When science and sales get mixed up

There’s an old adage in business and politics that when you need to release troubling news, issue the press release late on a Friday afternoon when it’s certain to get the least notice and be forgotten by Monday morning’s news. A remarkable and disturbing announcement was issued late yesterday that deserves to make the news and receive the attention of the scientific and medical community.

Background

JFS readers have been following the riveting pharmaceutical clinical trial melodrama that’s been playing over at Merck/Schering-Plough Pharmaceuticals. As you’ll remember, first, there were repeated delays in issuing the results of their long-awaited clinical trial, ENHANCE, which had been completed in April 2006. ENHANCE was designed to determine if Vytorin [Zetia (ezetimibe) combined with Zocor (simvastatin)] worked better than generic Zocor alone. Then, the company announced that, based on the advice of a secret panel it had convened, they were going to change the primary endpoints and only release part of their findings.

This raised a firestorm among medical ethicists and doctors. It was bad enough that the trial was using surrogate endpoints, and not actual clinical outcomes, as its primary endpoints; that the drug company sponsors controlled the raw study data and its interpretation, and not the primary investigators; and that the trial hadn’t been registered on the government website, clinicaltrials.gov, where all clinical trials are supposed to be listed before they begin and their designs clearly defined — but changing the primary endpoints after a trial is completed is not how sound science is conducted, as it’s easy to move the goal posts to match the results and claim positive findings. The repeated delays in learning the results of this trial were also affecting millions of patients who were being prescribed the combination, even though Zetia had never been shown to be effective in improving outcomes and had been approved by the FDA on the basis it could lower LDL-cholesterol by 15-20%. But Zocor’s patent expired and by adding it to Zetia, the drug manufacturer could create a “new” drug, Vytorin, that could be patented and save Zocor from generic death for the company. ENHANCE would help doctors know if this new combination was more effective than generic Zocor.

Then, in a surprising move, the ENHANCE results were announced showing there were no benefits in the primary endpoints seen among patients receiving Vytorin over generic Zocor, even among the study population of people at the highest risks and believed the choice group to demonstrate a benefit. This launched quite a tumult of marketing spins, controversies and conflicting information, and lost among it all was that this was about the integrity of the scientific process that could provide the soundest evidence upon which to base medical decisions for patients and doctors.

The pharmaceutical companies assured everyone that its new trial IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) would provide the conclusive evidence needed on the drug’s effectiveness, as it was designed to give definitive answers as to if the drug showed actual clinical benefits. The trial was due to be completed in January 2011.

While the IMPROVE-IT trial could be used to claim effectiveness if the results were favorable, it was actually designed to not give doctors any real answers. Even the ethics of this trial have been questioned by Dr. Scott K. Aberegg, M.D., M.P.H, Assistant Professor of Medicine at Ohio State University in Columbus, Ohio. IMPROVE-IT was designed to compare half doses of Zocor and Zetia to half doses of Zocor alone, so there will be no way for doctors to know if Zetia is better to Zocor at full dose, or if its addition to full dose Zocor offers any additional benefit, he said. Using full doses would be too risky for the company, he said because it might show no incremental value over full-dose Zocor and “this trial was designed primarily for the purpose of maintaining patent protection for Zocor in the combination pill.”

NEWS

A press release about the IMPROVE-IT trial was quietly issued late yesterday afternoon from Brigham and Women’s Hospital, not the pharmaceutical companies. For those concerned with the integrity of scientific research and clinical trials, this news was disturbing. It is a novel and effective way to delay releasing the results of this trial for an undefined period of time.

The researchers announced that they are changing the study protocol in order to nearly double the number of study participants to 18,000, reportedly to ensure the study is large enough to have the statistical power to measure the clinical effects. We are to believe that the original study was not correctly designed to measure effects.

The decision was made, according to the press release, “based on ongoing evaluation of blinded, aggregate” findings and a “further review of the statistical assumptions surrounding the relationship between LDL-cholesterol lowering and the expected reduction in clinical events.” Making the highly unusual move of changing a study in the middle of a trial makes you wonder if the data they were seeing wasn’t favorable.

This is not the first time that the investigators effectively created a delay by changing the trial design in the middle of the trial, either. It amended the trial in September 2007 to increase the targeted number of events to meet its primary endpoints from the original 2,955 to 5,250 and the study enrollment size from the original 10,000 to 12,500 people.

To help readers understand what this means, this trial is designed as an “event-driven” trial. So, its completion date depends on when the targeted number of primary endpoints events are reached and the last person enrolled will have been followed for a minimum of 2 ½ years. In other words, because of how its primary endpoint is defined, now, at least 5,250 people will have to die from “any cardiovascular events, non-fatal coronary events (such as heart attack), and non-fatal strokes” and everyone else enrolled in the trial has been followed for at least 2 ½ years.

They estimate that could take until 2012, but they couldn’t give an exact date when the trial will end. How much do you want to bet that won’t be until the Vytorin patent has expired and Merck and Schering have enjoyed $5 billion in annual sales? All the while, millions of people will be prescribed Vytorin or Zetia by their doctors, believing they’ll prevent heart attacks and strokes and help them live longer. With no evidence at all.