Statement by Merck & Co., Inc., Regarding the Fracture Intervention Trial (FIT) with FOSAMAX® (alendronate sodium) and Incidence of Atrial Fibrillation
WHITEHOUSE STATION, N.J.,- Merck & Co., Inc. responds to the publication in the New England Journal of Medicine (New Engl J Med, May 3, 2007) of the HORIZON Trial and a Letter to the Editor referencing adverse events of atrial fibrillation from the Fracture Intervention Trial (FIT):
FIT was the largest clinical study ever conducted to evaluate the effect of FOSAMAX® (alendronate sodium) on the risk of osteoporotic fracture. It was conducted over a period of five years, concluding in 1997. The overall risk of atrial fibrillation adverse events in FIT was similar between FOSAMAX and placebo (FOSAMAX (2.5%) and placebo (2.2%); p=0.42). Looking only at atrial fibrillation adverse events that were serious, the incidence was not statistically significantly different with FOSAMAX compared to placebo although it was numerically higher (FOSAMAX (1.5%) and placebo (1.0%); p=0.07).
Atrial fibrillation adverse experiences were collected throughout the duration of FIT and verified by an independent physician who was “blinded” to patient treatment. The study was also monitored by a Data Safety Monitoring Board (DSMB) which at no time found cause to stop the study due to a safety data finding.
At the end of the study, which was almost 10 years ago, the external, independent study investigators and Merck prepared analyses of all atrial fibrillation adverse experiences from FIT. Based upon these analyses, as noted in the NEJM letter, a true association between atrial fibrillation and treatment with FOSAMAX was considered unlikely by both the independent study investigators and Merck.
Merck reported these findings to FDA and other regulatory agencies worldwide after the conclusion of FIT in accordance with domestic and international reporting regulations and safety guidelines.
The finding that serious adverse experiences of atrial fibrillation were increased in patients treated with zoledronic acid in the HORIZON trial was first reported six months ago at the American Society for Bone and Mineral Research Annual Meeting in September 2006. Merck has since re-reviewed the data concerning atrial fibrillation adverse experiences in 28 other placebo-controlled trials in which reports of atrial fibrillation adverse experiences were not subject to independent adjudication. In this preliminary analysis that combined data from these other trials, the observed incidence of atrial fibrillation based upon counts of adverse experiences (whether all adverse experiences or only those that were reported as serious) was similar in patients receiving FOSAMAX compared to placebo.
About the FIT Study
FIT was a placebo-controlled, double-blind study that enrolled 6459 postmenopausal women who were followed for up to four and one-half years. FOSAMAX was dosed at 5 mg daily during the first two years of the study and 10 mg daily thereafter.
During FIT, atrial fibrillation adverse experience reports were collected by external study investigators and verified by an independent physician who was “blinded” to a patient’s treatment. Adverse events in the FIT study were reported as either serious or non-serious based on reporting regulations and conventions.
Consistent with Merck clinical practice in large, long-term trials, an external Data and Safety Monitoring Board (DSMB) conducted unblinded interim safety analyses through the duration of the study. The DSMB found no cause to stop the study due to a safety data finding at any time. The data from FIT are summarized in the table below as counts of atrial fibrillation adverse experiences.
Since the completion of FIT, atrial fibrillation adverse experiences in our clinical studies and post-marketing reports have been recorded and summarized in the clinical reports of these studies and have been reported to the FDA and other regulatory agencies worldwide in accordance with domestic and international reporting regulations and safety guidelines.
Merck has also re-reviewed the data concerning atrial fibrillation adverse experiences in 28 other placebo-controlled studies (in addition to FIT). We also re-reviewed data from two additional studies that compared daily FOSAMAX 5 or 10 mg to 35 or 70 mg once-weekly. A preliminary analysis that combined data from these studies is summarized in the tables below as counts of atrial fibrillation adverse experiences.
These trials had a duration of at least 3 months, studied doses approved for the prevention or treatment of osteoporosis, and included patients treated with oral FOSAMAX in 21 placebo-controlled trials of FOSAMAX 5 and/or 10 mg daily (duration from 3 months to 4 years), 7 placebo-controlled trials of FOSAMAX 70 mg once-weekly (duration from 3 months to 2 years), and 2 trials comparing daily FOSAMAX 5 or 10 mg to 35 or 70 mg once-weekly (duration of 2 years). These trials differed from FIT in several respects: the study population in these trials was generally younger than that in FIT, and the trials were mostly of a shorter duration. Moreover, these were trials in which reports of atrial fibrillation adverse experiences were made by the physicians at each study site and were not subject to independent adjudication.
Data from trials of FOSAMAX used either intravenously or in higher or lower oral doses were not included; also excluded were comparisons of FOSAMAX only to other active drugs.
As with all of its medicines, Merck regularly monitors adverse experiences with FOSAMAX in its clinical trials and post-marketing events and reports these events to regulatory agencies worldwide the world in accordance with domestic and international reporting regulations and safety guidelines.
FOSAMAX has been studied in over 13,000 patients treated with FOSAMAX and has been on the market for over 12 years during which time over 150 million prescriptions have been written in the US alone.
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