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How to create a blockbuster drug

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How to create a blockbuster drug (even if it doesn’t work very well)

Statin drug Crestor has been the world’s best-selling drug even though its effectiveness is questionable, and it’s been dogged by worries about its safety. So how did AstraZeneca do it? Bryan Hubbard investigates

The gravy train finally hits the buffers next year for drug giant AstraZeneca when its blockbuster statin, Crestor (rosuvastatin), loses its patent protection-which means that, from 2016, any of its competitors can make the drug using the same formula. And make it they will.

Crestor is America’s most-prescribed drug and currently achieving annual sales of $5.8 billion (lb3.9 billion), while globally, it’s the third highest-selling drug with worldwide revenues of $8.2 billion.

But finding reasons for this overwhelming success are not so easy to come by-and what can be uncovered gives little comfort to those who cling to the idyll that medicine is a science. As the drug-industry magazine Pharmaceutical Executive stated when awarding Crestor its Brand of the Year Award, “Crestor’s sales are a marvel-and something of a mystery”.
It seems to have little to do with the cholesterol-lowering drug’s effectiveness in reducing the risk of heart disease. Clinical trials have failed to definitively establish that the drug is both safe and effective, even though AstraZeneca itself paid for the studies, and there’s been a quiet but persistent campaign to have the drug banned on safety grounds.

Sidney Wolfe, senior advisor of the Washington-based health research group Public Citizen, has been lobbying America’s drugs regulator, the Food and Drug Administration (FDA), to do just that since 2004. Yet the FDA has consistently refused to do so, even though one of its own associate directors, David Graham, had told a US Senate hearing that Crestor was one of five drugs he would like to see banned.

Money and marketing

So, if it’s not effective and it’s not safe, how did it get to be the biggest-selling drug in the US? The phenomenon can be explained in two words: money and marketing. AstraZeneca was late to the statin party and looked on enviously as rivals like Pfizer, with its best-selling Lipitor (atorvastatin), cleaned up.

When it finally got Crestor off the blocks, AstraZeneca had a lot of lost time to make up. Hailed as a ‘super-statin’ during its development phase, Crestor was finally approved in 2003 as a cholesterol-lowering agent. However, the FDA declined to approve it as a therapy for reducing cardiovascular risk, something that its four rival statin products had achieved.
In other words, there was no evidence that Crestor could do the thing that really mattered: people taking it weren’t reducing their chances of developing heart disease or suffering a heart attack.

Undaunted, the drug company’s then chief executive Tom McKillop told investors that he was pledging to “do whatever it takes to persuade doctors to prescribe rosuvastatin, including launching an estimated $1 billion first-year promotional campaign . . . we’ve got to drive the momentum. You get one shot at launching a major new product. This is our shot.”

Alarmed by such aggressive marketing for a product with such a sketchy safety record, Richard Horton, as editor of the medical journal The Lancet, wrote a scathing editorial. “AstraZeneca’s tactics in marketing its cholesterol-lowering drug, rosuvastatin, raise disturbing questions about how drugs enter clinical practice and what measures exist to protect patients from inadequately investigated medicines. Physicians must tell their patients the truth about rosuvastatin-that compared to its competitors, rosuvastatin has an inferior clinical evidence base supporting its safe use. AstraZeneca has pushed its marketing machine too hard and too fast. It is time for McKillop to desist from this unprincipled campaign.”

FDA doesn’t approve

But far from desisting, AstraZeneca seemed to redouble its efforts even if it meant playing fast and loose with the facts. In 2004 and 2005, AstraZeneca was forced to pull two advertisements that had made false or misleading claims about the drug, its effectiveness and safety.

In the US, drug companies can directly advertise to consumers in the hope they might influence their doctors, an option that AstraZeneca exploited to the full. But its adverts went too far and earned a reprimand from the FDA.

In the first advert, published in The Washington Post in November 2004, its headline read: “You can be assured that at AstraZeneca, patient safety is our number one priority”. Apparently not, said the FDA’s consumer promotion analyst Christine Smith. “The ‘patient safety’ print ad makes false or misleading safety claims that minimize the risks associated with Crestor, thereby suggesting that Crestor is safer than has been demonstrated by substantial evidence or substantial clinical evidence,” she wrote in a letter to the company later that year.

Worse, AstraZeneca suggested in the advertisement that the FDA had “confidence in the safety and efficacy of Crestor”. No, we don’t, countered Smith, and quoted Dr Steven Galson, of the FDA’s Center for Drug Evaluation and Research, who said: “The agency has been very concerned about Crestor since the day it was approved, and we’ve been watching it very carefully.”

A year later, AstraZeneca was at it again, this time buoyed by the results of the STELLAR Trial, which compared the effectiveness of Crestor against three of its statin rivals, including Lipitor.

In a series of print and TV ads, it claimed that Crestor was superior to all the others, but the FDA’s Smith pointed out that the study data suggested no such thing. In fact, she pointed out, its arch-rival Lipitor was just as effective at the standard 80-mg dose.

At the time, Crestor had annual sales of just $908 million against Lipitor’s gargantuan $10 billion and Zocor’s (simvastatin) lb4 billion (about $7 billion)-but this would soon change, and dramatically so. The STELLAR Trial played an important part in the turnaround; no, Crestor may not have been more effective than its rivals, despite the interesting interpretation of the data by AstraZeneca, but no safety worries were noted by the researchers either.

Yet talk of the drug’s potential dangers had dogged it from even before it was approved. As Sidney Wolfe has pointed out, rosuvastatin is the only statin for which rhabdomyolysis (muscle weakness due to muscle cell destruction) was detected in studies even before it was approved. Even Baycol (cerivastatin), a statin banned in 2001 because it caused rhabdomyolysis that led to 31 deaths, showed no cases of the condition in its pre-approval trials.

The second concern was the kidney damage that Crestor could be causing. In the same trials, 41 per cent of people taking the highest dose of Crestor had raised levels of a blood marker that indicated renal (kidney) problems.

Dangers disappear

But with the STELLAR Trial finding none of these problems, AstraZeneca’s executives were finally able to move onto the front foot. Two major claims for Crestor were that it was more powerful than its competitors and that it could reduce inflammation, which can lead to atherosclerosis or hardening of the arteries. The ASTEROID study in 2006, headed by America’s leading cardiologist Steven Nissen, showed that Crestor could reverse the progress of atherosclerosis, although the researchers were criticized for not measuring outcomes, so there was no way to know if there were any accompanying health benefits or lower rates of heart disease with this finding.

Then, in 2007, the METEOR study of 984 participants demonstrated that Crestor could prevent atherosclerosis in low-risk people. Interestingly, Crestor’s chief function as a cholesterol-lowering statin was no better than any of its rivals, but this new benefit of reducing atherosclerosis-even in people who didn’t know they had it-was something the marketing department could run with. They star
ted a grassroots campaign-Us Against Athero-to raise awareness of this supposed disease, and they prepared an animated movie, The Artery Explorer.

Fear-based words like ‘build’ were employed to explain atherosclerosis, much to the admiration of independent marketing groups, which lavished praise and awards on the Crestor marketing team. Now we had two silent killers to contend with-cholesterol and atherosclerosis-when it came to cardiovascular health and, thankfully, Crestor could deal with both.
So even people who thought they were healthy-actually they were healthy-suddenly became candidates for Crestor. In one fell swoop, the statin market increased by 11 million Americans just for Crestor, because it was the only one able to reverse atherosclerosis, the new killer on the block. With fear as its driver, Crestor’s sales in the US started to rise and rise, reaching a peak of lb6.6 billion in 2011.

Perhaps it was a case of hubris, but AstraZeneca’s executives decided to take on statin market leader Lipitor just before it lost its patent protection. It was a fight they should never have started-because the SATURN study showed that, while Crestor was more effective for reducing the arterial plaque that leads to atherosclerosis, people weren’t living any longer as a result.

And the safety worries were raised again too: more people taking Crestor were showing signs of liver disease.6
In 2012, a group of patients filed a lawsuit claiming that the drug had caused sudden cardiac deaths while, that same year, another group filed a suit claiming that AstraZeneca was marketing a dangerous drug even though the company knew it was causing injury.

But nobody seemed to pay much attention, and perhaps that was because Steven Nissen was still supporting Crestor. Nissen has been a scourge of the pharmaceutical industry and was one of the early whistleblowers against Vioxx, the painkiller reckoned to have killed at least 60,000 people, so his continuing endorsement of Crestor seemed to be the perfect counterweight to any negative study results.

And as drugs sector analyst Seamus Fernandez says, it was the ‘Nissen effect’ coupled with the way AstraZeneca was able to handle bad news that seems to have made Crestor fireproof. All the ingredients, in fact, for creating a drug blockbuster.

Crestor and safety

Safety worries have dogged Crestor since its approval in 2003. In fact, drugs regulators in Germany, Norway and Spain are so worried about the drug that they have never allowed it to be sold in their countries.

Serious side-effects include:

o Memory loss
o Type 2 diabetes
o Muscle pain
o Liver damage, including jaundice
o Rhabdomyolysis, muscle damage that can lead to kidney failure and death.

Minor side-effects include:

o Heartburn
o Constipation
o Coughing
o Insomnia.

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