Should a pharmaceutical sales rep be allowed to tell a doctor that Topamax, a drug approved to treat seizures and prevent migraine headaches, might also help combat alcohol dependence? Or suggest the epilepsy drug Neurontin could also help treat bipolar disorders or insomnia? Or offer data showing that any number of other drugs could have uses beyond those listed on their labels?
For decades, the answer overwhelmingly has been no. The Justice Department has aggressively pursued companies that run afoul of rules against such “off-label” marketing – racking up billions of dollars in settlements. And the Food and Drug Administration has held firm to the idea that sales pitches generally should not include information on uses not approved by the agency.
But in the long-running conflict between federal regulators and drugmakers over how companies promote their drugs for unapproved uses, the landscape could be shifting, if only in subtle ways, and the outcome could affect doctors and patients alike.
Prompted in part by recent federal court decisions, the FDA is reviewing its rules on what kind of data drug companies should be allowed to distribute to doctors regarding off-label uses, as well as how they should respond to unsolicited questions from physicians about those uses. Its goal is to issue new guidelines by the end of the year.
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Critics of the current rules say allowing pharmaceutical companies, which know the most about their drugs, to share more information about off-label uses would lead to better-informed physicians and ultimately benefit patients. Others are skeptical, saying the industry could exploit even a minor loosening of the restrictions to hype drugs for unapproved uses, exposing patients to ineffective and potentially harmful treatments.
Traditionally, the FDA has approved drugs for specific conditions, and only after rigorous clinical trials for safety and effectiveness. It bars companies from promoting their products for off-label uses, a practice known as “misbranding.” Doctors are free to prescribe drugs for unapproved uses, and many do. The government, through Medicare, recognizes some off-label uses and covers their prescription.
In recent years, pharmaceutical companies have petitioned the FDA for clearer guidance, arguing that the rules are confusing and overly restrictive, especially in an age of social media and widespread access to reams of data beyond what is on any drug label. In addition, high-profile court decisions have bolstered drugmakers’ argument that the off-label rules violate their free-speech rights under the First Amendment, as long as the information being provided to doctors is truthful and not misleading.
In 2011, the Supreme Court struck down a Vermont law banning drugmakers and data-mining companies from accessing records about the prescribing habits of doctors as part of their marketing strategies. In late 2012, a federal appeals court reversed the conviction of a New York pharmaceutical representative, Alfred Caronia, who had been charged with promoting a litany of off-label uses of the narcolepsy drug Xyrem. Caronia, whose conversations with doctors had been recorded, argued that the government had violated his free-speech rights because it had not shown that his sales pitches were false or misleading. By a 2-to-1 vote, the federal appeals court agreed. The government chose not to appeal the case.
Some industry officials say the FDA has been slow to adjust to the reality of those court rulings.
“They were in denial,” said John Kamp, executive director of the Coalition for Healthcare Communication, which represents drug marketing agencies and medical publishers. “If doctors can talk to each other and major researchers can talk about off-label uses, the drug’s manufacturer should be able to talk about those uses, too. . . . If something is true and can be said by one party, it can be said by all other parties.”
That interpretation worries some regulators and public health officials who say relaxing the rules could undermine the FDA’s traditional gatekeeper role.
If First Amendment legal challenges prove successful, they “would turn back FDA’s proactive role in American medicine and jeopardize the safety of patients, as well as the future of innovation and medical progress,” FDA Commissioner Margaret Hamburg said in a 2010 speech.
She pointed to legislation, passed by Congress a half-century earlier, requiring drug manufacturers to provide robust evidence of a drug’s effectiveness before it begins promoting it. That meant “the best drugs, rather than the most aggressively marketed drugs, could rise to the top,” she said, adding, “Removing these protections would ignore the lessons of history.”
There are practical problems, too, said Aaron Kesselheim, a Harvard Medical School professor who has studied off-label promotion. Who gets to decide what qualifies as “truthful” information when it comes to sharing data about unapproved drug uses?
“Is it what the company with a financial conflict of interest says it is?” he said. “Or is it what a scientist at the FDA says it is? That’s the central tension here.”
So why don’t drugmakers more routinely seek FDA approval for new uses for existing drugs?
“In the ideal world, clinical trials would be quick, easy to conduct and free. Unfortunately, none of those conditions are true,” said Jeff Francer, vice president and senior counsel at the Pharmaceutical Research and Manufacturers of America. “Depending on where a drug is in its life cycle, it may not make economic sense for a company to pay for years of clinical study when the medicine is going to lose its patent in a short amount of time.”
That does not mean pharmaceutical companies should be barred from giving doctors legitimate information that comes to light after a drug’s initial FDA approval, Francer said. “Right now, the FDA essentially prohibits the communication of large swaths of information that is truthful and not misleading,” he said. “That information can be extremely beneficial.”
But doctors in hectic, real-life settings often do not have the time to sort through the literature or decipher which data is solid and which is suspect, said Michael Wilkes, a medical professor at the University of California at Davis who has written about drug promotion. “It’s hard to know what’s legitimate and what’s not,” he said. “I’d like to see 1 / 8the FDA 3 / 8 err on the side of overregulation and making companies prove that these drugs work” for off-label uses.
For their part, FDA officials say they are trying to find a reasonable balance. In a statement, the agency said that given “the emerging case law,” it is working to “harmonize the fundamental public health interests underlying FDA’s mission and statutory framework with the interests in the dissemination of truthful and non-misleading information.”
The agency permits companies to share certain off-label information with doctors, though with plenty of strings attached. For instance, the FDA has said manufacturers can distribute certain peer-reviewed medical-journal articles, but the articles should be unabridged and handed out separately from drug promotional materials. Also, the FDA says, companies should disclose any funding of the research behind such articles.
Thus far, the wrangling over the rules appears to have had little effect on the Justice Department’s determination to take on misbranding cases.
Last fall, Johnson & Johnson agreed to pay $2.2 billion to resolve civil and criminal allegations involving the marketing of off-label, unapproved uses for the antipsychotic drug Risperdal to the elderly, children and mentally disabled people, among other accusations. The previous summer, British manufacturer GlaxoSmithKline agreed to plead guilty to criminal offenses and to pay $3 billion to settle charges that included promoting its best-selling antidepressants for off-label uses.
Kamp, of the Coalition for Healthcare Communication, said the FDA has an opportunity this year to provide clarity on what has long remained a murky and contentious issue.
“As this plays out and the rules get more clear and more consistent with the First Amendment, the doctors who prescribe drugs and the patients who take them are going to know more about the safety and efficacy of those drugs than they would without these changes in the rules,” Kamp said. “It’s going to be a step forward.”
Wilkes, the medical professor, disagrees. Without maintaining stringent rules and harsh penalties for violating them, he says, companies could too easily push drugs for uses without the solid evidence to support them.
He pointed to the case of Vioxx, a once-popular painkiller that Merck, its manufacturer, illegally promoted for rheumatoid arthritis before the drug was discovered to actually increase risks for heart attacks.
“Our fiduciary responsibility is to our patients. This isn’t about profits. It’s really about patient safety,” Wilkes said. “As a rule, we ought to be offering our patients treatments and cures and interventions that have been proven to work.”