メイヨ・クリニック神経内科教授Dr. David W. Dodickによれば、プラセーボでは1ヶ月で80時間、ボトックスでは120時間、頭痛時間が減少したので明らかな効果があるという。Dodick教授はボトックス頭痛研究の中心の一人である。
アストラゼネカ 統合失調症治療薬の違法販売促進で５億2000万ドルの罰金／米国医療事情 ＦＤＡ
After Fine, Botox Awaits Approval for Migraine
By NATASHA SINGER
Published: September 8, 2010
In public relations, it’s known as “seeding the market” ― stirring up excitement for a forthcoming product or application.
It happens with smartphones, social networks and even designer handbags. But it is not supposed to happen with prescription drugs marketed to doctors, according to federal law.
That is the charge leveled against Allergan, the maker of Botox, in a phalanx of false-claims lawsuits and federal inquiries that resulted last week in the company’s agreeing to pay $600 million to resolve criminal and civil complaints of illegal marketing tactics. Allergan also agreed to plead guilty to one misdemeanor charge of misbranding Botox from 2000 through 2005, but the company denied the other allegations.
Allergan’s settlement with the Justice Department resolves the latest crackdown by the federal government against major drug makers. Last year, Pfizer and Eli Lilly paid hefty sums to resolve federal charges of illegal marketing.
The lengthy federal investigation of Allergan tracked the rise of Botox in an ever-expanding market. Over the last decade, Botox has gained fame ― and talk show notoriety ― as a wrinkle killer. Along the way, the drug has become a blockbuster brand, with worldwide sales last year of about $1.3 billion, in no small part because it can also be used to treat a variety of muscle and gland disorders.
The Food and Drug Administration has over time approved the injections to mitigate uncontrolled blinking, certain neck muscle spasms, excessive underarm sweating, and wrinkles between the eyebrows. This year, the agency again expanded the use of Botox, permitting injections for increased muscle stiffness in the elbows and hands, and it is now considering whether to approve Botox as a preventive treatment for severe migraines.
Meanwhile, Allergan is currently studying Botox as a treatment for overactive bladders, and owns patents on dozens of other potential Botox treatments.
The company denies most of the complaints in lawsuits by whistle-blowers and federal prosecutors. But documents released by the Justice Department related to the settlement outlined claims that Allergan had systematically built Botox sales by promoting it for unapproved treatments to relieve conditions like migraines, pain, muscle spasticity and cerebral palsy in children.
Doctors are allowed to prescribe drugs in unapproved ways as they deem medically appropriate, but it is illegal for a drug maker to promote those unapproved, or off-label, uses. Court filings have described an aggressive marketing strategy, saying that Allergan financed and widely disseminated a video, featuring a well-known neurology professor, to promote Botox as a headache treatment; set up an educational Web site called the Neurotoxin Institute, registered by Ogilvy Healthworld, an advertising agency, to promote Botox treatments to doctors; and paid kickbacks to doctors to induce them to prescribe Botox.
“What concerns F.D.A. is that, if companies can promote off-label uses without submitting evidence showing the drug to be safe and effective, it potentially puts patients at risk and subverts the drug approval system,” Dr. Joshua M. Sharfstein, the principal deputy commissioner of the F.D.A., said in a phone interview about the case on Tuesday.
Without an independent determination by agency experts on the optimal doses and precautions for a particular drug treatment, he said, doctors can wind up prescribing medications without good evidence.
Except for the one misbranding charge, Allergan has denied the criminal and civil accusations, including those of kickbacks and fraud, said Caroline Van Hove, a company spokeswoman, adding that the allegations were not proved.
“I want to be clear that Allergan is not charged with misleading doctors or causing any patient harm,” Ms. Van Hove wrote in an e-mail to a reporter on Monday, “and we adamantly deny any implication that this occurred.”
Allergan, she added, has spent hundreds of millions of dollars in medical research and development of new uses for Botox. The drug is approved in 81 countries to treat 21 different conditions, she said. Several drug makers finance the Neurotoxin Institute, an independent scientific group, she added.
The settlement agreement comes at a delicate moment for the potentially vast new use of Botox to prevent chronic migraines, a debilitating condition. The agency is expected to decide by the end of October on Allergan’s application for that use, which was submitted just last year.
Even so, according to evidence in a separate product liability lawsuit, Botox headache shots already had sales in the United States of nearly $56 million in 2007, signaling growing use for that treatment.
Ms. Van Hove of Allergan said the company had not promoted Botox for migraines, but it had communicated appropriate scientific information about studies on that use.
If the F.D.A. approves the headache shots, she added, the treatment will “address a significant and outstanding need in the treatment of chronic migraine that cannot be dismissed or discredited as a result of this settlement.”
Dr. Sharfstein of the F.D.A. said the Allergan settlement for off-label marketing would not influence the agency’s scientific review of the migraine application. “I think the approval should follow the evidence,” he said.
Millions of dollars are indeed at stake for Allergan.
The British medicines agency recently approved Botox as a migraine treatment. If the F.D.A. were to follow Britain’s lead, some Wall Street analysts have estimated that sales of the drug for migraines could reach $1 billion or more annually worldwide by 2016.
Millions of Americans suffer from migraines. Some neurologists say that the standard pill treatments for the most severe problem of chronic migraine do not improve many patients’ overall condition.
The Botox treatment is aimed at people who have the chronic condition in which people experience at least 15 days a month with headache, including at least eight days with migraine.
A Botox headache treatment session typically entails a total of about 30 to 40 shots around the head, neck and shoulders. The drug’s effect generally lasts three to four months.
The headache shots could cost $1,000 to $2,000 for each of those sessions, industry analysts said.
The F.D.A. is reviewing the latest clinical trials using Botox injections showing that at least some patients went headache-free for more days each month. But the studies also indicated that placebo shots reduced headaches for other patients, leading some experts to question whether Botox really provides much headache relief.
Patients in one study sponsored by Allergan, for example, typically experienced about five fewer headaches a month than they had before ― no matter whether they had injections of Botox or a placebo. In a second Allergan study, patients who received Botox shots had 2.3 fewer headache days a month than patients receiving placebo shots.
“It’s fair to ask, for all those very satisfied doctors and patients out there who are using medications like Botox to treat migraine, to what extent is that activity due to the drug and to what extent that might be a placebo effect,” said Dr. David M. Simpson, a professor of neurology at Mount Sinai School of Medicine in Manhattan.
But Dr. David W. Dodick, a professor of neurology at the Mayo Clinic in Scottsdale, said Botox has clear benefits.
Chronic migraine patients treated with Botox reported 120 fewer hours of headache a month, he said. By comparison, people treated with placebo injections reported 80 fewer headache hours a month, he said.
“I told patients that amounts to a one workweek difference,” said Dr. Dodick.
Both Dr. Simpson and Dr. Dodick have worked as consultants and investigators for Allergan. Dr. Dodick was one of the principal researchers on the two Botox headache studies.
The injections worked for Regan Larish-Hunter, a patient of Dr. Dodick’s who is a high school English teacher in Mesa, Ariz. Six years ago, she began receiving Botox shots for disabling migraines that had incapacitated her for 15 to 20 days a month.
The headaches were so severe that she could not drive a car, she said, and she feared losing her job.
Now she says she gets no more than five not-so-severe headaches a month.
“It was completely life-changing,” Ms. Larish-Hunter, 37, said.
But Dr. Sidney M. Wolfe, the director of the health research group at Public Citizen, a consumer advocacy group, said that a small benefit over a placebo was not worth the risk and suggested that acupuncture could be a less expensive alternative.
While the most typical side effects from injections of botulinum toxins like Botox include temporary bruising and muscle weakness, there have been reports to the F.D.A. of more serious problems. The agency requires all botulinum toxins to carry a “black box” warning label that the drug could spread to other parts of the body ― with the risk of difficulty in breathing or swallowing.
Dr. Wolfe said he worried about the hazard posed by neck injections. (Dr. Dodick, however, said the shots were directed at the back of the neck, not near the esophagus.)
“This is not to be taken lightly,” Dr. Wolfe said. “This is 30 needle jabs four times a year.”
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