammatories such as
Tylenol and Advil.
Lancet Says Vioxx Should Have Been Recalled in 2000
Documents May Show Merck Knew About Vioxx Side Effects
