The Lessons from Vytorin

What lessons should be drawn from the trials of Vytorin?

For those not paying close attention, let’s recap the events so far (this is my reinterpretation and supplementation of the
timeline the Merck/Schering-Plough joint venture, which markets Vytorin, released yesterday):

In November 2002, the Food and Drug Administration approves the first non-statin cholesterol-lowering drug, Zetia (generic name ezetimibe). The approval is based on a single clinical trial (“Add-on”) that shows it reduces cholesterol in patients with a family history of high cholesterol who haven't reached the target level with a statin drug (Zocor or simvastatin) alone. There trial provides no evidence that the patients taking the Zetia-Zocor combination pill suffered fewer deaths from heart attacks and strokes, which is, after all, the goal of lowering cholesterol.

Shortly before the drug was approved, Merck/Schering-Plough launch an unregistered clinical trial called ENHANCE that plans to measure arterial plaque at three sites around the heart. Again, the protocol contains no plan to compare death rates in the two arms of the trial. Scheduled completion date? April 2006 with results to be released in March 2007.

Under pressure from cardiologists to show that this new class of non-statins actually improves health, the joint venture in September 2005 finally launches a large, multi-center clinical trial designed to test actual outcomes with the combo pill, now called Vytorin. Targeted completion date? 2011. This trial, at least, gets registered in the government’s clinical trials database. (The FDA reform law passed last year made it mandatory that companies register most second- and third-stage pre-approval trials and all post-marketing trials.)

During 2006, as sales of Vytorin mount into the billions, the ENHANCE trial’s data monitoring committee gets the results from ultrasound image readings. The trial sponsors deem them “biologically implausible.” They postpone the scheduled March 2007 presentation to the American College of Cardiology annual meeting while a new process for reading the images is tested and implemented. They announce new plans to release the results at the November 2007 American Heart Association meeting.

After missing that deadline, too, the joint venture convenes an “independent” panel to review the data. It concludes the image readings still have “problems.” The panel votes to change the protocol of the trial to measure just the width of plaque in the common carotid artery because it “provided the most reliable and consistent measurements.” The companies announce the change on November 19.

On November 21, the New York Times carries a front page story headlined, “After a Trial, Silence,” questioning the long delays in releasing the results of the trial and the change in its primary endpoint – a major no-no in clinical trial behavior.

Three weeks later, after several Congressional committees launch investigations, the companies flip-flop and go back to the original endpoints.

On January 15, with sales of Vytorin plunging, the companies finally release the results of the ENHANCE trial. There's no difference in any plaque measurements between the two arms of the trial, even though Vytorin (Zetia plus Zocor) did reduce cholesterol more than Zocor alone.

The American Heart Association and American College of Cardiology on the same day issue statements cautioning patients not to stop taking the drug before talking to their physicians.

A week later, the New York Times reveals that the Merck/Schering-Plough joint venture had donated $2 million to the AHA, a fact still not revealed on the press release but reported elsewhere on the non-profit’s website.

A generation ago, the drug industry accounted for about a third of clinical trials, while academic medical centers, using largely government funds, accounted for two-thirds of the tests. Today, that ratio is reversed. One estimate I’ve seen suggested industry spends over $20 billion a year on clinical trials, well over half of its collective research and development budget.

The time has come to ask whether our privatized system of clinical trial research is serving the nation’s health. The fact that a drug like Zetia can be approved and sold to millions of people for nearly a decade without any evidence that it actually saves lives is absurd. The FDA has the authority to order companies to conduct conclusive post-marketing trials. But when it does, the companies often delay complying or ignore the requests. The agency does nothing. I am not aware of a single instance where the FDA has removed a drug from the market for failing to complete a requested post-marketing trial.

There’s much talk these days about identifying new biomarkers – like cholesterol – that will help industry end its drought in bringing new drugs to market. But why should the public trust the claims made on any new biomarker’s behalf when industry drags its feet in testing its validity in the only place where it matters – in a clinic trial testing whether affecting that biomarker actually improves health?

Our health care innovation system now relies on industry to finance clinical trials. But let’s not forget that the money spent on R&D is derived from patients and their insurers. It is a current cost of doing business, and accounts for about 20 percent of the price of every pill we pop. Perhaps the time has come to give patients more say over how that money gets spent.

One of the chief reforms talked about in the push for health care reform is creation of a new agency, either independent or within the government, that can conduct comparative effectiveness research on existing therapies. As the health care policy community debates that agency’s shape and scope, it should also consider giving it the authority to manage all late-stage pre-approval and post-marketing trials.

Companies would pay user fees for the trials, just as they now pay user fees to the FDA to review their results. But the new agency would design the protocols and manage the process. The goal is to ensure that data derived from the trials maximize knowledge for improving public health. And, it will be credible because direct industry influence over the conduct of the trial has been eliminated.

Dean Baker of the Center for Economic Policy and Research has suggested that all clinical trials get run through such an agency. But, in my view, early stage safety and proof-of-concept trials should stay in companies’ hands. Centralization too early-on in the process might result in frustrated innovators accusing the government or whoever ran this agency of picking winners and losers. Or, it might dampen capital markets’ willingness to invest in start-up firms if they come to believe “the agency” has become too tough in allowing experimental drugs into the pipeline.

Such an clinical trials agency would set a new gold standard for medical research: completely independent, double blind, placebo-controlled trial for truly new therapies; and completely independent double-blind, comparison-controlled trial for competing therapies.

The government has a long history of financing and managing clinical trials through the National Institutes of Health, especially the National Cancer Institute. Yet its authority and centrality has been undermined in recent years as industry-funded trials seized center stage. Companies, meanwhile, have an equally long and sordid history of refusing to fund or follow through on clinical trials that might jeopardize their bottom lines. The result? Crucial gaps in the information about new therapeutics go unaddressed.

To answer the question posed at the beginning of this post: the Vytorin episode teaches us that the time may be at hand to relocate responsibility for the nation’s sprawling clinical research enterprise.

Posted by gooznews at January 26, 2008 10:10 AM