Not losing sight of the real issue on the latest cholesterol-lowering trial

Inquiries into the ENHANCE statin clinical trial controversy continue to escalate. Politicians and lawyers are getting on the bandwagon and following the U.S. House of Representatives Committee on Energy and Commerce and its Subcommittee on Oversight and Investigation, which began its investigation last fall. The biggest issues in all of this may slip away from us if we aren’t careful to recognize them.

Senator Chuck Grassley of the Committee on Finance began his own investigation on Thursday, sending letters to the drug companies Schering-Plough and Merck, the American Heart Association, and the American College of Cardiology similar to those also sent by the U.S. House of Representatives Committee. These lawmakers are wanting explanations for when the companies learned of the trial results (possibly prior to corporate officers selling off significant amounts of stock and the companies continuing to advertise claims the research didn’t support), but also want answers on industry funding of AHA and ACC, “nonprofit organizations which purport to be independent in their viewpoints and actions,” and continuing education of medical professionals. They are asking for all communications between the companies and these organizations regarding recent public statements made that echoed the companies’ reassurances, and they want full accountings on industry-supported continuing medical education “regarding cardiovascular risk management, and/or cholesterol control, and/or Vytorin.”

Senator Grassley’s letters to drug makers Schering-Plough and Merck, also raised concerns over what the delay in reporting the trial results may have cost Iowa residents and American consumers, stating:

While the health benefits of Vytorin appear similar to a cheaper generic, the cost difference to the citizens of Iowa is certainly another matter. At a Wal-Mart pharmacy in Iowa City, generic simvastatin costs $54.54 for a month’s supply while Vytorin costs $112.46. I am confident that the citizens of Iowa would have appreciated knowing that a cheaper drug works just as well. Instead, Iowans and other Americans paid out their hard-earned dollars unnecessarily for almost two years, while waiting for Schering-Plough and Merck to announce the scientific results of ENHANCE.

That isn’t the half of it, though. As Brandweek reported, even “the generic Zocor pricing is a scam.” It called for an investigation into how generics, which are supposed to save us all money, are priced. This generic drug, they pointed out, costs as little as $11.66 at Costco to $221.89 at Walgreens in New York. Wide price variations exist with other generic drugs, too.

“The best kept secret by the retail pharmaceutical industry is the obscene profits made on generic drugs by the large chain stores,” said Dr. Cyril Wolf, a prescription sales researcher. “Whereas brand name drugs are all purchased, and therefore sold, for around the same price, generics are obtained for a fraction of that cost. The price at which the generics are sold is determined by the sellers, who thus have the ability to make exorbitant profits on these drugs.” These generics actually save customers “very, very little” money, said Dr. Wolf, as many generics aren’t sold at prices that much lower than brand names, but almost always above their true cost and most hurt people already having trouble affording medications.

But that isn’t the half of it, either. Drug prices at pharmacies is not the issue in a free market where customers can shop around for a better price. The bigger concern comes in, as JSF reported last September, when those who control the access (where we can purchase meds) and the costs of prescription medications are the same ones in control of our medical records, and manage the medical care we receive and the medications we must take in order to receive healthcare, health insurance or government benefits.

When these price mark-ups are not disclosed by insurer PBMs (pharmacy benefit managers), and insurers benefit from getting more of us onto medications they sell that make them the biggest profits, we need to be very concerned about the objectivity and the conflict of interest of their medical (“disease”) management. [See Generic formularies.]

How much more are we spending for medications due to excessive mark-ups, but also for medications that may not provide the clinical benefits they purport?

Amidst all of the congressional hearings and media notice, and amidst the recent infestation of shark lawyers filing class-action lawsuits across the country over alleged cover-ups of the ENHANCE trial results, we mustn’t lose sight of the far greater issue in all of this:

The integrity of the scientific process ... in how drugs are researched and approved, and clinical guidelines are developed.

JFS began covering the ENHANCE clinical trial issue last November. This trial provided an opportunity to examine the importance of randomized controlled clinical trials, the gold standards of evidence-based medicine. Sound trial designs that are fair tests include randomization; double-blinding; a placebo control group; control of study data and analysis of study data by bodies independent from drug company sponsors; and primary endpoints that are actual clinical outcomes, such as reduced premature deaths, versus false surrogate endpoints.

On January 17th, “How’d we get here?” described the foundations of clinical trial evidence for drugs approved by the FDA that have been abandoned, and called into question the use of surrogate measures, like cholesterol, as proxies for actual clinical benefits to lives. When surrogate endpoints are used in order to expedite R & D for new drugs, post-market clinical trials are supposed to follow to provide the FDA evidence that these markers are valid and that the drugs actually save lives. But those studies never seem to come.

Senator Grassley seems to have taken up this issue. According to KaiserNetwork Daily Reports, on Friday, Senator Grassley said that “in light of what’s happened with Avandia and Vytorin, maybe the FDA needs to examine when it’s appropriate to use surrogate endpoints.” The FDA had approved Vytorin and Avandia because of their effects on health risk factors, LDL-cholesterol and blood sugars, widely believed to be markers for clinical outcomes. But, as research has been showing more than 30 years, since the Framingham study, the traditional cardiac risk factors are proving poor predictors of those who get heart attacks, and most people who suffer heart attacks don’t have high LDL-cholesterol or the other popularized risk factors.

Perhaps this hubbub will lead everyone to question their own assumptions and fears about health risk factors and to look closely at the evidence on cholesterol lowering for prevention of heart disease and whether it extends lives. According to Dr. Malcomb Kendrick, M.D., who has researched cholesterol for years and authored The Great Cholesterol Con, it is biologically implausible for LDL-cholesterol to cause atherosclerosis. “High cholesterol levels do not cause heart disease and the benefits of statins have been hyped beyond belief,” he said.

Dear Doctor

There have been lighter notes this week, as doctors express their skepticism of lowering LDL-cholesterol as a key in preventing heart disease.

Dr. Matthew Mintz, an Associate Professor of Medicine at The George Washington University School of Medicine wrote an entertaining commentary about a letter that had been sent out to prescribing physicians from Merck/Schering-Plough. His article, “Dear Doctor,” responded to five points in the letter.

I might add one more point to think about, taken from Schering-Plough’s News Release issued on Friday. The press statement seemed to downplay the significance of the ENHANCE trial results by emphasizing that the trial “involved 720 patients with a rare form of inherited high cholesterol known as Heterozygous Familial Hypercholesterolemia that affects less than 0.2 percent of the population.”

If this medication is being tested on people with such a rare disorder, and hence appropriate for these rare situations, why is it being marketed to practically the entire adult population?

As Dr. Elena Citkowitz, M.D., Ph.D., FACP, Associate Clinical Professor of Medicine, Yale University School of Medicine and director of the Cardiac Rehabilitation and Cholesterol Management Center at the Hospital of St. Raphael in New Haven, CT explained: “Familial hypercholesterolemia is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol.” It is not simply “high cholesterol.” These are extreme cases, where people are born with a defective LDL receptor gene. Also known as heterozygous familial hypercholesterolemia, it occurs in about 1 in 500 people worldwide, with the homozygous form even rarer, at about 1 in a million. The cholesterol levels in babies and children with heterozygous FH are at least twice normal — 350 to 500 mg/dl — and in the homozygous form with no functioning LDL receptors, cholesterol levels are 700 to 1,000 mg/dl.

Does this describe your cholesterol level?

Or is this another case of extreme health indice levels associated with a health problem — levels multiple times normal or off the charts — being used to scare us that the moderate ranges normal in most people pose similar dangers? Have “high” risk levels been magically redefined to include levels that are far less significant? Is there evidence that a treatment for these rare and extreme conditions make it is a necessary and effective preventative for everyone else?

Only science that applies a rigorous and fair test can determine the answers. Only quality, randomized controlled clinical trial evidence, independently conducted and evaluated, can help to ensure we are making informed decisions that are based on evidence rather than beliefs, tradition and authority.