Concerns are brewing over strange events, quack science and possible scientific misconduct during reporting of the "Enhance" trial of the cholesterol-lowering drug Ezetimibe[1][2][3][4][8]. Ezetimibe is sold by Merck and Schering-Plough (trade names Zetia and Vytorin with annual sales of $4billion). No trials have shown that Ezetimibe reduces cardiovascular events (the main endpoint). No such trials were required prior to FDA approval. The drug does however lower the bad form of cholesterol (LDL). I personally have no problems with drug approval in the absense of evidence of efficacy, so long as customers (doctors and patients) are not misled. Its a free world. I guess all patients have been told that a) the relationship between LDL lowering and actual clinical disease is not straightforward, b) that some drugs lower LDL but increase risk, c) that the relevant science prescribers have been permitted to see is a sack of potatoes.
The "Enhance" study of Ezetimibe was supposed to look at a surrogate endpoint that is one step closer to actual cardiovascular events - namely the development of atherosclerotic arterial plaques. So what happened?
- Oddly the reporting of "Enhance" was put off by a year, and it is now planned to remove the shroud of secrecy sometime in 2008 (possibly.....). Cardiologists expected to see results at a medical meeting in November 2006, then at another in March 2007, then at another this month. But none materialized [8].
- It turns out the companies have decided to change the study's primary endpoint in retrospect. To convince everyone that this is the right thing to do, they brought in an "outside" expert advisory "panel" who concluded that the wrong thing is the right thing (presumably for a fee). They then refused to state who these supposed experts were.
- It turns out that the company has had full control over all of the study data and that the lead "author" has not yet seen any of it.
- Lead investigator of the study, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands)stated that "The suggestion that the results are being suppressed because they are negative is simply wrong. People are assuming that anyone can take a peek at the data, but how can they do that if it hasn't even been unblinded and there are 40 000 images to analyze?"
- Firstly, we have no confidence (P=0.3) that the study has not in fact been secretly unblinded. This lack of confidence is the logical assumption following numerous odd events and data alterations which have taken place in the past (random examples here[5][6]). Unblinding codes are presumably held by the same entity holding the raw data (I guess). That same entity has a huge financial stake in the outcome. That entity is not yourself Dr Kastelein. Nor is that entity a secure impartial honest third party (a complete guess).
- Secondly, as an experienced scientist you will be fully aware it is perfectly easy to fiddle the results of a randomized trial given a "blinded" study database even without the un-blinding codes. Ezetimibe has many side "effects" that distinguish it from placebo apart from it's intended clinical benefit (LDL lowering is itself such a "side effect"). It would be easy for an individual "exploring" the data to examine the relationship between LDL lowering and various "primary endpoints" without unblinding to get a pretty good idea of the "primary" endpoints to reject, exclusion criteria to be applied, or even the variables that might require a little "recoding".
Others [4] have pointed out some of the key problems with this research, and I have added a few more:
- Seek to get your drug on the market before we know whether it actually makes us live any longer or prevents real disease.
- Keep all the data under your strict control; don't even let the (so-called) lead investigator see it.
- Change the primary study endpoint in the middle of the trial.
- Pretend that this is science.
- Keep all the processes as secret as possible at each step of the way.
- Conduct studies that focus on patients who are not at all representative of the intended target customer for the drug.
- Pretend that you are a company based on science, but at the same time pretend out loud that altering data or endpoints in a still-blinded study cannot possibly be a means to induce bias.
References:
- Hughes, Sue (2007-11-23). Concerns Raised on Delay of Ezetimibe Data. Medscape/Heartwire.
- Merck/Schering-Plough Update on ENHANCE Trial. Merck Website.
- Berenson, A (2007-11-21). After a trial, silence Page C1. New York Times.
- Brody, Howard (2007-11-24). Here We Go Again: Everything That's Wrong with Industry Sponsored Trials. Hooked: Ethics, Medicine, and Pharma.
- Blumsohn, Aubrey (2007-10-21). Vioxx and a quacking duck. Scientific Misconduct Blog.
- Blumsohn, Aubrey (2007-05-19). On the redefinition of research misconduct. Scientific Misconduct Blog.
- Berenson, Alex (2007-11-24). Cardiologists Question Delay of Data on 2 Drugs. New York Times.
- Herper, Matthew (2007-11-19). Drug Trials: The Vytorin Question. Forbes. Retrieved on 2007-11-27.
5 comments:
Dear Dr. Blumsohn, your critique of a study about ezetimibe, part of Vytorin[TM], is well taken. This drug lowers cholesterol but has no patient health benefit studies to its name yet millions of people are taken it, by prescription. It is heavily advertised in the U.S. in print and in several times daily TV ads but it has yet to show it prevents a single heart attack or save a single life.
So, regarding study results: look for fewer deaths and fewer heart attacks, not for some other reporting point unless there is probable or demonstrated benefit in health from whatever reporting endpoint.
The trial in question, ENHANCE, has changed 'scope', indeed a very rare almost unprecedented event in large clinical trials.
You mention Dr. Kastelein, lead investigator of ENHANCE. He, I submit, is a man of shown integrity, having publicly been in a similar situation to the one you were once subjected to and when his like your good name was also abused for promotional purposes, in this case by a Dutch advertising agency paid by Pfizer. He immediately severed ties with all drug companies and stopped acting as consultant and court expert for them in The Netherlands. I believe that was in the summer of 2006. This thus happened after he and others were well committed to the ENHANCE study and that evidently should be properly reported.
I believe and hope that drug companies have learned a vital lesson [Baycol/Lipobay, torcetrapib, Vioxx] that badly reporting data in their possession leads to gigantic financial losses and patient and doctor confidence and which is why torcetrapib data [a drug discontinued since it killed people] continue to be reported.
Dr. Kastelein has to be one of the better situated people to do the reporting, be they what they may. My problem with many Pharma owned study reports, no matter how objectively presented, is that the interest groups involved [the drug company and the websites like Medscape, theheart.org, WebMD and others] that heavily depend on drug company money will generate the most positive spin possible and that no researcher [not even Kastelein, Genest or Nissen] can control the entirely positive message generated for consumers and prescribing doctors.
vos@health-heart.org
P.S. my take on cholesterol: http://www.health-heart.org/cholesterol.htm
That 'spin' mentioned in Eddie Vos' comment above has worked wonders for UK's NICE who appear to have endorsed ezetimibe for NHS treatment already. It seems a rather reckless 'hit and miss' (though perhaps not particularly unusual) attitude towards patient safety when they don't know for sure whether data is being supressed, or what that data might show.
NICE waves through new cholesterol treatment
"29 November 2007
Patients with poorly-controlled levels of cholesterol have been given another treatment option after the National Institute for Health and Clinical Excellence issued formal guidance endorsing the use of Merck & Co/Schering Plough’s Ezetrol on the National Health Service.
Specifically, the Institute recommends Ezetrol (ezetimibe) as a stand-alone option for patients unable to take a statin, and that the drug be added to statin therapy in patients with poorly-controlled levels of cholesterol despite an increase in statin dose where possible..."
This Zetia debate just emphasizes an important concept. Surrogate markers don't necessarily mean anything. It's similar to the Pfizer HDL drug that was axed before making it to the market. HDL levels increased, which is what everyone wanted. But patients had worse clinically important outcomes. So the surrogate marker was worthless for that drug. Could it be a similar case for Zetia? If so, everyone who prescribed this drug, telling patients that "it's important to lower your risk of stroke or heart attack" should be ashamed.
News update comment on 'withholding data':
Reuters
MERCK, SCHERING-PLOUGH CHOLESTEROL TRIAL FACES PROBE
"LOS ANGELES (Reuters) - Schering-Plough and Merck & Co are being investigated by U.S. lawmakers on allegations that the drugmakers are withholding data from a study that may change how doctors treat high cholesterol.
In a letter dated Dec. 11 and emailed to journalists, Rep. John Dingell, Chairman of the Committee on Energy and Commerce, and Rep. Bart Stupak, Chairman of the Oversight and Investigations Subcommittee, requested information on the delayed release of data from their ENHANCE trial concluded in April 2006.
"We are aware of the letter, but have not yet officially received it, so we cannot offer a comment at this time," said a Schering-Plough spokesman.
No one at Merck was immediately available for comment.
The ENHANCE trial compared the effectiveness of Vytorin -- a product of Schering-Plough and Merck in partnership -- with Merck's Zocor in treating patients with a genetic predisposition to dangerously high cholesterol levels.
Vytorin combines the active ingredients from Zocor and Zetia -- also from Schering-Plough and Merck in partnership -- into a single pill.
The patent on Zocor has expired, and economic research firm Global Insight said in November the two groups hoped to show that Vytorin is superior to Zocor, also known as simvastatin, in a bid to fend off competition from makers of generic simvastatin.
Cardiologists have been clamoring for full results from the ENHANCE trial, which involved some of the industry's best-selling cholesterol-lowering drugs.
In recent years, drug companies have vowed to promptly deliver clinical trial findings after being chastised for failing to disclose negative trial results.
In the letter, Schering-Plough CEO Fred Hassan and Merck CEO Richard Clark were asked to make the study's principal investigator and corporate officials available for interviews with committee staff.
Dingell and Stupak also raised concern that the companies changed the trial's primary endpoint -- its main objective.
Merck and Schering-Plough said in a Nov. 20 press release they changed the primary endpoint on the recommendation of an independent panel of clinical and biostatistical experts.
The companies also said it has taken longer than expected to examine artery scans collected during the trial, but they plan to present ENHANCE data at the American College of Cardiology conference in March.
On Tuesday, Schering-Plough posted updated ENHANCE trial information on its Web site. It said researchers now plan to present both the original endpoint and the newer endpoint at the college.
The company also said that as of Dec. 11, neither the company nor the investigators knew the results of the trial."
Meanwhile...
Merck to Boost Profit With Obesity, Cholesterol Drugs
By Shannon Pettypiece
Dec. 11 (Bloomberg) -- Merck & Co., the maker of the top- selling osteoporosis drug Fosamax, plans to seek regulatory approval next year for a new obesity treatment and begin selling a medicine for raising levels of good cholesterol.
The new drugs should help offset some of the $2 billion in sales Merck may lose next year as generic copies of Fosamax reach the market. Merck has seven treatments in the final stages of testing, the Whitehouse Station, New Jersey-based company said today in a statement.
Merck's shares have gained 76 percent since Richard Clark, 61, took over as chief executive officer in May, 2005. Under Clark, the company has won U.S. approval of nine new therapies, including the cervical-cancer vaccine Gardasil, which has generated $1.4 billion in sales since it was cleared last year. Merck has more new drugs in final testing than Pfizer Inc., the world's largest pharmaceutical company, which has four.
``This is going to lead to reasonably robust growth over the next several years until the early stage pipeline can manifest itself,'' said Robert Hazlett, an analyst with BMO Capital Markets in New York.
The drugmaker today updated investors on its products in development during a meeting at its headquarters.
Merck fell 37 cents, or less than 1 percent, to $60.40 at 4:04 p.m. in New York Stock Exchange composite trading and has gained 39 percent this year, making it the top performer in the Standard & Poor's Pharmaceuticals Index.
2008 Profit
Merck said last week that 2008 profit, excluding certain items, will increase about 7 percent to $3.28 to $3.38 a share. This year the company expects earnings of $3.08 to $3.14, excluding one-time costs.
CEO Clark has also been cutting costs by eliminating more than 6,000 jobs and plans to cut another 1,000 by end of 2008, he said. ``Our momentum is what makes us confident to achieve our long-term results,'' he said today.
The company said it expects to begin selling in the U.S. the niacin drug Cordaptive, which raises ``good'' HDL cholesterol without a side effect, known as flushing, that causes patients' faces to swell. Sales of Abbott Laboratories' similar-acting drug Niaspan, with $167 million in third-quarter revenue, have been limited because of the effect of niacin.
Another experimental cholesterol drug, anacetrapib, will advance into final tests required to meet U.S. approval, Merck said. The medication is from the same class as Pfizer Inc.'s drug torcetrapib, which research has shown to raise risk of death from heart disease, heart attack and stroke.
Approval Skepticism
Some analysts said they are skeptical Cordaptive will win approval because of safety concerns and limited data. A 12-week study of about 1,400 patients presented at the American Heart Association meeting in November showed higher blood sugar levels and a rare increase in liver enzymes, a sign of liver damage, in some patients.
The cholesterol pill may have $430 million in annual sales by 2012, Corso said.
Merck is also seeking approval next year for a new obesity drug called taranabant. The drug is similar to Sanofi-Aventis SA's Acomplia, which was rejected by a panel of FDA advisers in June because of concern it may increase the risk of suicide.
Both Merck and Sanofi's drugs are designed to block a receptor in the brain called CB-1, the same one activated by marijuana that makes pot smokers feel hungry. Researchers say the receptor also may play a role in regulating mood since activating it appears to make people feel happy or elated.
`High Risk'
``There is still a healthy amount of skepticism surrounding that program,'' Hazlett said. ``We know where we sit with that, which is hugely high risk.''
The company will start a study next year to assess the effectiveness and safety of anacetrapib, which analysts said may have $15 billion in annual sales. Merck said it also plans a large scale trial to assess whether the drug reduces the risk of heart attack and stroke as early as 2009. It could be more than four years before the drug gets U.S. regulatory approval.
``We think the mechanism remains untested as to whether it will be a benefit, but it has the potential to have a significant benefit in terms of treating people,'' said Peter Kim, president of Merck's Research Laboratories, in an interview today. ``We think we have the best molecule in the class of drugs to test this mechanism.''
Good Form of Cholesterol
Anacetrapib is designed to reduce the ``bad'' LDL cholesterol that clogs arteries and increase the good form that sweeps it away. Unlike Pfizer's torcetrapib, which was terminated last year, the Merck drug hasn't been shown to raise blood pressure in testing.
Merck is also seeking U.S. approval to allow non- prescription sales of older cholesterol drug, Mevacor.
A review today by staff of the Food and Drug Administration said that Mevacor is `` safe and effective,'' though patients may not know how to properly use the drug. A panel of FDA advisers is scheduled to recommend tomorrow whether Mevacor should be sold over the counter.
The company said it has 25 drugs in the first of three stages of testing generally required to win U.S. approval and 15 in the second phase. "
If mevacor is so safe and effective,
why...
"During the initial development of Mevacor well over a decade ago, it is to Merck’s credit that they were sufficiently concerned about the potential side effect reactions to consider offering a combined Mevacor / Ubiquinone pill to help offset the side effects to come from the of inhibition of ubiquinone that inevitably must result from Mevacor and, indeed, any other statin drug.
All pharmaceutical researchers were well aware that to inhibit the mevalonate pathway, and thereby substantially diminishing cholesterol, one inevitably must inhibit ubiquinione, known to most patients as Coenzyme Q10.
You simply cannot have one without the other. Although Merck obtained a patent for its combined Mevacor / CoQ10 pill, no further action was taken on this matter."
That might be why "patients may not know how to use the drug"!
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