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Premature Release of Data from Clinical Trials of Ezetimibe

Robert M. Califf, M.D., Robert A. Harrington, M.D., and Michael A. Blazing, M.D. The recent controversy about whether the cholesterol-lowering drug ezetimibe causes cancer raises urgent questions about the systems we use to develop drugs and medical devices and then to evaluate their safety and effectiveness.1-3 There is widespread recognition that large, multinational clinical outcomes trials are essential to understanding the risks and benefits of new treatments. Although such studies are dubbed simple, their organizational complexity entails huge investments of money, time, and energy. Given this context, the events surrounding the development and testing of ezetimibe present a useful opportunity for reflection on the future direction of the clinical research enterprise. We discuss the circumstances that led to the unexpected and untimely release of safety data surrounding cancerassociated results from ongoing trials of ezetimibe (Table 1) and present recommendations for addressing such premature release in the future (Table 2). but the most glaring of complications were inadequate, because the number of subjects was insufficient and the follow-up time too short; and only a very small number of cardiovascular events had accumulated when ezetimibe was evaluated for marketing approval. After the short-term studies were conducted, there was no observed excess of any serious side effects or adverse events with ezetimibe, either alone or in combination with simvastatin: the side-effect and adverse-event profiles of the simvastatinezetimibe combination appeared to be almost identical to those of a simvastatinplacebo combination. Ezetimibe alone lowered LDL cholesterol levels by up to 18%, a modest amount equivalent to tripling the dose of a statin. Furthermore, these LDL-lowering effects were additive when combined with any statin and with increased doses of a statin. The use of ezetimibe seemed to incrementally reduce levels of C-reactive protein,6 an evolving biomarker7 thought to indicate risk independently of LDL level.8 Ezetimibe used in combination with a statin was noted to effect a small but measurable increase in the high-density lipoprotein cholesterol level, as compared with use of a statin alone. Given such a profile, coupled with belief in LDL levels as a validated surrogate end point,9 ezetimibe was easily approved for marketing, without an advisory committee meeting, by the Food and Drug Administration on October 25, 2002, and the simvastatinezetimibe combination (marketed in the United States as Vytorin) was approved on July 23, 2004.

Initial Approval of Eze timibe

Ezetimibe, which was discovered serendipitously during a search for inhibitors of acylcoenzyme A:cholesterol acyltransferase at Schering-Plough Research Institute,4,5 underwent the conventional program for evaluating cholesterol-lowering drugs. A series of short-term studies focused on the surrogate end point of the drugs capacity to lower low-density lipoprotein (LDL) cholesterol rather than on improvements in clinical outcomes such as death, myocardial infarction, and stroke were performed in subpopulations representing patients likely to receive ezetimibe. In pursuing this surrogate-end-point approach, researchers evaluated sufficient numbers of subjects to yield ample evidence that ezetimibe is an effective means of lowering LDL cholesterol. However, this approach had three shortcomings: patients at high risk for clinical events were not included in most trials; safety analyses for all
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S t udie s Initiated af ter Comple tion of Pivotal Trial s

After results of the pivotal trials of ezetimibe easily met predefined safety and efficacy targets (with the latter based on the surrogate measure), further trials measuring longer-term, more complex outcomes were designed. Among these were three

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large-scale clinical outcomes studies: the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis, ClinicalTrials.gov number, NCT00092677),10 begun in March 2001; SHARP (Study of Heart and Renal Protection, NCT00125593),11 begun in June 2003; and IMPROVE-IT (Examining Outcomes in Subjects with Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs. Simvastatin, NCT00202878),12 begun in October 2005 (Table 1). The SEAS trial10 evaluated the combination of simvastatin and ezetimibe, as compared with placebo, in subjects with valvular aortic stenosis, a clinically significant cause of death and disability for which there is no effective medical treatment. Thus, the SEAS trial was novel, addressed an important issue, and was the first study with statistical power adequate to evaluate this potential indication. Because of the older age of the study population, the SEAS trial also offered a first look at the effects of the ezetimibesimvastatin combination on cardiovascular events as a secondary end point. SHARP11 also evaluated a simvastatinezetimibe combination as compared with placebo, but it enrolled subjects with renal dysfunction, of whom approximately one third had end-stage renal disease. Enrollment in SHARP was completed in 2007, and treatment with ezetimibesimvastatin or placebo is ongoing and will continue during the follow-up period until sufficient numbers of end points occur (expected to be during 2010). IMPROVE-IT12 is examining the use of ezeti mibe plus simvastatin, as compared with placebo plus simvastatin, in subjects with a recent acute coronary syndrome. In the study, treatment is begun after an episode of the acute coronary syndrome and is continued for at least 2.5 years to assess both short-term and long-term treatment. Unlike the SEAS trial or SHARP, IMPROVE-IT is evaluating ezetimibe as compared with placebo, each in combination with simvastatin, in patients with extremely low LDL values, since the use of a placebo control in patients with higher values was determined to be unethical. Reflecting current guidelines, the trial is enrolling only subjects in whom achieving an LDL level of less than 70 mg per deciliter (1.8 mmol per liter) is realistic, with a goal of a median of 52 mg per deciliter (1.3 mmol per liter) in the experimental group and 66 mg per deciliter (1.7 mmol per liter) in the control group. IMPROVE-IT currently has en-

Table 1. Recent and Ongoing Trials of Ezetimibe.* SEAS Randomized, double-blind study of ezetimibe and simvastatin as compared with placebo involving 1873 subjects with asymptomatic, mild-to-moderate aortic stenosis (196 subjects from the precursor Simvastatin in Aortic Stenosis trial were rolled over to the SEAS study) Enrollment started: March 2001 Enrollment completed: March 2004 Follow-up completed: Summer 2008 Design paper: Rosseb AB, Pedersen TR, Allen C, et al. Design and baseline characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Am J Cardiol 2007;99:970-3. Primary-outcome paper: Rosseb AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56. No effect on primary end point (progression of aortic stenosis) was seen; a higher incidence of newly diagnosed cases of cancer and deaths from cancer was observed in the ezetimibesimvastatin group than in the control group; fewer patients had ischemic cardiovascular events in the ezetimibesimvastatin group SHARP Randomized, double-blind study of ezetimibe and simvastatin as compared with placebo involving 9000 subjects with chronic kidney disease Enrollment started: June 2003 Enrollment completed: 2007 Follow-up completed: 2010 (estimated) Design paper: Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003;63:84:S207-S210. Primary-outcome paper: pending final end-point events Primary end points: major vascular events (nonfatal myocardial infarction or death from cardiac causes, nonfatal or fatal stroke, or revascularization) by end of study IMPROVE-IT Randomized, controlled, double-blind study of ezetimibe and simvastatin as compared with placebo and simvastatin involving 18,000 subjects with high-risk acute coronary syndromes Enrollment started: October 2005 Enrollment completed: June 2012 (estimated) Follow-up: will continue until at least 5250 subjects have a primary end-point event and have been followed for at least 2.5 years Design paper: Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:826-32. Primary-outcome paper: pending final end point events Primary end points: Death from cardiovascular causes, myocardial infarction, hospital admission for unstable angina, revascularization (>30 days after randomization), or stroke * IMPROVE-IT denotes Examining Outcomes in Subjects with Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs. Simvastatin (NCT00202878), SEAS Simvastatin and Ezetimibe in Aortic Stenosis (NCT00092677), and SHARP Study of Heart and Renal Protection (NCT00125593).

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Table 2. Recommendations for Clinical Trials That Measure Outcomes. Sustain and enhance requirements for independent data and safety monitoring committees. Engage in long-term efforts to house clinical trial databases in not-for-profit institutions whose primary mission is acting for the common good rather than returning value to shareholders; these efforts must include the development of more effective infrastructure by academic medical centers. Require all major clinical trials that have outcome data to have independent steering committees chaired by a leader widely recognized for expertise in the field of interest and in the practical running of clinical trials. Reform Securities and Exchange Commission regulations, in light of the special rules that clinical trials require, by creating an orderly process for revealing major results of clinical trials to the public and to corporate research sponsors that may be affected.

rolled more than 14,000 of the projected total of 18,000 subjects. All three trials have international steering committees and independent data and safety monitoring committees. None allow industry sponsors or others outside the data and safety monitoring committee to have access to the unblinded study data. More than 200 academic leaders and 50 national regulatory agencies, together with thousands of institutional review boards, are responsible for overseeing the conduct of these trials.

Unveiling of the SE A S Re sult s

While SHARP and IMPROVE-IT were moving through enrollment and follow-up phases, the SEAS trial became the first major clinical outcomes trial of ezetimibe to be completed. Plans were made to analyze the data in summer 2008 and to present preliminary findings at the American Heart Associations annual meeting in November 2008. When the study data were unblinded, however, no effect on the primary end point was seen. Evaluation of the adverse-event data collected within the trial database revealed an imbalance in the numbers of newly diagnosed cases of cancer and deaths from cancer in the ezetimibesimvastatin group as compared with the control group. Although the betweengroup differences were not found to be significant by means of any multiple-testing procedure, such safety signals need not be significant according to conventional methods to merit public notice and further investigation.
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The SEAS sponsors cited several reasons for making a public announcement after the unblinding, rather than waiting for the planned scientific presentation and publication in the peer-reviewed literature. First, because of recent vehement calls for greater transparency in industry-funded trials, they believed that a prompt announcement would provide exactly the type of forthrightness demanded by industry critics. Second, some thought that alerting providers and patients would help them make more informed decisions, since ezetimibe was already on the market, with substantial clinical use. Finally, the findings represented material information of interest to Merck and ScheringPlough shareholders. Withholding such information arguably would violate Securities and Exchange Commission (SEC) regulations governing publicly traded companies; accordingly, a press conference was scheduled before a regular investor conference. In addition, the sponsors concluded that they were required to report both the SEAS results and the interim cancer-related findings from SHARP and IMPROVE-IT to global regulatory groups. Since the sponsors lacked access to the databases and were not privy to unblinded results from those ongoing trials, such communication required the production of reports that could be sent to the regulators by the academic leaders of the two trials. At this point, the leaders of SHARP and IMPROVE-IT faced a dilemma. First, when ap prised of the SEAS findings, they were obliged to inform their own data and safety monitoring committees and ask them to assess whether these external data, combined with confidential information from internal analyses of each trial, should affect the conduct of the two ongoing trials. Second, they had to decide whether it would be appropriate to release any further information to investigators and to study subjects (and thus to the public). The first issue was quickly addressed: both data and safety monitoring committees reviewed the available data (to which investigators had no access) and concluded that the trials should continue unaltered, although the IMPROVE-IT data and safety monitoring committee elected to increase surveillance of cancer-related events. The second issue was much more complex and required multiple discussions among trial leaders and data and safety monitoring committees. Con-

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siderations were balanced and included strong arguments for and against disclosing specific results.2 The current system for evaluating clinical trial results relies on maintaining equipoise, which is accomplished in part by protecting investigators and subjects from being unduly swayed by possibly random fluctuations in interim data. This system has served the public well.13 However, the compelling argument for disclosure was that investigators and subjects in the ongoing trials would be exposed, at the planned SEAS press conference, to a detailed summary of the signal of a risk of cancer, but that disclosure would be balanced only by a general recommendation from the data and safety monitoring committees, such that the studies would be continued despite the risk. In addition, from the public health perspective, release of a one-sided safety signal, even if it reflects only random variation, could cause the unfortunate discontinuation of cholesterol-lowering therapy by patients outside the trial. Accordingly, the investigators decided to pool the cancer results from SHARP and IMPROVE-IT by submitting both data sets to independent statisticians with extensive experience in the study of both cancer and cardiovascular disease. The statisticians performed the analysis and prepared a report entirely independently of the sponsors, which they then submitted to study leaders, sponsors, and regulators. They also presented the results at the same press conference where the SEAS results were discussed. The combination of reports essentially ruled out the existence of an excess incidence of cancer with ezetimibe but found a nagging excess of deaths from cancer that seemed highly unlikely for various reasons.3 These findings3 appeared in tandem with the SEAS results1 in the New England Journal of Medicine and simultaneously with a detailed presentation of results at the European Society of Cardiology. The study sponsors did not see the manuscript until it was accepted for publication and, to date, do not have access to the databases from either trial.

Discussion
In light of the examples presented above, we believe that four specific elements should be implemented as quickly as possible in clinical trials that measure outcomes or are likely to have a major effect on practice (Table 2).

First, the requirement for independent data and safety monitoring committees should be maintained and enhanced. For this to be meaningful, however, academic centers must increase support for education in biostatistics and clinical investigation, because the supply of academicians trained in quantitative methods is dangerously insufficient. In addition, specific training in methods used by data and safety monitoring committees and in the management of complex situations that arise in trials is needed to swiftly prepare a larger pool of qualified persons with a broad understanding of ethical, quantitative, clinical, and regulatory issues to serve on such committees. We are concerned that the National Institutes of Health (NIH) and its academic medical center grantees are not sufficiently focused on closing this considerable gap. Second, long-term efforts should be made to house primary clinical trial databases at nonprofit institutions whose primary mission is acting for the common good rather than returning value to shareholders. We recognize that anyone paid to perform the complex tasks of maintaining, analyzing, and interpreting a clinical trial database has an inherent conflict of interest. Although academic medical centers are no exception to this rule, they are granted nonprofit status and they are regularly audited to be sure their behavior is consistent with the societal mission. This is distinctly different than in a for-profit company, where the direct financial repercussions of clinical outcomes trials can create different and even more potent conflicts of interest if results run counter to corporate interests. Providing an unbiased and complete picture of results can be problematic if personal salary and promotion or the well-being of ones employer is at stake. We readily acknowledge the complexities of relegating such activity solely to the nonprofit sector. Many excellent data managers and statisticians work in the medical products industry and at for-profit clinical research organizations. In addition, the NIH and most academic institutions, being primarily focused on basic science, have failed to provide adequate support for the training and sustenance of a national infrastructure for clinical research. This has led, in turn, to a serious dearth of adequate data coordinating centers with qualified clinical trialists and biostatisticians to shoulder these responsibilities. Because this recommendation cannot be imple715

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mented quickly, rules governing the transparency of research data should be enhanced to make it impossible to conduct secret experiments on humans and to improve public confidence that results of studies of humans are being carefully and fairly assessed. Recent legislation14 extending the purview of ClinicalTrials.gov,15 formerly a voluntary trial registry, to requiring reporting of results in many cases, is an excellent step forward. By making unexpurgated databases available to independent statisticians whose primary obligation is to the trial committees and the public good, we can be confident that authors are genuinely accountable for their publications. In our view, the housing of trial databases at nonprofit institutions does not mean that trial sponsors should be denied access to study data. An improved system of checks and balances could include independent data programmers and statisticians on data and safety monitoring committees and independent analysis and housing of databases of key analyses for publication. It is entirely reasonable for the sponsor and the data coordinating center to share database custody during trials, with synchronization and quality checks of the blinded database before simultaneous locking and unblinding by both parties, as well as validation of results by generation of prespecified results, including primary and secondary end points. Such a joint system would preserve the sponsors ability to respond to its legal responsibilities to inform global regulators as well as its corporate duty to provide timely, accurate information to shareholders. Third, all major clinical outcomes trials should have independent steering committees chaired by a leader widely recognized for expertise in the field of interest and in the practical running of clinical trials. These committees should have a majority of nonindustry personnel and, together with the executive committee, should have independent access to the database at trials end. Furthermore, a manuscript describing primary results should be submitted to a relevant peerreviewed journal. Because publishing a trial with negative findings can be challenging, if a peerreviewed journal cannot be found to publish the manuscript, it should be placed in an archive created by ClinicalTrials.gov. Fourth, SEC regulations should be reformed, recognizing that clinical outcomes trials are a special case needing special rules. In a recent edito716

rial, Taylor and Nissen16 lament the role the SEC has played in the public revelation of trial results. Although most medical practitioners have little knowledge in this arena, the legal obligations of publicly traded companies nonetheless can decisively affect how results are disclosed. The law essentially states that if employees of a publicly traded company become aware of information that would cause the man on the street to change his view of the value of company stock, they are obliged to make the information available with dispatch. An obvious solution would be to create structures for trials that facilitate database analysis without notifying company employees in a manner that would lead to incomplete release of premature data. Companies that fund studies understandably wish to be able to prepare internally for the release of results, so this solution will require standards that meet the publics need for transparency, the clinical and scientific communitys need for proper communication of study results, and sponsors need for a reasonable period in which to deal with study results in an organized fashion. Another option is a special regulation permitting a reasonable period for internal consideration of trial data in return for a rapid, complete public presentation of results. Ezetimibe modestly lowers LDL cholesterol levels with no known major side effects with regard to symptoms. A difficult decision to unblind the data on cancer incidence and mortality in ongoing ezetimibe trials was made largely because of the impending early release of data from the SEAS trial; this disclosure was prompted at least in part by SEC regulations. A systematic approach to conducting and monitoring clinical outcomes trials that reduces the risk of inappropriate influence is needed: a system that offsets conflicts of interest through checks and balances and provides accurate, verifiable results to the scientific community, thus ensuring that stakeholders, decision makers, and the general public have access to reliable, accurate, and timely information.
Full listings of financial disclosure information for Dr. Califf and Dr. Harrington are publicly available on the Duke Clinical Research Institute Web site at http://dcri.org/research/coi.jsp. Dr. Blazing reports receiving speaking or consulting fees from Merck and Pfizer and being the principal investigator on a research grant from Schering-Plough that is administered through the Duke Clinical Research Institute. No other potential conflict of interest relevant to this article was reported.

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From the Duke Translational Medicine Institute (R.M.C.) and the Duke Clinical Research Institute (R.A.H., M.A.B.) both in Durham, NC.
1. Rosseb AB, Pedersen TR, Boman K, et al. Intensive lipid

lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56. 2. Fleming TR. Identifying and addressing safety signals in clinical trials. N Engl J Med 2008;359:1400-2. 3. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357-66. 4. Meng CQ. Ezetimibe (Schering-Plough). Curr Opin Investig Drugs 2001;2:389-92. 5. Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem 2004;47:1-9. 6. Sager PT, Melani L, Lipka L, et al. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414-8. 7. Casas JP, Shah T, Hingorani AD, Danesh J, Pepys MB. C-reactive protein and coronary heart disease: a critical review. J Intern Med 2008;264:295-314. 8. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in Creactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175-82. 9. Division of Metabolic and Endocrine Drug Products, Food and Drug Administration. Guidelines for the clinical evaluation

of lipid-altering agents in adults and children. Center for Drug Evaluation and Research, September 1990. (Accessed July 23, 2009, at http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM071586.pdf.) 10. Rosseb AB, Pedersen TR, Allen C, et al. Design and baseline characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Am J Cardiol 2007;99:970-3. 11. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003;84:S207-S210. 12. ClinicalTrials.gov registry Web site. IMPROVE-IT: examining outcomes in subjects with acute coronary syndrome: Vytorin (eze timibe/simvastatin) vs simvastatin (Study P04103). ClinicalTrials. gov identifier: NCT00202878. (Accessed July 23, 2009, at http:// www.clinicaltrials.gov/ct2/show/NCT00202878?term= IMPROVE-IT&rank=1.) 13. DeMets DL, Fleming TR, Rockhold F, et al. Liability issues for data monitoring committee members. Clin Trials 2004;1:525-31. 14. Public Law 110-85. FDA Amendments Act of 2007 (FDAAA). (Accessed July 23, 2009, at http://frwebgate.access.gpo.gov/cgi-bin/ getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110. pdf.) 15. Wood AJ. Progress and deficiencies in the registration of clinical trials. N Engl J Med 2009;360:824-30. 16. Taylor AJ, Nissen SE. Preliminary observations from preliminary trial results: have we finally had enough? Circ Cardiovasc Qual Outcomes 2008;1:54-7.
Copyright 2009 Massachusetts Medical Society.

collections of articles on the journals web site

The Journals Web site (NEJM.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.

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