Even gold can be tarnished

A riveting pharmaceutical clinical trial melodrama has been playing this past week. It’s a story filled with conspiracy theories of cover-ups and secret manipulations of clinical trial data and clinical trial design that’s leaving cardiologists and medical ethicists rankled. Most consumers are unaware of these debates, however, as there’s not been a peep on network news or in our local newspapers. But this incredible tale gives us a glimpse as to why even published clinical trials, the gold standard of research, deserve close scrutiny.

The firestorm began last Monday when Merck/Schering-Plough Pharmaceuticals issued a press release to medical professionals announcing that an independent review panel had been convened by the company the previous Friday to advise them on how to analyze the data of its ENHANCE trial. As a result, the company had decided to change the primary endpoints to expedite their analysis. They also said that only some of the original primary results would be released. They hoped to present their report of the trial at the American College of Cardiology meeting in March 2008. The significance of this may not be immediately clear, so let’s get caught up.

This trial had begun in 2002 on 720 people with very high cholesterol, and the study ended in April 2006. Cardiologists had been expecting to learn the results last November. That didn’t happen. Then, they were promised them in March of this year. Again, they never materialized. The delays are concerning cardiologists because millions of people have been being prescribed Zocor (simvastatin) with Zetia (ezetimibe), believing they prevent heart attacks and strokes.

The only problem, no study has ever shown Zetia to be effective in improving clinical outcomes (such as reducing cardiovascular events or deaths), despite bringing in $5 billion a year in sales for Schering-Plough. It turns out the Zetia had been approved by the FDA on the basis of trials showing it could lower LDL-cholesterol, a surrogate endpoint, by 15-20%.

The ENHANCE trial was designed to see if Zetia with Zocor works better than Zocor alone. Again, however, it wasn't using actual clinical outcomes as its primary endpoints, but surrogate endpoints of arterial obstruction as measured by carotid intima-media thickness at three locations and femoral artery IMT.

What makes this trial especially critical for the pharmaceutical makers is that Zocor’s patent expired, so it has been combined with Zetia to make a “new” drug, Vytorin, that can be patented. Multi-billions of dollars are at stake in protecting their interests from generic drug companies.

This exemplifies what Dr. Marcia Angell, M.D., former Editor-in-Chief at The New England Journal of Medicine and author of The Truth About the Drug Companies: How They Deceive Us and What to Do About It, had warned. Most drugs brought to the market aren’t new drugs or improvements over drugs already available. Most don’t even contain new chemical compounds, but are old drugs in new combinations or formulations, often created just as patents are about to expire. “The idea is to grab a share of an established, lucrative market by producing something very similar to a top-selling drug.” As she wrote:

Of the seventy-eight drugs approved by the FDA in 2002, only seventeen contained new active ingredients, and only seven of these were classified by the FDA as improvements over older drugs. The other seventy-one drugs approved that year were variations of old drugs or deemed no better than drugs already on the market. In other words, they were me-too drugs.

More would come out about this trial as the days went on...

On Monday, Matthew Herper wrote in Forbes’ business section that the delays were raising suspicions among cardiologists that the ENHANCE trial results weren’t favorable, because with so much money at stake if the news was good, the company would rush to report the results. Two other sources of suspicion were revealed: the pharmaceutical companies hadn’t listed the trial on the government website, clinicaltrials.gov, where all clinical trials are supposed to be recorded; and credible clinical trial protocols standardly recommend that the drug company sponsors not have control over the study data and how it is analyzed. “In this case, that database is held by Schering-Plough,” he wrote.

After the Forbes article was published, the Merck/Schering-Plough press release came out announcing they were changing the primary endpoints. That fueled an article on Wednesday by Alex Berenson in the New York Times. As he reported, scientists consider for a clinical trial to be valid that its goals must be clearly defined at the start and not changed later, otherwise it’s easy to change the goals to match the data the trial actually came up with. Two other worrisome facts were made clear in that story. The lead investigator didn’t have access to the raw study data or any control over its analysis, as that was all in the hands of the drug company sponsors. The drug companies were also not disclosing the “experts” they’d convened, who’d advised the primary endpoints be changed.

Was everyone just being paranoid and getting caught up in conspiracy theories, as some wondered?

The next day, an article appeared on Heartwire (a news service of WebMD), trying to counter speculations that the results were bad and the companies were delaying their release. Reiterating the companies’ press release, the lead investigator said that the study was late in reporting because of technical difficulties with nearly 40,000 images to process. “That’s an incredible amount of data to deal with,” he told Heartwire. “Maybe we were a little ambitious on the timeframe required to process so much data. That is why there has been some delay. The suggestion that the results are being suppressed because they are negative is simply wrong.” He said the data was still blinded but the companies’ expert panel felt that the secondary endpoint would be better as the primary endpoint and the primary endpoints would now be secondary. When asked why the company made this unusual move after the trial was completed, he admitted:

These are very important data for the company. The drug has huge sales, and this study will be the first real indication as to whether it is working. Everybody is understandably nervous. My opinion was that everything was fine the way it was and we should just continue, but they wanted some additional reassurance from outside experts and they got it. I didn't like it very much, but it was necessary to settle their minds.

According to Heartwire, he said the whole debacle has highlighted the tensions that exist between the lead investigator of a study and the sponsor. Readers could feel the unease in this situation, when he said:

The other experts supported me, but maybe we have had more difficulties with this study because the sponsor has control over the database. If the investigators have control, then we get to do the analysis our way. In future, I will try very hard to get this.

Most of the discussions of this situation have been among bloggers. Dr. Aubrey Blumsohn suspected that the study data had been secretly unblinded, and may be why the endpoints were changed, as the unblinding codes are presumably held by the same entity holding the raw data. “That same entity has a huge financial stake in the outcome,” he said. However, it’s also “easy to fiddle the results of a randomized trial given a blinded study database even without unblinding codes,” he said. Zetia has enough side effects that it could easily be distinguished from placebo, he said.

But the harshest critic of these drug trials may be Dr. Scott K. Aberegg, M.D., M.P.H, Assistant Professor of Medicine at Ohio State University in Columbus, Ohio. Writing on his blog, Medical Evidence, he made three interesting observations about this situation.

While the drug companies aren’t releasing the findings even nearly two years later, saying that analyzing the IMT data is taking longer that they anticipated, they could greatly allay concerns by simply releasing the more easily compiled data on mortality and safety endpoints, which are monitored for safety on all clinical trials. “It doesn’t take very long to add up deaths,” he said.

He also pointed out concerns about the endpoints, saying that by pre-specifying multiple endpoints (carotid IMT at three locations and femoral IMT), their chances of meeting one of them by chance alone was increased. But changing their primary endpoints after the trial is completed breaks the most hallowed position on endpoints. If you fail to prove your hypothesis, you lose, you don’t move the endposts. Worse, the sponsors are now not even planning to release all of their former primary endpoint data at all.

Discussing the design of the ENHANCE trial, he said it compares full 80-mg doses of Zocor to 80-mg of Zocor and 10-mg of Zetia, but isn’t looking at any clinically meaningful endpoints. To test the drug’s effectiveness with hard clinical endpoints (heart attacks, strokes and death), Shering-Plough has launched the IMPROVE-IT trial, due to be completed in 2011. But the company is up to some tricks to save Zocor from generic death with this trial, he wrote. They designed the study to compare half doses of Zocor and Zetia to half doses of Zocor alone, so there will be no way for clinicians to know what works better, he said. Doctors won’t have the important information they need to know if Zetia is superior to an alternative (going generic soon) at maximum dose, or if its addition to maximum dose Zocor offers any additional benefit. They didn’t use full doses, he said: “Such trials are too risky for the company — they may show that there is no point to prescribing [Zetia] because it is either less potent than max dose [Zocor] or that it has no incremental value over max dose [Zocor].” He went on to say:

You see, this trial was designed primarily for the purpose of maintaining patent protection for simvastatin [Zocor] in the combination pill. Its potential contribution to science and patient care is negligible. So much so in fact, that I think this trial is unethical. It is unethical because patients volunteer for research mainly out of altruism (although in this case you could argue it's for free drugs). The result of such altruism is expected to be a contribution to science and patient care in the future. But in this case, the science sucks and the main contribution patients are making goes to the coffers of Schering-Plough.

Such harsh criticism is reminiscent of concerns raised by Dr. Angell when advocating for scientific integrity and pointing out the abuses of science and the inferior research that is increasingly the norm. As she’s said, the medical profession needs to break its dependence on the drug industry and the inappropriate control sponsors have over the evaluation of their own products. As she wrote:

Clinicians know privately that results can be jiggered. You can design studies to come out the way you want them to. You can control what data you look at, control the analysis, and then shade your interpretation of the results. Even the most careful research can be fraught with murky results that require sifting and weighing, a measure of judgment that the researcher hopes will bring him closer to the truth.

The ENHANCE trial appears to be a worse case scenario of how pharmaceutical company sponsors can manipulate and control the design, completion, data analysis and reporting of a clinical trial of its products, blurring the lines between scientific research and marketing. For doctors and patients, this makes it hard to even guess where the valid science lies and what to believe.