Merck and Vytorin: Malfeasance or Incompetence?

In "Why Pharma Fails" I made several observations regarding pharma competence as a key factor in their success in the brutal drug market - or failure thereof.

The Philadelphia Inquirer reports:

Merck Shares Fall Nearly 15 Percent

By Karl Stark, Tue, Apr. 1, 2008

Inquirer Staff Writer

Merck & Co. Inc. yesterday saw the largest daily drop in its stock value since the pain reliever Vioxx was withdrawn in the fall of 2004.

Shares of Schering-Plough Corp., its partner in the cholesterol-lowering drug Vytorin, took an even larger hit, losing 26 percent of their value.

The cause appeared to be fresh criticism of Vytorin in the New England Journal of Medicine and at the annual meeting of the American College of Cardiology on Sunday.

Many doctors already knew that the drug, a combination of Zetia and a generic statin that Merck formerly sold under the name Zocor, had failed to show benefit in the cholesterol trial, named ENHANCE. But over the last few days, an expert panel of cardiologists ramped up the criticism.

"The compound did not work," and it should be used as a last resort, said cardiologist Harlan M. Krumholz of Yale University, speaking for colleagues at the cardiology conference in Chicago.

I know Harlan from my time at Yale, and he is a reasonable fellow. Unfortunately, I do not agree with him in this matter.

One major advantage of Zetia I recall around the time of its launch when used in combination with a statin was its ability in the otherwise unremarkable hypercholesterolemic patient to permit a lower statin dose while achieving comparable levels of lipid reduction. This struck me as potentially quite valuable considering the adverse events profile of the statins, especially at higher doses in typical target populations. Zetia, unlike the statins, reduces blood cholesterol by simply inhibiting its absorption at the small intestine.

From its indications:

Monotherapy
ZETIA, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.

Combination Therapy with HMG-CoA Reductase Inhibitors [Statins]
ZETIA, administered in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.

The ENHANCE study, which began in June 2002, focused on a group of 720 patients with a rare genetic condition, heterozygous familial hypercholesterolemia, that affects approximately 0.2 percent of the population, predisposing them to high cholesterol.

While the new drug appears not to reduce plaque buildup in patients with the rare genetic disorder, it does improve the blood lipid profile; we don't yet have enough data to know if the drug ultimately improves outcomes in the common multifactorial, non-familial hypercholesterolemic patient. (The homozygous hypercholesteremia variant, another situation entirely, is rarer and is often drug resistant, causing severe cardiovascular disease even in childhood.)

In other words, Zetia/Vytorin cannot be completely ruled out as a failure since the ENHANCE study focused only on a very small subset of patients with a rare hereditary disease in which they produce too much LDL, or "bad cholesterol." It is not clear if the results of this focused trial are relevant to patients with non-familial hypercholesterolemia. We do not know. This is one risk of surrogate endpoints.

One possible explanation for the unexpected result is that the genetically abnormal patients had been extensively pretreated with lipid-lowering therapy, possibly limiting the amount that carotid artery plaque thickness could change with further LDL cholesterol-lowering therapy. This could consequently limit the ability to detect a differential response in this subset. Again, we do not know.

Thus, I feel it is too early to declare the drug ineffective as is now being done. I believe what is driving this outcry is hostility towards the industry, not science. In the context of the social issues of our time regarding the pharma industry (i.e., disdain for the industry in many circles), seeking plaque differences in a small group of people with genetic issues as a surrogate endpoint while knowing that clinical outcomes data would take far longer to obtain in a large group of genetically "ordinary" people, was probably a terrible strategy: the wrong study at the wrong time, likely due to incompetence over the social environment of the industry in 2008.

There have also been allegations by Sen. Grassley and others that the results of the ENHANCE trial were deliberately withheld for several years as well, to "enhance" profit via protecting sales of these drugs.

It has been said not to attribute to evil what can be more easily attributed to stupidity. I do not believe malfeasance was the issue here, "merely" bureaucratic-led incompetence, as bad as that alone is.

While my evidence is anecdotal, consider the following personal observations related to competence of pharma on basic R&D issues, again in the context of today's pharma environment:

• What pharmaceutical company knowing that "pipeline is lifeline" would put a non-biomedical computer bureaucrat in charge of research computing and its scientific libraries and its informatics tools crucial to scientists for drug discovery, and allow that person to severely ration those tools to save a few million dollars a year out of an R&D budget of several billion?


• What pharma conflates information technology (working with what are, in essence, physical trinkets) and information science (a high-cognitive function of the mind) in this manner?


• What pharma would then allow that bureaucrat to provide only 1/3 of the money asked for to alleviate the rationing, based on compelling evidence and testimony from the senior scientists themselves -- then lay off the only person who opposed the rationing, a competent medical informatics expert?


• What pharma would allow its executives to dismiss and humiliate an informaticist in an interview, who is an expert in clinical IT, EMR's and social issues regarding same, upon being shown his proven work in building cardiology databases of national calibre (cardiology of all things!), databases used for detection of unexpected medical device and drug problems?


• What pharma would allow that treatment be shown to a candidate, even though the informatics expert demonstrated innovations from his work in another country that could improve access by adverse events personnel to their data -- in ways the adverse events personnel themselves said was potentially highly useful?


• Worse, what pharma would break a century of tradition of not laying off people, and create an internal environment of hostility, suspicion and insecurity not to mention depression (anathema to creativity) and transition suddenly to "just another pharma" where people are simply "expendible labor units? (Hint: this is yet another social issue.)


• In an age of easy teleconferencing, what pharma would diss its frightened-for-their-jobs employees and local residents by continuing to shuttle its senior executives between PA and NJ sites (that most employees drive) in expensive ($10K per ride?) helichoppers? Does the company have any clue regarding social issues, I ask?
  

The good news is that these personal observations, while anecdotal, points more to incompetence rather than malfeasance on these issues. The bad news is that Occam's Razor dictates that these issues are tip-of-the-iceberg events, as opposed to just isolated, but extremely bad luck caused by and experienced by only a small number of individuals.

The only solution to incompetence is firing the incompetent, hiring the competent, ceasing putting people in charge who lack specific domain expertise (such as, say, biomedicine!), and doing so before a company and its leaders get into really severe hot water, such as insolvency or - jail.

Unfortunately, one hallmark of incompetence is lack of recognition of same (see this article).

As a result, I see little short term hope for this industry.

I also repeat what I've written numerous times before: try as hard as you like, but you cannot do business from an empty wagon. Pharma has gotten to the point internally where even low hanging fruit cannot be plucked because midgets are not tall enough, and the giants whose shoulders they might once have stood on have been removed, or driven from, employment in the industry.

-- SS