A U-turn by Merck/Schering-Plough Pharmaceuticals over the primary endpoint of a controversial trial with the joint venture’s combination cholesterol management drug Vytorin/Inegy (simvastatin + ezetimibe) has done little to quell speculation over potential data manipulation in the ENHANCE study – or, indeed, over whether Vytorin offers any real clinical benefit compared with statin monotherapy.

In a further development that has proved a boon to conspiracy theorists, Merck/Schering-Plough revealed it was backpedalling on last month’s decision to narrow the primary endpoint in the ENHANCE study (quietly, through an unlabelled ‘Frequently Asked Questions’ sheet for investors on the Schering-Plough website) on the same day that the US House Committee on Energy and Commerce sent a letter to the joint venture partners requesting information on the planned change in endpoint and other issues around “the withholding of clinical trial data that may significantly affect the medical management of hypercholesterolaemia”.

When Vytorin was first approved by the US Food and Drug Administration in July 2004, it was regarded with suspicion by some cardiologists due to the lack of long-term outcomes data (something that did not particularly hamper AstraZeneca’s Crestor (rosuvastatin)). ENHANCE, a multicentre randomised, double-blind trial assessing the effect of the highest approved dose of Vytorin (10mg ezetimibe + 80mg simvastatin) versus the highest approved dose of simvastatin alone (80mg) in more than 700 patients with the rare genetic condition Heterozygous Familial Hypercholesterolaemia (HeFH), was one study designed to address the outcomes gap.

The controversy has arisen from Merck/Schering-Plough’s failure to date to publish or present in full data from a trial that started in 2002 and was completed in April 2006. While the joint venture put the delay down to technical difficulties – notably, the need to examine more than 40,000 scans of the arterial intima-media thickness (IMT) of patients’ carotid and femoral arteries collected from 18 multinational study sites – some observers inevitably concluded that the companies had something to hide.

Their suspicions were further pricked on 19 November, when Merck/Schering Plough announced that it would be following the recommendation of an “independent panel of clinical and biostatistics experts” to focus the primary endpoint in the prospective analysis of the ENHANCE study on the common carotid artery, “to expedite the reporting of the study findings”. The joint venture expected to report these results at the American College of Cardiology meeting in March 2008, it added.

Before that, the primary objective of ENHANCE had been to measure the change in IMT at three points of the carotid artery – the internal carotid, the carotid bulb and the common carotid – at the beginning of the study and after two years. Sorting through the IMT scans had proved time-consuming and “taken longer than originally anticipated because, during the analysis, observations of variability in some of the data were detected as part of the validation/data review procedures”, Merck-Schering-Plough noted.

Back to base
But in its latest update the joint venture said it would now present the pre-specified primary endpoint for ENHANCE, including data from the common carotid artery, following input from “other respected clinical trialists and scientists”. The goal was still to unveil these results at the American College of Cardiology meeting next March, subject to acceptance by the College.

“We view the expert panel’s advice to focus the primary endpoint on the common carotid artery as helpful, as the common carotid artery is viewed by many clinicians and experts of the IMT procedure as the most reliable, reproducible and clinically meaningful segment of the carotid artery and least subject to artifact and variability,” the statement read. “In consideration of this independent expert advice and the evolving medical science, Merck/Schering-Plough and the lead investigator have had further discussions about the trial, including input from other respected clinical trialists and scientists.”

“The companies respect and appreciate the advice of the expert panel as well as the others whose advice and input we sought,” it continued. “As a result, we are planning to examine closely the data from the common carotid artery, and to present that data from the pre-specified endpoints, in accordance with the study protocol and study analysis plan.”

The requests from the House Committee on Energy and Commerce included making available the ENHANCE study director, Dr Enrico Veltri, and its principal investigator, Dr John Kastelein, as well as officials from both Merck & Co and Schering-Plough for interviews with Committee staff; and providing written explanations as to: why the ENHANCE study was not included on the ClinicalTrials.gov registry until 31 October 2007, 18 months after its completion; and why the study’s primary endpoint as indicated in the ClinicalTrial.gov entry “appears to differ” from the one described in the initial study design.

“We are concerned with the delay in releasing the results of the study, the timing of ENHANCE trial registration, and the apparent manipulation of trial data,” the Committee said.