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FEATURE: Harlan M Krumholz, Joseph S Ross, Amos H Presler, and David S Egilman What have we learnt from Vioxx? BMJ 2007; 334: 120-123 [Full text]

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A great deal to learn

Radhika Vohra   (20 January 2007)

Some day, we may have to swallow the bitter pill

Rajan TD   (20 January 2007)

Hindsight

zahid bashir   (26 January 2007)

We have not learnt enough

Edward Auersperg   (27 January 2007)

competing toxicity-what about the gut?

Maarten Boers   (31 January 2007)

correction: and what about the gut?

Maarten Boers   (2 February 2007)

Aspirin versus acetaminophen for pain control in patients with cardiovascular and gastrointestinal risk factors

Michal R. Pijak   (6 February 2007)

Assessing adverse events in randomised controlled trials : a challenge for methodologists

Isabelle Pitrou   (23 February 2007)

On Selective Learning

Theordore V.H. Mayer   (24 February 2007)

Re: On Selective Learning

Mark E. McConnell   (16 March 2007)

Re: On Selective Learning

David S. Egilman, Amos H. Presler   (9 April 2007)

A great deal to learn 20 January 2007
Radhika Vohra, Non principal GP Surrey Send response to journal: Re: A great deal to learn	This is a fascinating account of Vioxx and it's pitfall. What concerns me is how many other drugs there may be with serious risks that are unrevealed? Surely, the appraisal, monitoring and regulation of research is under question? Should drug companies be performing research on their own drugs? The scope for conflict of interest and bias is huge. As a GP it makes it difficult to trust studies and reassure patients. A difficult but necessary task. Competing interests: None declared
Some day, we may have to swallow the bitter pill 20 January 2007
Rajan TD, Specialist, Skin & Sex Transm Diseases Consultant, CMPH Med College, Mumbai, India. Tel: 0091-22-66982747 Send response to journal: Re: Some day, we may have to swallow the bitter pill	The Vioxx case has harmed thousands of people across the globe with its adverse cardiovascular events as has been established by published studies. Yet, it has done a world of good to millions of people who have now been saved! The case serves as a stern warning to pharmaceutical companies as well as medical researchers who are launching drugs without adequate safeguards. It is unbelievable that the company did not realise the possibility of adverse cardiovascular effects during the course of the drug's evolution. Krumholz et al have clearly established that critical data on the drug's toxicity was obscured. One hopes that greed does not convert the healthcare industry from being a saviour to a killer. Every practising physician, clinical researcher, medical representative, marketing manager and owner of pharmaceutical companies should constantly remember that each one of them could potentially be at the receiving end of a physician's prescription. Let him not forget that in such a situation he will have little choice but to swallow the bitter pill! Competing interests: None declared
Hindsight 26 January 2007
zahid bashir, SHO bristol royal infirmary BS2 8ED Send response to journal: Re: Hindsight	Hindsight is beautiful thing is it not? The article by Krumholz et is all very well written but we should not forget that medical journals like NEJM and JAMA and Annals of internal medicine should step forward and take their share of blame for publishing these papers and I strongly feel that issuing corrective statement is not enough. As far as I understand, there is a peer review system in place and I seriously hope the people who review these articles are expert in their field and able to spot flaws and loopholes in studies which sound dodgy in their design and analysis of results. There is very little benefit in issuing corrective statement few years down the road when every thing is done and dusted and case almost settled. Medical and research community has to look at itself in this case and share the blame as much as Merck should do. Competing interests: None declared
We have not learnt enough 27 January 2007
Edward Auersperg, Clnical Instructor, University of British Columbia Male Ridge BC V2X 5Z6 Send response to journal: Re: We have not learnt enough	What have we learnt? The pharmaceutical industry knows that we have not learnt enough. Physicians and the lay public have become justifiably suspicious of the COX2's as well as NSAIDs, and desire an alternative. So just this month, a smiling pharmaceutical representative revealed to me the new great hope, lumiracoxib. As evidence, I was presented with a reprint of the Target Trial, a "megatrial" published in a top tier journal (1). I was not shown the accompanying editorial. Although the abstract and the article are strictly correct in stating that an increased risk was not shown, they skillfully neglect to point out that they did not show no difference. This is a subtlety which many busy physicians will overlook. They will also likely overlook the fact that the study was intentionally designed to have too few cardiac events to have a significant likelihood of showing danger. And they will commonly overlook the 95% confidence intervals which show a significant possibility of lumiracoxib inceasing cardiac risk by as much as 8-fold for certain groups. Major journals must do more than provide editorials to counteract the flagrant optimism of clinical trial reports, because too many physicians do not routinely read them. Journals must ensure that the titles and abstracts of articles accurately reflect the reality of what is shown by the data. Actually, we learnt that long ago. It is time for our journals to act accordingly. 1. Farkouh et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004 Aug 21-27;364(9435):675-84. Competing interests: None declared
competing toxicity-what about the gut? 31 January 2007
Maarten Boers, Professor of Clinical Epidemiology and Biostatistics, Rheumatologist VU University Medical Center Amsterdam, Netherlands Send response to journal: Re: competing toxicity-what about the gut?	This article is enlightening in its exposure of Merck policy. However, in the current climate the science is in danger of being forgotten altogether. My view: - all nonsteroidal antiinflammatory drugs (NSAIDs) are 'dangerous' but their main toxicity is in the gut. - in most patients the absolute risk of a cardiovascular event is dwarfed by the risk of an ulcer, bleed or perforation. - patients at high risk of a cardiovascular event should be taking low-dose aspirin, in which case the choice for a selective cox-2 inhibitor (instead of a nonselective NSAID) is probably useless, i.e. will not decrease risk to the gut. - when studied dispassionately and disregarding legal and economic considerations, the evidence for increased cardiovascular risk of rofecoxib, and the level of this increased risk is not strong enough to warrant a retraction of the drug. - If present, the risk is mostly limited to doses above 25 mg/d. - the assessment of benefits and risks of a drug should take place in the target population. Patients with polyposis are not the current target population, hence results from a placebo-controlled trial are not very useful to guide practice, as the target population will most likely be taking an NSAID. Finally, as rheumatologist I am puzzled by the extent of the outrage over 'excess cardiovascular deaths' caused by vioxx, but the shattering silence over the fact that gastroprophylaxis is never on the menu for patients taking low dose aspirin, even though many of these patients can be regarded as having a high gastrointestinal risk profile. I guess the gut is simply less sexy than the heart, and bleeding to death less worrisome than cardiac arrest. Maarten Boers Ref.: Boers M. NSAIDs and selective Cox-2 inhibitors: competition between gastroprotection and cardioprotection. Lancet 2001;357:1222-3. Competing interests: I have been an advisory board member for Pfizer and Novartis in the past
correction: and what about the gut? 2 February 2007
Maarten Boers, Professor of Clinical Epidemiology and Biostatistics, Rheumatologist VU University Medical Center Amsterdam, Netherlands Send response to journal: Re: correction: and what about the gut?	In my previous letter, the third statement was too simple and can be improved: - patients at high risk of a cardiovascular event should be taking low-dose aspirin. When these patients need analgesia there is no real gastrointestinal advantage to choose a selective cox-2 inhibitor above a nonselective NSAID (nsNSAID) plus gastroprotection, i.e. proton pump inhibitor or misoprostol. However, the increasing evidence that some nsNSAID (but not selective cox-2 inhibitors) seriously interfere with aspirin's beneficial effect on platelets has made this setting very complex, and treatment should be assessed on a case-by-case basis. Competing interests: See above
Aspirin versus acetaminophen for pain control in patients with cardiovascular and gastrointestinal risk factors 6 February 2007
Michal R. Pijak, Assistant Professor and Consultant in Internal Medicine, Rheumatology and Clinical Immunology Department of Internal Medicine, Slovak Medical University, Bratislava, Slovak Republic Send response to journal: Re: Aspirin versus acetaminophen for pain control in patients with cardiovascular and gastrointestinal risk factors	I read with great interest the article by Harlan Krumholtz and colleagues enlightening the sad story of Vioxx and what we have learnt from it.(1) This inspired me to add a few words of comment regarding the use of analgesics in patients with cardiovascular (CV) and gastrointestinal (GI) risk factors. In my opinion the rational choice for such patients is the use of aspirin combined with a proton-pump inhibitor. First, both coxibs and traditional NSAIDs should not be prescribed in patients at higher CV risk. On the contrary, there is good evidence that analgesic doses of aspirin (up to 1500mg) are associated with protection from CV events.(2,3) Furthermore, aspirin dose or its higher lifetime use is not significantly associated with hypertension(4) or renal toxicity.(5,6) Importantly, a recent meta- analysis of 24 randomised controlled trials found no evidence of dose- responsiveness for bleeds over a wide range of doses (50 to 1500 mg/day).(7) Indeed, aspirin in doses commonly used in practice, seems to have an excellent safety profile.(8) Second, recent evidence suggest that not only NSAIDs but also acetaminophen can raise cardiovascular risk.(9) High acetaminophen use may also increase the risk of hypertension(4) and a decrease of renal function.(5) Interestingly, increased acetaminophen use has now been linked to increased prevalence of asthma and chronic obstructive pulmonary disease, and with lowered lung function.(10) Surprisingly, a recent case- control study showed that acetaminophen (>2 g per day) was associated with a greater risk of GI perforation or bleed(11) and one cohort study reported a dose-response relationship between acetaminophen and dyspepsia.(12) It appears that regular use of acetaminophen is also associated with symptoms of severe diverticular disease, particularly bleeding.(13) Lastly, compelling evidence suggests that both aspirin and other NSAIDs are superior to acetaminophen for improving moderate-to-severe pain in patients with osteoarthritis(14,15,16) and rheumatoid arthritis.(17) Likewise, in acute pain states aspirin provides significant and more rapid analgesia than acetaminophen.(18) References 1. Krumholz HM, Ross JS, Presler AH, Egilman DS. What have we learnt from Vioxx? BMJ. 2007;334:120-3. 2. Antithrombotic Trialists' Collaboration. Collaborative meta- analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. 3. Johnson ES, Lanes SF, Wentworth CE 3rd, Satterfield MH, Abebe BL, Dicker LW.A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248-53. 4. Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension 2005;46:500-7. 5. Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 2004;164:1519-24. 6. Dubach UC, Rosner B, Sturmer T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987) N Engl J Med 1991;324:155-60. 7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7. 8. Fries JF, Ramey DR, Singh G, Morfeld D, Bloch DA, Raynauld JP. A reevaluation of aspirin therapy in rheumatoid arthritis. Arch Intern Med 1993;153:2465-71. 9. Chan AT, Manson JE, Albert CM, Chae CU, Rexrode KM, Curhan GC, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113:1578-87. 10. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med 2005;171:966-71. 11. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6. 12. Rahme E, Pettitt D, LeLorier J. Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population. Arthritis Rheum 2002;46:3046-54. 13. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255-60. 14. Lee C, Straus WL, Balshaw R, Barlas S, Vogel S, Schnitzer TJ. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta- analysis. Arthritis Rheum 2004;51:746-54. 15. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257. 16. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004;63:901-7. 17. Wienecke T, Gotzsche PC. Paracetamol versus nonsteroidal anti- inflammatory drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2004;(1):CD003789. 18. Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM. An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J 2003;194:153-7. Competing interests: Dr. Pijak has received speaker fees and travel assistance from Fournier.
Assessing adverse events in randomised controlled trials : a challenge for methodologists 23 February 2007
Isabelle Pitrou, MD, Master 2 Methodology for assessing pharmaceutic and non pharmaceutic products Groupe Hospitalier Bichat-Claude Bernard, INSERM U738. 75018 Paris Send response to journal: Re: Assessing adverse events in randomised controlled trials : a challenge for methodologists	I read with great interest the article by Krumholz H. et al. about VIOXX case. As a methodologist, I would be tempted to precise that assessment of benefits and risks in clinical trials is complex and not as easy as it seems : 1. A clinical trial is often designed to assess benefit of a new drug. The study is designed to show a difference for this primary outcome. Then assessment of risk (secondary outcome) can be limited by an inadequate sample size. Statistical power might be insufficient to show a difference in terms of adverse events (AE) : results are not statistically significant for AE even if risk exists. 2. Adverse events when they are unexpected are difficult to isolate in clinical trials. In the case of VIOXX, AE was myocardial infarction (MI). MI is a common event in the general population and was not expected : this increased difficulty to conclude on elevation of risk of MI with rofecoxib. Elevated delays between treatment and AE also made it difficult to conclude : in VIOXX case, IM did not appeared immediately after first intake but months after. 3. Adverse events are often reported for each event individually instead of using composite outcomes that would increase statistical power. Research for improving safety assessment and reporting of AE is still needed. 4. New drugs are tested on selected populations with strict inclusion criteria. After drug approval, real users of the new drug might differ from experimental group. Post-marketing study in “real world” and observational study can be useful for AE monitoring. To finish, the highly covered VIOXX story is not an isolated case. Every year about 2% of drugs are removed from the market (1). Recent examples include diet drugs associated with cardiac valvular disease. Reference 1. Friedman MA, Woodcock J, Lumpkin M, Shuren J, Hass A, Thompson L. The safety of newly approved medicines. Do recent market removals mean there is a problem? JAMA 1999; 28: 1728-34 Competing interests: None declared
On Selective Learning 24 February 2007
Theordore V.H. Mayer, Partner, Hughes Hubbard & Reed LLP One Battery Park Plaza, New York, NY 10004 Send response to journal: Re: On Selective Learning	23 February 2007 Fiona Godlee Editor-in-Chief British Medical Journal Dear Fiona Godlee: The authors of “What have we learnt from Vioxx?” featured in BMJ 2007; 334:120-123 (20 January) refer to their “recent involvement in litigation at the request of plaintiffs” and the “unique opportunity” it presented them to examine and reflect upon court documents, research and other evidence relating to Vioxx. And, suggesting the story to be told was complete and balanced – perhaps even objective – the authors offer to share “important lessons.” But the story they offered sounded surprisingly like an opening statement by plaintiff attorney Mark Lanier, whose picture graced the pages of the BMJ article. Coincidently, the article was published just as Mr. Lanier started his current Vioxx case against Merck & Co., Inc., of Whitehouse Station, N.J., USA – another case in which Dr. Harlan Krumholz was paid to testify for the plaintiff. To be clear about who’s who, I am an attorney representing Merck & Co., Inc. in the Vioxx litigation. As the authors disclosed in the article, all four of the authors have been consultants to plaintiffs’ attorneys in the Vioxx litigation. Dr. Krumholz testified earlier this month for Mr. Lanier in the pending New Jersey Vioxx cases and acknowledged that he and his assistants will be paid roughly $300,000 for the work they have done to date for Vioxx plaintiffs. One of his co- authors, Dr. David Egilman, previously testified as an expert witness against Merck & Co., Inc. in the Vioxx litigation, also for Mark Lanier. Dr. Egilman also served as an expert consultant for plaintiffs in the Zyprexa litigation against Eli Lilly, again in consultation with the Lanier Law Firm, which was founded by Mark Lanier. Despite what the authors claimed was a thorough examination and reflection upon the “accumulated court documents, research and other evidence,” Dr. Krumholz got several important facts wrong and omitted many others from his purported lesson. While this list is not exhaustive, the following warrants correction: The Merck & Co., Inc.-sponsored study that measured metabolites of prostacyclin in the urine was published and widely discussed before Vioxx was ever approved for marketing. Merck & Co., Inc. included the study in the regulatory filings that led to the FDA approval of Vioxx. Further, Merck & Co., Inc. discussed the study and other relevant data with distinguished outside scientific consultants, who also considered data suggesting that medicines in this class might be cardio-protective. In response to the recommendations of its outside advisors, Merck & Co., Inc. instituted a cardiovascular standard operating procedure that established a panel of independent experts to adjudicate in a blinded fashion all investigator-reported cardiovascular events from future Merck & Co., Inc. clinical trials. Merck & Co., Inc. took this action to rigorously monitor the cardiovascular safety profile of the medicine and Merck & Co., Inc. continued to study the medicine in large-scale trials after it was on the market. And incidentally, an increasing body of evidence casts doubt on the decade-old hypothesis that Cox-2 might be the mediator of prostacyclin in the vascular endothelium. Merck & Co., Inc.'s new drug application for Vioxx included approximately 60 randomized clinical trials in approximately 10,000 patients. These trials, which in the main compared Vioxx either to the traditional non-steroidal anti-inflammatory drugs (ibuprofen and diclofenac), or to placebo, yielded no evidence of statistically significant thrombotic cardiovascular events associated with Vioxx. With regard to Merck & Co., Inc.’s VIGOR study, the authors appear to falsely imply that the cardiovascular events in VIGOR were not subject to the adjudication procedure. They were. Indeed, Merck & Co., Inc. convened a data safety monitoring board composed of highly- qualified outside rheumatologists and gastroenterologists and a biostatistician -- a fitting line-up for a gastrointestinal outcomes study in a rheumatoid arthritis population. The implication of conflict of interest with which the authors seek to taint that Board’s distinguished chair comes with particularly ill grace from physicians using a medical journal as a platform for the very opinions a plaintiff’s lawyer pays them to give. In trumpeting the “expression of concern” published by The New England Journal of Medicine in 2006, with regard to the use of a cutoff date for data in the VIGOR publication, the authors fail to point out that Merck & Co., Inc. presented the post-cutoff data publicly at the U.S. Food and Drug Administration Advisory Committee hearings in February 2001. Despite their participation in the Vioxx litigation and the alleged thorough review of court documents, the authors also failed to mention that the editor of NEJM admitted in sworn testimony that he knew of the post-cutoff data from its publication in August 2001, in the very JAMA article the authors cite. And the fact that the NEJM’s editors “expression of concern” was published five years later and after trial lawyers sought their deposition was somehow not relevant to the lessons the authors offered. The medical and scientific communities continue to study and build upon the collective knowledge about Cox-2 and the medicines that affect it. As for the important questions of who knew what and when with regard to Vioxx, the authors of the BMJ article present only a fraction of the facts necessary to answer those questions and, as you would expect given the authors’ support for the plaintiffs’ cause, the facts they chose to include were all favorable to the plaintiffs’ theories. I'm paid to represent Merck & Co., Inc. so I will not offer my views and claim them to be objective. But I suggest your readers consider that in a jury trial, Merck & Co., Inc. and the plaintiffs each have an opportunity to present their respective positions and the supporting evidence. If the Vioxx story were as Dr. Krumholz and his colleagues suggest, one might wonder how it could be that to date Merck & Co., Inc. has won more than two-thirds of the cases decided by juries so far. Ted Mayer Hughes Hubbard & Reed LLP New York, NY Competing interests: I am an attorney representing Merck & Co., Inc. in the Vioxx litigation.
Re: On Selective Learning 16 March 2007
Mark E. McConnell, physician 54601 Send response to journal: Re: Re: On Selective Learning	What did we learn? That a drug can be marketed to physicians in such a way that they will prescribe this for patients at 10 times the cost of over the counter anti- inflammatories when it was never demonstrated to be better or safer in terms of real clinical outcomes. I suppose that we can blame Merck and the FDA for promoting and approving the use of Vioxx but they were not responsible for choosing to prescribe Vioxx over many cheaper products. Who wrote the prescriptions...and why? That's what we should seek to learn: the factors that result in irrational prescribing. Competing interests: None declared
Re: On Selective Learning 9 April 2007
David S. Egilman, Physician Never Again Consulting, 8 North Main St., Attleboro, MA 02703, Amos H. Presler Send response to journal: Re: Re: On Selective Learning	Merck’s lawyer writes that he “will not offer [his] views,” as he offers his views in his critique of our article. Unfortunately his letter, which he claims is a “correction” of our article, misrepresents Merck’s conduct and the results of Merck’s drug trials. Merck included some data from the prostacyclin study in its regulatory submission but excluded the most important part – the non-Merck authors’ conclusion that the “inhibition of urinary PGI-M by Vioxx implies a major role for Cox-2 in the vascular biosynthesis of prostacyclin in humans.” Furthermore, the primary FDA reviewer responsible for reviewing the data concluded in 1999 that Merck’s pre-market Vioxx trials did contain important signals of cardiovascular risk when he wrote: 1. Vioxx caused vascular-renal adverse events, i.e., hypertension- and edema-type, serum creatinine increased, hyperkalemia, and to a lesser degree proteinuria in a dose-dependent manner. 2. The vascular-renal safety profile of Vioxx is clearly distinguishable from placebo, and is qualitatively similar to other NSAIDS. 3. The aforementioned adverse events occur at a higher rate with VIOXX at 50 mg, than with other NSAIDS at their recommended dosage. However, whether that will translate into clinically significant differences in vascular-renal morbidity cannot be determined from the current osteoarthritis clinical database. [http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_06_G-FDA-Tab- D-2.pdf] Another FDA review noted that “The data seem to suggest that in 6 - week studies, thromboembolic events are more frequent in patients receiving rofecoxib than placebo but do not show a clear dose response relationship with rofecoxib.” [http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_05_F-FDA-Tab- D-1.pdf] Both reviewers observed that the studies were not large enough to find an effect since they were short term, excluded high risk patients and failed to include tests designed to detect CV events. For example, Merck failed to perform exit EKGs. These studies were also underpowered. Power is a function of the number of expected events in a trial, not the total number of patients studied. As the manufacturer, Merck had the responsibility to follow up and warn about this early signal of harm. We did not suggest that Merck failed to adjudicate CV events in Vigor. Merck, however, did manipulate the adjudication process. During VIGOR, but after Merck personnel were unblinded to overall results, Merck deleted 21 cardiovascular diagnoses from the Standard Operating Procedure list of events eligible for adjudication (SOP for all Vioxx trials). Deletions included CHF, pulmonary edema and a variety of new EKG changes. These changes were made on December 29, 1999 one week after the external safety board told Merck to perform an analysis of CV events for this particular trial. At that time Merck had no plans to analyze any of the CV data from VIGOR or any other individual Cox-2 trial. Merck pre-dated the change to October 3, 1999. In regards to the Vigor DSMB’s chairman’s ownership of Merck stock, the article simply pointed out the potential for a meaningful conflict of interest and the fact that such stock ownership violates Merck’s own guidelines, which we cited in the article (print citation #10). Those guidelines say, “DSMB members should not have such a substantial financial investment in Merck or in any of our competitors that their independence would be questioned. All members should issue a periodic report describing potential conflicts of interest. The DSMB chairman should review these potential conflicts prior to each meeting, and forward them to the DSMB chairman along with the status report.” The chairman also signed a contract with Merck on March 6, 2000 (11 days prior to end of the Vigor trial) to consult on the marketing and research and development of COX-2 agents including Vioxx: The consultant will provide confidential advice, counsel, and assistance in the development, planning and execution of commercial and scientific initiatives related to Merck’s COX-2 Inhibitor program (the “Consulting Service”). The Consulting Services may cover topics including, but not limited to, market development, strategic product planning, and educational activities as well as the design and the conduct of the clinical and preclinical development program. (Ref. 12 in our article) Readers should be able to decide whether the stock ownership and consulting contract constitute a conflict of interest, and Merck should allow readers that opportunity, rather than objecting to the disclosure of this information. Merck’s lawyer asserts that we omitted information from Dr. Curfman’s deposition conducted after the submission of our article and that this information supports Mayer’s assertion that Dr. Curfman, “…knew of the post-cutoff data from its publication in August 2001, in the very JAMA article the authors cite.” Mr. Mayer conflates access to the “full data” with the issue of whether or not the data should have been included in the NEJM VIGOR paper. The latter question centered on knowledge of different cut off dates for analyzing CV and GI events and whether or not the “full data” was available to Merck when they submitted the Vigor paper to the NEJM. The NEJM authors reasonably believed that the late data was unavailable when the VIGOR paper was submitted or that this data fell outside of a scientifically justifiable “cut off.” Neither was the case. Dr. Curfman’s testimony directly contradicts Merck’s lawyer’ assertion: Q. Doesn't that suggest to you that there was evidence that the sponsor [Merck] had on CV issues that were not in the paper that were in hand before the paper was published? A. No. Q. So, you read this sentence to conclude that all this evidence came to Merck after the paper was published? A. It doesn't specify when they had the data, and I don't think that these authors would know. They [the authors of the JAMA article] are not authors of the VIGOR article. They had no access to the primary data. They weren't involved in the study. They're writing a commentary article here. They are commentators, they are not authors, and this is not our Journal [NEJM]. Dr. Curfman repeatedly told Merck’s lawyer’s that their client had played “hide and seek” with the data. Merck initially designated several lines of this deposition “confidential,” claiming it contained trade secrets, but in correspondence Merck told us that they withdrew their confidentiality claim. We have made Dr. Curfman’s deposition available to the public [http://www.vioxxdocuments.com/browse.php] so readers can make their own evaluation of Dr. Curfman’s knowledge. Merck complains that we omitted key information that was available in this deposition but, but the final version of our paper was submitted to BMJ, and the issue went to press, before the deposition even occurred. If Merck’s lawyers believe we misrepresented the facts surrounding their handling of Vioxx, they should lift the veil of secrecy they have placed on their data and documents and make them accessible on the web as the tobacco companies have done. The drug is off the market; the only “trade secrets” are marketing practices and methods of data manipulation. The medical community has much more to learn from these documents. Competing interests: Dr. Egilman has served as an expert witness at the request of plaintiffs in the Vioxx litigation. Mr. Presler has served as a consultant at the request of plaintiffs in the Vioxx litigation.