If an expensive, name-brand cholesterol drug costs four times more than a generic but provides no clear clinical benefit, why do insurers—both public and private—continue to pay for it? The answer, in the case of Vytorin, a combination of two drugs designed to lower LDL or bad cholesterol, is that the influence of big Pharma in maintaining the status quo—even when unsupported by evidence—remains a formidable barrier. By suppressing negative studies, relentlessly pursuing positive trial results, and paying academic researchers to promote their therapy, Merck Schering-Plough has managed to hold onto a $4.6 billion market for a drug that has never been proven to be better than cheaper generics in preventing heart attacks or death.
Why is this important? When we talk about reducing health care costs, the discussion eventually turns to cutting waste out of the system—the costly treatments and procedures that don’t provide clear benefits and might even cause harm. Within this group there are “low-hanging fruits;” the treatments and procedures that so clearly meet this criteria that they should be among the first to go. In the nearly $20 billion market for cholesterol-lowering drugs, Vytorin—a combination of simvastin, an off-patent statin and Zetia, a proprietary drug that is designed to inhibit the body’s absorption of cholesterol from food—is one fruit that may be worth plucking.
The case against Vytorin (and Zetia, as well) begins with a large, multi-year trial called ENHANCE that pitted Vytorin against simvastin alone. By at least 2006, executives from Merck and Schering Plough learned of results showing that Vytorin, although more effective in lowering patients’ cholesterol levels, did not reduce plaque in the carotid arteries of patients any better than simvastin alone. Instead of publishing these results, the companies (who at that time were jointly marketing the drug) kept them quiet and launched a massive marketing campaign for Vytorin—featuring upbeat pictures of food and quirky relatives to illustrate the point that to fight heart disease, patients need a drug that controls high cholesterol due to genes and diet. In 2006, the drug brought in $1.5 billion with sales climbing 25% in the first half of 2007 to over $2 billion, according to IMS Health.
In articles for HealthBeat, “The Cholesterol Con—Where Were the Doctors?” and “The Origins of the Cholesterol Con,” that question whether lowering cholesterol will really help most people ward off heart attacks, Maggie reports that Merck and Schering/Plough, “were shy about reporting the results of the clinical trials. It was only when they were threatened with a Congressional investigation that they made the results public on January 15 [2008]—more than a year and a half after the clinical trials were completed.”
This delay in releasing negative data about Vytorin by Merck and Schering-Plough (which have since merged) has led to legal headaches for the companies. In the last few months the companies have agreed to pay out a combined total of $46 million to state attorney generals and consumers to settle class action lawsuits alleging that the companies violated consumer protection laws by marketing Vytorin and Zetia as being superior to other cholesterol-lowering drugs and selling them at higher prices when, in fact, they were not more effective. Merck continues to deny wrongdoing, and this financial penalty is merely a drop in the multi-billion dollar bucket of profits the company made selling the drugs during the delay.
Investors are also seeking recompense; several large pension funds have now joined a separate class-action lawsuit being filed against Merck/Schering-Plough. This suit alleges that the company knew about the negative results of trials as early as 2005 and continued to make “false and misleading statements that artificially elevated the price of the company’s shares.”
It’s clear that the legal problems surrounding Vytorin and Zetia are not going away anytime soon. And in the meantime, the scientific evidence for the drugs’ benefits continues to be negative—except in merely lowering serum cholesterol levels. Two new studies, presented last week at the American Heart Association meeting in Orlando, have disappointing results that back up the ENHANCE findings:
1) One trial, published in the New England Journal of Medicine, looked at patients who either had coronary artery disease or were at high risk of the disorder and took statins to lower their LDL (bad) cholesterol levels. The participants were given a prescription version of niacin (a b-vitamin) which raises the levels of HDL (good) cholesterol in the body, or alternately, ezetimibe (Merck’s Zetia) which lowers LDL levels even further but has no effect on HDL. The idea was to see which drug regimen worked best in reducing buildup of plaques in the neck artery. When plaque builds up on artery walls it causes them to narrow, leading to heart attack or stroke.
The results were not encouraging. Researchers found that patients in the niacin group saw their HDL cholesterol rise and had a “significant regression in artery wall thickness.” In the group that took Zetia, LDL cholesterol levels fell, but there was no change in the plaque buildup on the artery walls. HDL actually removes LDL from the blood-stream in a process called “reverse cholesterol transport.” Additionally, the researchers found the incidence of heart attacks and strokes to be lower in the group taking niacin.
The results of this trial were not surprising to some experts. According to this article from back in 2007 in the New York Times, niacin has been known to prevent atherosclerosis and to reduce the risk of second heart attacks since 1975.
“Here you have a drug that was about as effective as the early statins, and it just never caught on,” Dr. B. Greg Brown, professor of medicine at the University of Washington in Seattle told the Times. “It’s a mystery to me. But if you’re a drug company, I guess you can’t make money on a vitamin.”
2) In another study, also presented in Orlando, researchers with UnitedHealth Group Inc.’s pharmacy benefits unit Prescription Solutions analyzed medical claims of 30,000 patients taking either Vytorin, Lipitor (a statin made by Pfizer) or simvastatin, the cheaper generic. They found no difference in rates of heart attacks or strokes among the three groups. Although this analysis comes from a pharmacy benefit manager and hasn’t been published in a medical journal, it has major implications. Vytorin costs more than four times more per dose than simvastin—and again, hasn’t shown any clear benefits other than lowering cholesterol.
In the face of all this negative data, Merck continues to insist that Vytorin and Zetia have real benefits worthy of their high price tags—merely by lowering cholesterol levels somewhat lower than generic statins. At the Orlando conference, the company went on “a public relations offensive,” according to an article in Forbes. Merck sent research chief Peter Kim and marketing head Kenneth Frazier to Orlando to defend Zetia and even trotted out the inventor of the drug to talk to analysts and doctors.
In their defense of Zetia and Vytorin, the Merck researchers continue to stress that the drugs reduce cholesterol levels some 20% more than generic statins. This is not a huge benefit to begin with. And many experts question the wisdom of putting so many otherwise-healthy people on prescription drugs to reduce their cholesterol levels when this seems to have modest or no benefit in preventing heart attacks and strokes.
Merck is continuing to pursue this elusive evidence that its drugs will prevent heart attacks. It started enrolling people in a study looking at the benefits of
Zetia versus a placebo in preventing heart attacks in 2005 and has yet to meet its goal of enrolling 18,000 patients. Results are not expected until 2012 at the earliest, and critics wonder if the study will ever be completed—especially as patients drop out due to bad press about Zetia’s benefits.
Merck has also enlisted some of the top names in cardiovascular medicine to help in its public relations offensive. An article last month in the Chronicle of Higher Education provides details of how Merck Schering-Plough is using prominent doctors to convince their colleagues of Vytorin’s benefits:
“Fourteen university-affiliated physicians collected more than $400,000 from the makers of the anti-cholesterol drug Vytorin as part of a campaign to encourage the use of the medication. The 2008 campaign went on after an internal company study showed that the drug, with several billion dollars in sales, had little or no overall value for most patients.
“The physicians, many of them prominent in the field of cardiovascular disease, accepted the money from the manufacturers Merck & Company and the Schering-Plough Corporation for delivering speeches to health practitioners and attending advisory meetings. Sergio Fazio, a professor of medicine at Vanderbilt University, was paid $82,260, for example. Michael H. Davidson, a professor of medicine at the University of Chicago, was paid $71,150, and Antonio M. Gotto Jr., dean of the Weill Cornell Medical College, collected $27,146.”
So far insurers continue to buy the pitch. According to Merck, 81% of managed care customers have access to Vytorin at the “lowest branded copay.” Medicare continues to list Vytorin as a “Tier 2” drug, the best spot for a branded drug—Tier 1 drugs are generics and require the lowest co-pays from subscribers. Once a drug moves in Tier 3 in Medicare or managed care plans, the co-pays become much larger and the drug is prescribed far less.
How will the government, which stands to save billions over the years in removing these expensive drugs from their formularies, respond to this new evidence? The New York Times
reports that “Senator Charles E. Grassley, Republican of Iowa, wrote to the Department of Health and Human Services, asking its director, Kathleen Sebelius, what action she intended to take in light of the study results. Mr. Grassley sits on the Senate Finance Committee which has jurisdiction over Medicare and its drug spending. In 2006 and 2007, the drug makers made more than $300 million through Medicare Part D in sales of Vytorin, a drug that combines Zetia and a statin, Mr. Grassley wrote.”
Secretary Sebelius has not yet responded publicly. But the issue begs her consideration—if only because refusing to pay for expensive medications with no clear benefit over cheaper alternatives seems to be at the heart of efforts to drive down sky-rocketing health care costs. It will also provide a good test case for how successful the government can be in using evidence-based medicine as a defense against Big Pharma’s lobbying machine.
I agree with you that the pharmaceutical industry have not been Eagle Scouts. Negative studies should not be buried and physicians should not be paid off to hawk their products. The spooky practice of ghostwriting needs to disappear. However, these companies, like any industry needs to make a profit. It takes tens of millions of dollars to develop the medicines we all seek – drugs for arthritis, diabetes, cancer vaccine, genetically tailored medicines, etc. We don’t want these companies to simply go for safe choices to develop more ‘me too’ drugs that we don’t really need. If they are to take risk, then they need the hope of large profits to fund their expensive R & D. So, let’s make sure that the anti-corruption brigades don’t become OperationOVERKILL. http://www.MDWhistleblower.blogspot.com
Naomi – Thanks for another insightful post. The relentless promotion of Vytorin despite the lack of evidence for superiority over far less expensive drugs typifies the abuses that drive healthcare costs skyward in our chaotic system.
Before addressing the Vytorin issue further, I’d like to respond briefly to Michael Kirsch, because the Vytorin mythology is matched by drug industry mythology on the need for exorbitant profits. In fact, that industry has consistently seen very high profit margins year after year, and this consistency should put to rest the notion that high profits in one time interval are needed to offset losses due to risk taking in another.
The problem goes beyond this, however, because in truth, the drug industry is not needed for the development of effective medications. Faster and more effective drug development is possible without requiring any profits whatsoever –
http://tpmcafe.talkingpointsmemo.com/talk/blogs/fredmoolten/2009/06/prescription-drug-costs-can-be-2.php
While political considerations preclude a massive shift away from industry-based drug development, it should be feasible even now to take small steps in that direction. Some changes in patent law may help.
Getting back to Vytorin, it is conceivable that some small subpopulation of individuals exists for whom this drug combination of a statin plus Zetia would be desirable, but its mass marketing is unconscionable in the light of evidence that Zetia adds nothing to the effectiveness of the statin. The statins, including the generic symvastatin, are known to be highly effective in preventing cardiovascular morbidity and mortality in high risk groups, and if anything might be worth combining with them, it would be niacin – itself an effective drug for dyslipidemia although beset with more adverse side effects than the statins. The recent studies on carotid artery intima thickness imply that the combination should at least be explored further in selected patients.
A final dilemma deserves mention. There is currently no good evidence that statins would benefit individuals with normal lipid profiles – i.e., those at normal rather than elevated risk, but the possibility has not been studied adequately. Let’s imagine that it turns out that daily doses of statins would save the lives of many thousands of individuals annually. Some medical scientists, in fact, have jokingly suggested along these lines that statins should be added to the drinking water.
In this hypothetical circumstance, what should we do? Today, it is convenient to assert that when large populations at risk for serious diseases are concerned, remedies that work well are inexpensive, and remedies that are expensive work poorly or not at all. Eventually, however, we will face a circumstance in which something expensive works better for millions of individuals than any other intervention. This is a moral dilemma that I don’t think can be dodged forever, and we should be prepared to face it, whether or not statins prove to be its exemplar.
To tie this in with my point above that the drug industry is not the optimal resource for drug development, I would like to suggest that the public sector, through its ability to spread costs over an entire society in equitable fashion, and by virtue of its non-profit status, could mitigate the dilemma by permitting almost all reasonably likely future interventions to be made available at reasonable cost to those who could benefit from them. There will be no perfect solution to a problem of effective but expensive drugs, but the pharmaceutical industry can at least be asked to get out of the way.
I had this question on your october post but much later, so likely you didn’t see it there. There was this weird study in U.S news – “influential doctors for 2009”, the list looked very suspicious. Do pharma feed this info based on docs prescribing brand names? It was conducted by Qpharma. I’m stunned the list is published for public use based on god knows what data. Any comments?
Michael–
This is Naomi’s post, but I thought I should weigh in on the economics of the pharmaceutical industry because that is something I wrote about at Barron’s in the late ’80s and ’90s and in my book.
Pharma has been the most profitable industry in the U.S. for a good part of the last 10 years.
Currently the industry enjoys a profit margin of just over 16%.
No industry needs such a fat profit margin.
Wall Street analysts who cover the drug industry will tell you this.
They will also tell you that Pharma spends twice as much on marketing and advertising as it does on reserach.
Sometimes people suggest that Pharma’s investors need double digit earnings, year after year after year, becuause they are taking a risk investing in a business where no one knows which drugs will work out.
Big drugmakers (Phamrma–the folks making 16% profits) do not take risks. They haven’t for years. They wait until NIH or someone else (sometimes a very small company) has
done enouogh reserach to make it clear that the product should make it–and then they come in.
Investors know this. For much of the past 20 years, drug stocks have been considered “safe haven” stocks. No matter how bad the economy might be, very sick people Have to buy drugs. Whatever the price.
Drugmakers have them over a barrel. And they know this–which is why prices are so high.
In recent years, drug stocks have been somewhat less stable as people worry (rightly) about price regulation. Talk to the most knowledgable analysts on Wall STreet and they will tell you that Pharma has pushed too far–they’re just asking to be regulated.
(There is a saying on the Street: “Pigs get fed. Hogs get slaughtered.”)
Tiny drug outfits funded by venture capital take the risks–not the big boys. They’ll be developing the genetically tailored medicines.
Meanwhile, for the past decade Pharma has been focusing on “me too” drugs–variations on drugs that already exist rather than trying to make groud-breaking discoveries.
It’s safer.
If they took some of the money that they squander on advertising and “marketing” (much of that is pay-offs to doctors to speak at confernences touting their products) they could put more money into reserach.
But they don’t want to. Reserach is risky.
Even people on Wall STreet are disgusted with the industry’s greed–particularly its pricing of cancer drugs.
There are a number of excellent books on the industry. My favorite is by Dr. Jerry Avorn, “Powerful Medicines”.
Ray,
I really dont have an answer for
you as I dont know how US News picks their influential doctors. It may
have something to do with publishing research or being the first to try new
therapies–but hopefully it is not based on prescribing habits!
Michael,
I agree with Maggies comments on
Big Pharma and would add that as far as bringing out game-changing new
drugs, the examples of Vytorin and Zetia are not the drugs to pick. Merck
developed and sold Zocor and when it was going off-patent the company was
looking for a way to keep patent protection for its blockbuster statin
(simvastin). Combining it with Scherings Zetia, which has yet to be proven
to do anything except lower cholesterol (something statins already do) was a
way to achieve this. There are many examples of me-too drugs coming out of
Pharma and example of companies tweaking older drugs (new tablet size,
longer-acting version, etc.) to give new legs to drugs ripe for generic
competition.
Naomi
It may
have something to do with publishing research or being the first to try new
therapies–but hopefully it is not based on prescribing habits!
Michael,
The list of “influential docs” in my area have nothing to do with research, they are in private practice and no publications. Google this and see your local list.I wonder if Qpharma has anything to do with Pharma research and these doc promote their meds.
Maggie, I appreciate your comments. Thanks.
I AM WORKING WITH DIET CONTROL AND SLO NIACIN 500MG.
NO FLUSH FOR ME. AS FOR DIET, GIVE UP BEEF AND ADD OAT BRAN TO YOUR DAILY DIET. GIVE UP BEEF AND SAVE THE ENVIRONMENT AND YOUR HEALTH.
SIMPLE LITTLE GESTURES GO A LONG WAY. NO FLUSH WITH SLO NIACIN, IF YOU FLUSH ADD A BABY ASPIRIN. THERE IS SO MUCH WE CAN DO WIHTOUT PHARMA!
More info like this should be put out. America’s got a major weight problem, and not to mention the cholesteral stuff.
No industry needs such a fat profit margin. Wall Street analysts who cover the drug industry will tell you this. They will also tell you that Pharma spends twice as much on marketing and advertising as it does on research.
In recent years, drug stocks have been somewhat less stable as people worry about price regulation. Talk to the most knowledgable analysts on Wall STreet and they will tell you that Pharma has pushed too far–they’re just asking to be regulated.
The relentless promotion of Vytorin despite the lack of evidence for superiority over far less expensive drugs typifies the abuses that drive health-care costs skyward in our chaotic system.
Talk to the most knowledgable analysts on Wall STreet and they will tell you that Pharma has pushed too far–they’re just asking to be regulated.
There is currently no good evidence that statins would benefit individuals with normal lipid profiles – i.e., those at normal rather than elevated risk, but the possibility has not been studied adequately.
Examples like this are the problem that I had with Obamacare from the start. It did nothing to control out of sight costs. Big Pharma and insurance companies were the first to get on board with the plan because of this fact.
Statins come with some serious side effects for about 15% of people. The best way to lower cholesterol is not with drugs but by natural means of diet ans exercise. You can find out more on how to do this at http://bit.ly/cy3PWW