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Commentary By Paul Howard

The End of the Age of Lipitor? You'd Better Hope Not.

Health, Health FDA Reform, Pharmaceuticals

Today Lipitor, the world’s best selling drug and Pfizer’s single most profitable product, loses patent protection and goes generic. If Lipitor (generic name atorvastatin) holds true to form for other generic transitions, Pfizer can expect to lose much of its market share and the price of atorvastatin will eventually plummet by as much as 80%. But while everyone is celebrating the “birth” of yet another cheap generic from an expensive blockbuster, it would be good for policymakers and the press to pause and reflect on where generic drugs come from.

The stork doesn’t bring them to your local pharmacy. They are often the products of years or even decades of enormously expensive and painstaking research by innovative (and yes, profit-driven) companies.

What is the proper response to Lipitor going generic? Thank God for blockbuster drugs.

Because without those drugs we wouldn’t have the tremendous health gains from statins and other widely used drugs to treat stroke and hypertension - or the cheap generics that the health care system gains once those drugs lose patent protection.

Cardiovascular disease has been the leading killer in the U.S. every year since 1900, except for 1918 (pandemic flu?). Mortality peaked in 1950, but declined by 60 percent between 1950-1999. Undoubtedly, much of that decline was driven by changes in population health (i.e, declining smoking rates, etc).

However, as the chart above shows, declines in cardiovascular disease - with the exception of a slight uptick for hypertension - continue in the most recent data. For instance, U.S. age-adjusted mortality rates (per 100,000 population) for coronary heart disease fell by 35% from 1999-2007 (from 194.6 to 126); for stroke by 31% (from 61.6 to 42.2); and by 43% for myocardial infarction (from 73.2 to 41.4). Those gains are not all attributable to statins - stents, better drugs for hypertension, better surgeries and diagnostics all play a role - but medical innovation is a central part of the story.

Those gains are even more remarkable considering recent and rapidly rising obesity rates in the U.S., since obesity is a known risk factor for cardiovascular disease (particularly through complications like diabetes). This massive decline in mortality rates from cardiovascular disease is one of the most astonishing phenomenons of modern American medicine - and yet it goes largely unnoticed.

Fifty-something year-old men dying of heart attacks used to be unremarkable. Now, it is considered a terrible tragedy.

Statins were not developed by the U.S. government, or the NIH. As Zycher, Dimasi, and Milne wrote in a 2008 Manhattan Institute report:

“Beginning with the ongoing Framingham Heart Study, which has been conducted by the National Heart, Lung, and Blood Institute of the NIH since 1948, the causal relationship between elevated cholesterol levels and cardiovascular disease has become widely recognized.

In 1976, Akira Endo and other researchers at the Sankyo Company and at Beecham Research Laboratories independently isolated mevastatin from fungi, after having screened more than 8,000 microbial extracts. Further research by Endo and colleagues showed that mevastatin reduced cholesterol levels in the liver; subsequently, Endo and researchers at Merck separately isolated lovastatin from a different fungus.

Lovastatin was shown to be more potent than mevastatin and was the first HMG-CoA reductase inhibitor approved by the FDA, in 1987, for the reduction of plasma cholesterol. Further research by private-sector laboratories has yielded additional statin drugs more potent and/or with fewer side effects than lovastatin: pravastatin, simvastatin, atorvastatin, and others, the newer of which have been synthesized in laboratories rather than isolated from natural materials. Private-sector research, in short, developed compounds exploiting new knowledge of a specific disease process, and developed improvements in terms of potency and side effects.”

The development of statins also depended on the passionate belief of industry scientists that they had discovered life-saving medicines, and who championed their development even when bad data suggested that they probably should give up. As Harvard Medical School Professor Thomas Stossel wrote in the Boston Globe in 2008:

“When Endo published his findings in scientific journals, other companies started searching for statins. One of these companies was Merck, whose researchers demonstrated by the early 1980s that a statin could lower LDL cholesterol in the blood of healthy volunteers without side effects.

But Merck discontinued statin development upon learning that Sankyo abandoned its statin program after discovering what seemed to be cancerous changes in experimental animals fed large statin doses. Despite a well-established association between high LDL cholesterol levels and cardiovascular complications, researchers worried that reducing blood cholesterol would cause side effects, because cholesterol is an essential component of body cells.

Statin development stalled for three years until Edward Scolnick assumed a research leadership role at Merck. Scolnick devoted a large fraction of Merck’s research budget to overcoming concerns about statin toxicity, and the results convinced the Food and Drug Administration that the findings that killed Sankyo’s program were not really cancers and that proceeding with human trials of stain therapy was reasonable.

Prior to the discovery of statins, the only way to lower blood LDL cholesterol was to combine an unpalatable diet with medications causing unpleasant side effects. A clinical trial had concluded that this regimen could reduce cardiovascular complications of high LDL cholesterol, but few believed patients would stomach it. When the FDA approved Merck’s statin in 1987 simply on the basis of its ability to lower cholesterol safely, the stage was set for a revolution in the treatment of heart disease.

A subsequent clinical trial completed in 1994 confirmed that Merck’s statin also reduced cardiovascular events. This watershed study set the stage to demonstrate subsequently that more potent statins could lower LDL cholesterol even further, with greater clinical benefits.

The development of statins required luck, perseverance, and great expense; but, above all, a passionate champion and a willingness to take risks. Without Akira Endo, and later Edward Scolnick’s, passionate research into statins, hundreds of thousands more Americans would have lost their lives to heart attacks and strokes. In that light, Stossel’s conclusion should be incredibly sobering:

The controversy surrounding Merck’s painkiller Vioxx so empowered anti-industry critics that imagining any company (or the FDA) taking similar risks today is difficult, given the toxicity data that came close to killing the industry’s work on statins. Critics vilified the same Edward Scolnick and Merck for developing Vioxx after it unexpectedly promoted the very same cardiovascular problems prevented by statins. One has to wonder if medical product companies are shelving potentially life-saving products because industry critics are pushing policymakers and regulators to near zero tolerance for rare adverse events.”

Stossel’s concern is sadly warranted. Policymakers and the media need to be continually reminded that there is still much about human biology that we do not understand, or understand incompletely, but that ignorance should not be taken to be an indictment of industry or cause to embrace a precautionary principle that penalizes innovation through risk-averse FDA regulations or reimbursement strategies that limit physicians to prescribing cheap generics.

Several years ago, Pfizer lost over $800 million dollars when their attempt to improve on statins by raising “good” HDL cholesterol through a new drug called torcetrapib imploded in a late stage clinical trial. Companies continue to take those enormous risks because of the tremendous good they can achieve when they are successful, and because the financial rewards of success still (at least for the time being) compensate them for their many failures.

Patent expiration - for Lipitor or any other drug - is part of a virtuous cycle of innovation than can take decades. Losing sure cash-cows like Lipitor pushes companies to invest billions of dollars in the hope that they will uncover even better drugs for treating heart disease and stroke, or cure Alzheimer’s. Some of these drugs may be blockbusters that treat large populations, and others will be “niche busters” that treat patients who don’t respond (for genetic or other reasons) to those blockbusters.

But we must continue to defend and explain the virtuous cycle of innovation if we want companies to find the next public health breakthrough, like statins. Even though, in time, we’ll take those miracle drugs for granted too - and cheer loudly when they become cheap generics.

This piece originally appeared in Medical Progress Today

This piece originally appeared in Medical Progress Today