Cumulative pooled analysis of investigator-reported cardiovascular thrombotic events and all-cause deaths among all randomized, placebo-controlled rofecoxib trials of 4 weeks' duration or longer conducted by Merck & Co Inc (Whitehouse Station, New Jersey).
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Ross JS, Madigan D, Hill KP, Egilman DS, Wang Y, Krumholz HM. Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial DataLessons for Postmarket Pharmaceutical Safety Surveillance. Arch Intern Med. 2009;169(21):1976–1985. doi:10.1001/archinternmed.2009.394
Copyright 2009 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2009
In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts.
We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event.
We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001).
Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3½ years before the manufacturer's voluntary market withdrawal.
During its brief availability on the worldwide market, rofecoxib, a selective cyclooxygenase 2–selective agent, was a striking commercial success, its sales reaching $2 billion annually soon after its introduction in May 1999. Merck & Co Inc, Whitehouse Station, New Jersey (hereinafter, “Company”), the maker of rofecoxib under the brand name Vioxx, promoted it as a safer alternative to traditional nonsteroidal anti-inflammatory drugs (NSAIDs), although there were concerns about its cardiovascular adverse effects early in its development, years before its launch.1,2 In September 2004, the manufacturer voluntarily withdrew rofecoxib from the market after an interim safety analysis indicated that the drug was associated with increased risk of cardiovascular events within the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial.3 The APPROVe trial, which tested the hypothesis that rofecoxib reduced the risk of colon polyp recurrence (and thus colorectal cancer), was terminated early by its data safety and monitoring board (DSMB). In November 2004, the manufacturer's chief executive officer testified to the United States Senate Committee that “Until data from [APPROVe] . . . , the combined data from randomized controlled clinical trials showed no difference in confirmed cardiovascular event rates between Vioxx and placebo.”4
Today, the medical community acknowledges the cardiovascular risks associated with rofecoxib.5-7 A “scientific statement by the American Heart Association”8 affirmed that selective cyclooxygenase 2 inhibitors have adverse cardiovascular effects, including increased risk for myocardial infarction, stroke, heart failure, and hypertension. A pertinent question is whether the US Food and Drug Administration (FDA) and the manufacturer could have known before the time of its withdrawal that rofecoxib increased the risk of cardiovascular events compared with placebo through the analysis of the manufacturer's published and unpublished clinical trial data. Three Company-sponsored and -conducted meta-analyses reported no increased cardiovascular risk associated with the drug while it remained on the market in 2001,9 2002,10 and 2003,11 although none of the 3 focused specifically on placebo-controlled studies or used all available data.
This question is particularly relevant as we consider current and future challenges in drug safety monitoring. Can the example of the rofecoxib experience inform and improve the approach used by industry and regulators to conduct postmarket pharmaceutical safety surveillance? If all available data, both published and unpublished, had been independently and iteratively analyzed, could the increased cardiovascular risk compared with placebo have been known earlier? Understanding whether this approach may be informative is of even greater importance after the September 2007 enactment of the FDA Amendments Act (FDAAA) in the United States, which requires the sponsors of all drug, biological, and device trials not only to register their studies at inception in the publicly available ClinicalTrials.gov database (with the exception of phase I clinical trials) but also to update the registry for approved drugs and devices within 12 months of study completion (24 months if the studied drug is under review at the FDA) to include primary and principal secondary outcomes as well as safety outcomes from the trial results. Therefore, our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal, using the manufacturer's trial data made available through the rofecoxib litigation, as an example to inform future postmarket pharmaceutical safety surveillance efforts.
We included in our analyses all randomized clinical trials that compared rofecoxib with placebo and were completed as of termination of the APPROVe trial.3 Consistent with the manufacturer's protocol for earlier meta-analyses of rofecoxib, we included only trials that examined adults using rofecoxib at daily doses of 12.5 mg or more for 4 weeks or longer and excluded data from trial arms using rofecoxib in other doses or for shorter time periods.9-11 In addition, we included only data from subjects enrolled in the clinical trials who took at least 1 dose of the study drug (rofecoxib or placebo). We excluded data from 6 trials that did not include a placebo arm (eFigure). In addition, we excluded data from 2 large ongoing trials that were terminated shortly after the APPROVe trial and the market withdrawal of the drug: “Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer”12 (hereinafter, “the VICTOR trial”) and the “Vioxx in Prostate Cancer Prevention study”13 (hereinafter, “the ViP trial”). At the time of termination, both of these trials had enrolled 25% to 33% of the planned number of subjects for a median treatment duration of 7.4 and 4.1 months, respectively.12,13 However, data from these trials were not pooled with APPROVe data at its termination to evaluate rofecoxib's safety. A complete list of the randomized clinical trials included in this analysis is provided in Table 1.
To confirm that the data made available by the manufacturer were accurate, we compared the following characteristics of the data made available through the rofecoxib litigation with the data published within trial manuscripts or data reported to the FDA as part of each trial's clinical study report: number of study subjects, mean age, and proportion of women in each trial arm (eTable 1).
Our prespecified outcome measure for the present study was incidence of any investigator-reported death or cardiovascular thromboembolic (CVT) adverse event that occurred in an enrolled clinical trial subject. As prespecified by the Company, all trials collected adverse event data on subjects either while they were using the study medication (rofecoxib or placebo) or within 14 days after they stopped using it. In addition, studies 078, 091, and 122 collected adverse event data on subjects beyond 14 days after they stopped using the study drug until study termination. For these trials, all available data were used in an intention-to-treat fashion, the gold standard approach for analysis of clinical trial data.35
The randomized controlled trials conducted by the Company used either Clinical and Regulatory Information Strategic Program (CRISP) or Medical Dictionary for Regulatory Activities (MedDRA) terms for the reporting of trial adverse events; approximately 50% of trials used each set of terms. The CRISP is the Company's clinical data system medical terminology, and MedDRA is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. We identified CVT events from lists of terms used by both the CRISP and MedDRA systems. Two of us (J.S.R. and H.M.K.) independently reviewed all adverse event terms used by the medical terminology systems and categorized those terms that represented CVT events without knowledge of the effect on the results. Disagreements were resolved by consensus. Examples of selected terms include acute myocardial infarction, embolic stroke, and unstable angina. The complete list of included CVT event terms is provided in eTable 2.
All statistical analyses used subject-level data and did not pool summary information. We first calculated event rates and relative risks using Cox proportional hazards models stratified by study with treatment as the sole covariate. To replicate the manufacturer's analytical practice,3 if there were fewer than 11 events in either study arm, we computed the rate ratio by using exact methods. We then cumulatively calculated event rates and relative risks using Cox proportional hazards models (or exact methods), pooling new data as clinical trials were completed and became available for analysis. To account for the time necessary in practice to prepare and organize a final clinical trial data set for analysis, with 3 exceptions, we made certain that data were eligible for pooling only 3 months after the last-person-out date of each randomized clinical trial or the trial termination date (trial 126 [unpublished] was terminated early after the researchers of trial 09131 found rofecoxib to not be effective).
Exceptions to this rule were made for trials 07830 and 122.3,34 Because data from trial 078 were included in 2 pooled analyses of cardiovascular events by the Company within safety update reports required by the FDA while the study was ongoing, we likewise included data from trial 078 in our pooled analysis as of the same dates.36 The first safety update report included all clinical trial data available as of March 16, 2001, and the second as of January 31, 2002. As of these report dates, trial 078 was the only sizable placebo-controlled trial for which data were included while collection was ongoing. Similarly, data from trial 122, the APPROVe trial,3 were initially analyzed by the trial's data and safety monitoring board while the study was ongoing; these interim results were subsequently published3 before completion of the long-term postdrug follow-up of participants.34 We likewise included data from trial 122 as of the date of the interim analysis, September 30, 2004.
For every fitted Cox model on complete data sets, we checked the proportionality assumption using a standard test based on the scaled Schoenfeld residuals. No failures of proportionality were noted. We did not include drug dose as a covariate in our analyses because more than 90% of the patient-years of observation were of patients using 25 mg of rofecoxib. All statistical tests were 2 tailed, and analyses were performed using the R statistical software environment, version 2.8.0 (http://www.r-project.org).
We identified 30 randomized placebo-controlled trials including a total of 17 256 subjects that met our inclusion criteria. Fifteen of these trials examined the efficacy of rofecoxib for treating osteoarthritis; 6 for treating rheumatoid arthritis; 3 for preventing or delaying the progression of Alzheimer disease; and 6, including the APPROVe trial,3 for other indications, (Table 1). To our knowledge, reports of 24 of these 30 trials were published as articles, although 6 (excluding APPROVe) were published after Merck withdrew rofecoxib from the worldwide market; therefore, data representing 36% of patients studied in placebo-controlled clinical trials prior to APPROVe had not been published prior to market withdrawal. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects assigned either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 to 50 mg, although more than 90% of the patient-years of observation were of patients using 25 mg of rofecoxib.
Through September 2004, there were 301 CVT adverse events reported by investigators during these 30 randomized placebo-controlled trials, 182 among 7034 patient-years of rofecoxib use and 119 among 6695 patient-years of placebo use (rate ratio [RR], 1.48; 95% confidence interval [CI], 1.17-1.87) (P < .001) (Table 2).
Through September 2004, there were 130 deaths from any cause reported by investigators during the 30 randomized placebo-controlled trials, 81 among 7158 patient-years of rofecoxib use and 49 among 6805 patient-years of placebo use (RR, 1.71; 95% CI, 1.20-2.45) (P = .003) (Table 2).
Through September 2004, there were 372 subjects for whom an investigator reported either a CVT adverse event or death from any cause during these 30 randomized placebo-controlled trials, 221 among 6357 patient-years of rofecoxib use and 151 among 5723 patient-years of placebo use (RR, 1.43; 95% CI, 1.16-1.76) (P < .001) (Table 2).
Results of the cumulative pooled analysis of the 30 identified randomized placebo-controlled trials are displayed in the Figure. As of December 2000, 21 of these trials had been completed (70%), having enrolled 9884 subjects for 1749 patient-years of observation to either the rofecoxib or placebo arm, during which time 36 subjects experienced either a CVT adverse event or death from any cause. At that time, risk of either of these events was greater among subjects assigned to rofecoxib (RR, 2.18; 95% CI, 0.93-5.81) (P = .07), raising concerns from a safety standpoint (Table 3).
With the analysis of additional data available through June 2001, 12 207 subjects had been observed for 4946 patient-years. At that time, rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05).
The association between rofecoxib and risk of CVT adverse event or death strengthened with the addition of subsequently collected data. As of January 2002, 14 406 subjects had been observed for 7806 patient-years, and rofecoxib was associated with a 39% increased risk of a CVT adverse event or death (RR, 1.39; 95% CI, 1.07-1.80) (P = .02).
Finally, after the addition of all data available as of the date of interim analysis of data from trial 122 (APPROVe),3,34 September 2004, 20 152 subjects had been observed for 17 310 patient-years, and rofecoxib was associated with a 43% increased risk of a CVT adverse event or death (RR, 1.43; 95% CI, 1.16-1.76) (P < .001).
Our cumulative pooled subject-level analysis of the data from all published and unpublished randomized placebo-controlled trials of rofecoxib demonstrates a trend toward increased cardiovascular risk associated with the medication compared with placebo as early as December 2000, the association reaching a P value of .05 by June 2001, nearly 3-½ years before the manufacturer voluntarily withdrew rofecoxib from the worldwide market. These findings are particularly compelling because as early as the late 1990s there were concerns about cardiovascular risk that emerged in the drug development process.1,2
The present analyses provide a roadmap for how drug safety can and should be assessed, particularly after a drug has been introduced into the market. Because the recently enacted FDAAA requires the public disclosure of trial results within the ClinicalTrials.gov database within 12 to 24 months of study completion, including both efficacy and safety outcomes, clinical trial data will be available to conduct comprehensive iterative meta-analyses independent of the FDA and manufacturers. Substantial amounts of clinical trial data that have rarely been fully used to understand drug efficacy or safety will now be available and can be used by independent investigators to complement and corroborate surveillance done by the FDA and the manufacturers.
The data used in our study were not publicly available for analysis by independent investigators at the time rofecoxib was being marketed and have only now become available through litigation. One critical advantage of our approach was the use of subject-level data, which allows far more flexibility with respect to prespecifying and defining the outcome of interest, using statistical methods to manage heterogeneity, and investigating specific subgroups of subjects as well as rare outcome events, a critical issue in pharmaceutical postmarket safety surveillance. Currently, the data that will be available through the ClinicalTrials.gov database will be summary-level data, which may lack information necessary to investigate specific subgroups or outcomes, particularly rare safety outcomes.
In 2006, the Institute of Medicine (IOM)37 released a report commissioned by the FDA to examine drug safety. Until recently, the centerpiece of the FDA's pharmaceutical postmarket surveillance has been the adverse event reporting system (AERS),37 which combines voluntary reporting of adverse events by patients and clinicians and mandatory reporting of adverse events by manufacturers. The FDA traditionally relied on AERS because clinical trials conducted by industry as part of the new drug approval or indication application are often not large or long enough to evaluate safety outcomes. In addition, many of the large phase IV randomized trials requested by the FDA at the time of drug approval to further investigate potential drug safety issues are not conducted for a wide variety of reasons, including feasibility, recruitment barriers, and cost.
The IOM report37 included 25 recommendations that together suggested that the FDA needed to better prioritize ongoing, systematic efforts to monitor drug safety during the product's entire market life, such as the approach we have modeled. Nevertheless, identifying those safety outcomes that should be monitored prospectively through an iterative and timely meta-analysis will be challenging and should be driven by biological plausibility; safety signals that arise during the drug development process; during preapproval studies; and by systematic monitoring of surveillance systems such as AERS and other health care data sources through the FDA's Sentinel Initiative (http://www.fda.gov/Safety/FDAsSentinelInitiative/default.htm), including Medicare Part D claims, the Department of Veteran Affairs, the HMO Research Network, and others.
Our analysis builds on the prior work of Jüni et al,7 published shortly after rofecoxib was withdrawn from the market, which concluded that rofecoxib was associated with more than twice the risk of myocardial infarction by the end of 2000, although it differs in several ways. First, our analysis used all published and unpublished data at the patient level, whereas Jüni et al were restricted to published data at the summary level. Moreover, the cumulative meta-analysis of Jüni et al examined the risk of myocardial infarction, whereas ours examines the risk of CVT event or death, a more comprehensive assessment of drug safety. In addition, the meta-analysis of Jüni et al included all randomized clinical trials, including trials that used NSAIDs as a comparator. The largest trial with the largest effect size was the Vioxx Gastrointestinal Outcomes Research Study (VIGOR) trial,38 which compared rofecoxib to naproxen. In fact, the stratified analysis of Jüni et al7 estimated a tripling of the risk associated with rofecoxib compared with naproxen and a nonsignificant increase in risk associated with rofecoxib compared with placebo, although a test of interaction by comparator was not significant. Our analysis extends and strengthens these findings, demonstrating an increased cardiovascular risk associated with rofecoxib compared with placebo.
Our analysis differs in several ways from those conducted by the manufacturer and published before rofecoxib's withdrawal from the market.9-11 First, each of the earlier pooled analyses focused on the Antiplatelet Trialists' Collaboration (APTC)39,40 and Antithrombotic Trialists' Collaboration (ATTC)41 end point, which accounts only for cardiovascular, hemorrhagic, and unknown deaths, including hemorrhagic gastrointestinal deaths, as well as nonfatal myocardial infarctions and strokes (ischemic and hemorrhagic). The APTC/ATTC end point is a composite outcome developed for the purpose of testing the net efficacy and safety of antiplatelet therapeutics that may prevent ischemic events but simultaneously may cause hemorrhagic events. Specifically, the APTC/ATTC end point captures overall benefits and risks of antiplatelet medications, but it is not appropriate for evaluating the CVT risk of cyclooxygenase-2 inhibitors. In contrast, we accounted for all ischemic-related CVT adverse events as well as deaths from any cause. Accounting for all deaths is important for studies of cardiovascular risk (particularly among clinical trials not designed to examine cardiovascular outcomes) because cardiovascular deaths are not always apparent as such. In addition, nearly three-quarters of deaths in the present analysis occurred within the 3 Alzheimer trials. Studying all-cause death is particularly important among patients with Alzheimer disease or cognitive impairment who may not report symptoms accurately and may not always be as thoroughly evaluated when brought for medical attention.
Second, we examined all available data from all 30 trials with a placebo-controlled arm, including data not used in company-conducted analyses9-11 (eTable 3), although we did exclude data from the VICTOR12 and ViP13 trials, 2 large ongoing trials that were terminated shortly after APPROVe and the decision to withdraw the drug from the market. Finally, we accounted for all investigator-reported adverse events among all trials and included outcomes observed beyond the 14-day window after the subjects stopped taking the study drugs in an intention-to-treat fashion, the gold standard approach for analysis of clinical trial data35 and the approach prespecified within these trials' data analysis plans.
Our analysis raises the issue of how investigators should interpret data relevant to drug safety. Although we want to avoid false-positive interpretations, conventional standards of statistical significance may be too strict for issues of safety.42,43 The importance of a safety finding depends on many factors, including plausibility of harm, effect size, number of people exposed, and alternatives to treatment. Understanding the range in the estimation of the risk may be more important than focusing on hypothesis testing using a P value threshold for significance of .05.42 For instance, when the VIGOR trial38 findings were published in November 2000, 4 years before rofecoxib was withdrawn from the market, concern about rofecoxib's cardiovascular risk was already heightened, and clear alternatives for treatment of osteoarthritis and rheumatoid arthritis were available. Our analyses suggest that rofecoxib was associated at that time with more than a doubling of the cardiovascular risk that nonetheless did not reach statistical significance (95% CI, 0.93-5.81) (P=.07). Notwithstanding the lack of statistical significance, this indication of risk should have been interpreted along with the 5-fold increased risk of myocardial infarction among rofecoxib users44 found in the VIGOR trial as well as with the concerns about cardiovascular risk that emerged in the drug development process.1,2
Physicians and the public deserve to be in a position to make informed choices about risks and benefits, and the disclosure and dissemination of information about potential risk immediately after its recognition is absolutely essential. Our study provides insight into what should have been known about the risks of rofecoxib. The signal of cardiovascular risk appeared soon after the drug was FDA-approved and made available in May 1999. But more importantly, our study suggests that such analyses should be ongoing for all drugs for which trials are being conducted, with attention to the rapid addition of new data about potential harm to any cumulative pooled analyses. Ideally, subject-level data should be made available to the public to allow for independent assessments. If we are to detect harms early and protect the public's health, while ensuring the availability of new, clinically effective therapeutics, a system must be established that makes full use of all existing evidence.
Correspondence: Joseph S. Ross, MD, MHS, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1070, New York, NY 10029 (email@example.com).
Accepted for Publication: August 5, 2009.
Author Contributions:Study concept and design: Ross, Madigan, Egilman, and Krumholz. Acquisition of data: Madigan and Krumholz. Analysis and interpretation of data: Ross, Madigan, Hill, Wang, and Krumholz. Drafting of the manuscript: Ross and Krumholz. Critical revision of the manuscript for important intellectual content: Ross, Madigan, Hill, Egilman, Wang, and Krumholz. Statistical analysis: Madigan and Wang. Administrative, technical, and material support:Egilman and Krumholz. Study supervision: Krumholz.
Financial Disclosure: Dr Madigan is currently a consultant for plaintiffs in litigation against Merck & Co Inc related to rofecoxib in Australia and was previously a consultant in litigation in the United States. All other authors were previously consultants for plaintiffs in litigation against Merck related to rofecoxib in the United States. Over the past 5 years, Dr Madigan has been a consultant to Pfizer, Wyeth, Sanofi-Aventis, and Takeda and currently serves on the clinical review team of iGuard.org. Dr Krumholz has had research contracts with the American College of Cardiology and the Colorado Foundation for Medical Care; has previously served on the advisory boards of Alere and Amgen; and currently serves on an advisory board with UnitedHealthcare. He is a scientific advisor for Centegen; has been a subject expert for VHA Inc, Irving, Texas; and has received speakers' compensation from the American College of Cardiology. Dr Krumholz also has a contract with the Centers for Medicare and Medicaid Services to develop and maintain performance measures.
Funding/Support: This project was not directly supported by any external grants or funds. However, Dr Ross is currently supported by National Institute on Aging grant K08AG032886 and by the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program.
Disclaimer: While we obtained access to study data through participation in litigation, no attorneys or others related to the litigation had any role in the study conception or design, data analysis or interpretation, or the writing, review, or approval of the manuscript; we are solely responsible for the decision to submit the manuscript for publication.
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