Drug Makers Say FDA Safety Focus
Is Slowing New-Medicine Pipeline

June 30, 2008; Page A1

Nearly four years after Merck & Co. yanked the painkiller Vioxx off the market, beleaguered pharmaceutical-industry executives say they are facing a tough new regulatory climate that is altering the landscape of drug development.

Over the past 16 months, Schering-Plough Corp. Chief Executive Fred Hassan and his top scientists have pulled the plug on two drug-development projects -- one for obesity and the other for cholesterol -- that had the potential to produce big sellers. And they're considering scrapping a third.


   What's New: Some drug-industry executives think the FDA has become more conservative about approving new drugs.

  The Background: Merck's withdrawal of Vioxx in 2004 prompted criticism that the FDA wasn't vigilant enough about safety.

  What It Means: Some companies are changing their drug-development plans because of the regulatory climate.

The reason: Mr. Hassan believes an intensifying focus on safety and a diminished tolerance for side effects at the Food and Drug Administration have dramatically lowered the odds that the drugs would make it to market -- at least not without a lot of extra time and money.

"What will it take to get new drugs approved?" Mr. Hassan asks. "The point is, we don't know."

Just last week, Eli Lilly & Co. and Japan's Daiichi Sankyo Co. said the FDA wants an additional three months to decide whether to approve their highly anticipated new heart drug called prasugrel. Days earlier, Merck said the FDA wanted to wait for the results of a huge clinical trial before ruling on its cholesterol drug Cordaptive, which could delay a decision on the medicine until 2013. On Tuesday, an FDA panel is set to consider whether to recommend that the agency adopt tougher standards for diabetes drugs, which could lengthen the development process for many other types of medicines.

[Fred Hassan]Last year, the FDA approved just 19 new medicines, the fewest in 24 years, and announced about 75 new or revised "black-box" warnings about potential side effects -- the agency's strongest -- twice the number in 2004. The number of so-called approvable letters, which typically postpone FDA decisions pending more data, increased by 40% last year, according to a unit of Sagient Research Systems Inc., which tracks the regulatory paths of drugs.

Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, denies that the agency has become "more conservative" about drug safety. Rather, she says, the industry's faltering research efforts are mostly to blame for the fewer product approvals. She says the agency continues to base its decisions on science, not outside pressures. New methods, she adds, have helped it become more vigilant about side effects. She attributed the increase in black-box warnings primarily to a few large groups of medicines that were relabeled.

[Tapering Off]Some outside observers disagree. "There is no question that the FDA is more safety-oriented than it has been in years," says Ira Loss, senior health-care analyst at Washington Analysis, a research firm. "Regulation tends to be a pendulum, and a series of things, the most dramatic of which was Vioxx, has sent the pendulum back in the direction of safety."

Grousing by drug-industry executives about the FDA is nothing new. It's a product of the perennial tension between regulators and the companies they oversee.

But the Vioxx debacle, which sparked harsh criticism of both drug companies and their chief regulator, appears to have led to a climate shift. The drug industry largely has itself to blame for allegedly manipulating clinical data, concealing dangerous side effects and aggressively promoting risky products, which created widespread mistrust. The FDA, for its part, was harshly criticized for its decisions on Vioxx and in a litany of subsequent drug scares.

Outspoken scientists, watchdog groups, medical-journal editors and politicians have fanned worries about safety. The wave of post-Vioxx drug scares included concerns that GlaxoSmithKline PLC's widely used diabetes drug, Avandia, could raise heart-attack risk, and that Pfizer Inc.'s smoking-cessation drug, Chantix, may be connected to suicides. More than 80 U.S. deaths linked to contaminated heparin from China have further ratcheted up public anxiety. The FDA has been battered by criticism that it wasn't vigilant enough, including from Cleveland Clinic cardiologist Steven Nissen, Sen. Chuck Grassley of Iowa and Rep. John Dingell of Michigan .

Serious Dangers

Now, the agency is considering such measures as adding warnings about cancer risk to arthritis drugs for children, and warnings about suicide risk to epilepsy drugs. For most drugs, such side effects strike only tiny percentages of users. But when millions take the medicines, the numbers can add up.

Consumer advocates have welcomed many of the agency's recent warnings and some drug withdrawals, arguing that they have brought serious dangers to the attention of patients and doctors.

[Safety First]Industry executives acknowledge some excesses. Dan Vasella, Novartis AG's chief executive officer, says direct-to-consumer advertising lulled many Americans into thinking that taking prescription drugs was as safe as eating candy, leading some doctors to feel pressure to prescribe.

New medicines fall out of development pipelines all the time when they raise safety flags, underperform in studies, or when marketing prospects dim in the face of rival compounds. But worries about a costly and uncertain regulatory road are now prompting drug makers to withdraw applications for some medicines and to remove some once-promising compounds from their pipelines.

Novartis has stopped trying to get U.S. approval for its diabetes drug Galvus and its painkiller Prexige, even though Galvus is on the market in Europe and Prexige has been approved in about 50 countries. Sanofi-Aventis SA, which markets the weight-loss drug Acomplia in Europe, withdrew its application in the U.S. after an FDA panel recommended additional studies to address concerns about psychiatric side effects. On Friday, Merck and Schering-Plough said they were withdrawing their FDA application for a combination asthma and allergy medicine after the agency turned down the drug earlier this year.

"There are no drugs that are 100% safe," says Novartis's Dr. Vasella, who thinks the FDA has become inconsistent. "Look at Tylenol. It's over-the-counter, but if you take doses of it that are too high, you're dead."

Growing Discrepancy

The industry points to the growing discrepancy between drug approvals in the U.S. and Europe as evidence that the FDA has become too cautious. Europe's drug regulator, the European Medicines Agency, has greenlighted a number of drugs recently that haven't received the nod in the U.S. , including Galvus, Prexige and Acomplia. The FDA has delayed approval of Glaxo's cancer vaccine, Cervarix, and Schering-Plough's sugammadex, a drug designed to be used after surgeries to quickly undo the effects of muscle relaxants, and rejected Merck's pain medicine Arcoxia. Cervarix and Arcoxia are on the market in Europe , while sugammadex has been recommended for approval there.

The FDA's Dr. Woodcock responds that "it's long been true that different countries looking at the same facts and data arrive at different conclusions."

Over the years, the FDA's approach to drug safety -- the way it balances the risks and benefits posed by new drugs -- has swung like a pendulum.

In the early 1960s, thousands of birth defects in the U.K. linked to the morning-sickness drug thalidomide triggered an overhaul of drug evaluation in the U.S. The FDA began demanding more extensive evidence from drug companies that their products were effective and safe.

In the 1970s, a report showed that approval of drugs for high blood pressure and other ailments had all but stopped in the U.S. , while several new medicines for the conditions were introduced in the U.K. That fueled a debate, complete with congressional hearings, about whether the FDA was keeping life-saving drugs off the U.S. market. Several classes of heart drugs were subsequently approved, benefiting the public and generating enormous profits for the industry.

In the 1980s, several painkillers known as nonsteroidal anti-inflammatory drugs, or NSAIDs, which had been approved by the FDA, were pulled off the market because of safety problems. Critics questioned the FDA's attention to safety. But by the end of that decade, the AIDS crisis prompted patient activists to demand faster access to experimental drugs. That led to sweeping changes aimed at speeding FDA approval of drugs that could save lives.

A new law required drug companies to pay for the FDA to review products, and set time limits for the FDA to deliver its verdicts. In the 1990s, the agency began conferring "fast track" status to drugs that address unmet medical needs. It also began granting "accelerated approval" to drugs for cancer and other life-threatening conditions, based on promising preliminary data, not proof, that they extended survival.

The changes paved the way for new drugs for cancer and AIDS. But a new string of safety problems emerged. In 1998, Wyeth's analgesic Duract was pulled off the market due to possible links to liver failure. In 2000, one of the first fast-tracked medicines, the diabetes drug Rezulin, was also pulled because of potential liver toxicity. In 2001, Bayer AG had to withdraw its cholesterol drug Baycol because of a rare but potentially lethal muscle-wasting effect.

When Merck withdrew Vioxx in 2004 after the painkiller was linked to heart attacks and strokes, it triggered an uproar over drug safety. Critics charged that drug companies snared customers with clever marketing campaigns that overstated drug benefits and underplayed risks. Plaintiffs lawyers filed some 28,000 lawsuits against Merck. They accused the industry of putting profits ahead of safety, and the FDA of allowing unsafe products to reach the market.

Merck spokeswoman Amy Rose says the company's "voluntary withdrawal of Vioxx, whether pivotal or not, was taken in the interests of patients."

Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development, says: "Everything pointed to the notion that the FDA and the industry had lost their compass, and that the FDA needed a course correction." With the ensuing changes, he says, the FDA is now "viewed as an agency that is supposed to keep unsafe drugs off the market, not to speed access to life-saving drugs."

The FDA's Dr. Woodcock says that the quality of research coming out of the pharmaceutical industry is slowing the number of drug approvals. New drug applications submitted by the industry, she says, dropped 33% in 2006, which helps explain the decline in 2007 approvals. "You can't approve drugs you don't get applications for," she says.

The constant criticism of the FDA, she says, has hurt employee morale and depleted staffing. Since last October, her group has been working to fill 500 vacancies among its staff of 2,700 reviewers. That process, as well as training the new hires, is contributing to delays in reviewing drug applications, Dr. Woodcock acknowledges.

Over at Schering-Plough, Mr. Hassan remains convinced there's been a paradigm shift, and he's been taking a hard look at medicines in the company's pipeline. In the spring of 2007, Schering-Plough canceled a program studying good cholesterol and abandoned plans to license a cholesterol drug. Later in the year, it scrapped an obesity medicine after Sanofi-Aventis's Acomplia, which worked in a similar way, ran into regulatory trouble. Although Schering-Plough's researchers believed its version might have less pronounced psychiatric side effects, Mr. Hassan and his team killed the effort because they may have had to mount large and expensive clinical trials, with little certainty that the studies would resolve the safety question.

Voluminous Testing

Now Schering-Plough is weighing the future of a novel pill for multiple sclerosis, called a VLA4 antatonist. It's a concept that Mr. Hassan and his researchers still believe in. But a related medicine made by Biogen Idec Inc. and Elan Corp., called Tysabri, was temporarily withdrawn after it was linked to several cases of a rare brain infection. Now the Schering-Plough team is unsure about whether to invest in the voluminous testing the FDA could require in the wake of the scare.

Schering-Plough's version of the medicine would be taken orally, unlike Tysabri, which requires a once-a-month intravenous infusion, typically in a doctor's office. Stephen Lore, a 51-year-old retired lawyer from Atlanta with multiple sclerosis, says he had heard the drug industry was working on an oral version, and that he "absolutely" wants to try it. He says he had tried almost every therapy on the market before finding relief in 2005 with Tysabri.

When Tysabri was pulled from the market later that year, Mr. Lore says, he was emotionally and physically devastated by the return of his symptoms, including stumbling, slurred speech and vision problems. He blames an overreaction at the FDA for his relapse.

Mr. Lore says he was one of the first patients to go back on Tysabri in 2006, when it returned to the market with the FDA's strongest warning. Taking the medicine again made him feel like he'd "walked through a fountain of youth," he says.

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