The U.S. Food and Drug Administration will hold a public meeting this summer to address drug company concern that restrictions on what they can say about off-label use of drugs violate their First Amendment right to free speech.
The meeting, announced last month by FDA chief counsel Elizabeth Dickinson, comes as a bill known as 21st Century Cures, designed to speed new drugs to market, is moving through Congress. Language in the bill is adding pressure on the agency to relax its guidelines.
Efforts by drug companies to change the rules gained steam after a 2012 decision from the Second Circuit Court of Appeals, which overturned the conviction of Alfred Caronia, a sales representative for Orphan Medical, which was later acquired by Jazz Pharmaceuticals Inc. After Caronia was caught talking to physicians about various off-label uses of the narcolepsy drug Xyrem, the court said the First Amendment protected truthful and non-misleading off-label speech.
Under current rules, physicians are allowed to prescribe medicines off-label for whatever condition they want. But drug companies are not allowed to promote them for uses that have not been approved by the FDA.
If companies can market drugs for off-label uses there will be no incentive for them to conduct the clinical trials needed to show the products work and are safe, critics say.
"If you're a community physician it's hard to stay current," said Coleen Klasmeier, a partner at Sidley Austin LLP, which petitioned the on behalf of a coalition of pharmaceutical companies to "adequately justify and appropriately tailor its regulatory regime" in light of Caronia and similar rulings.
The coalition, known as the Medical Information Working Group, includes Pfizer Inc, Sanofi, Novartis AG, Johnson & Johnson, Eli Lilly and Co and GlaxoSmithKline Plc, among others.
At stake are billions of dollars in potential sales if manufacturers can persuade physicians to use their products for unapproved uses and a potentially significant weakening of the FDA's regulatory authority.
Karen Riley, an FDA spokeswoman, said the agency decided to hold a public meeting "because of the wide range of views held by different stakeholders and the importance of the underlying public health issues."
OFF-LABEL PROMOTION
Drug companies have a long history of breaching the off-label rules. Over the past decade 17 companies paid more than $16 billion in settlements for off-label promotion, according to the American Medical Association, including Pfizer, GlaxoSmithKline and Eli Lilly.
In September, Shire Plc agreed to pay $56.5 million to settle charges it overstated the benefits of its attention deficit disorder drug Adderall XR and claimed, with little evidence, that it would prevent criminal behavior, traffic accidents and sexually transmitted disease.
"At my own medical center we have banned pharmaceutical reps from coming because we don't think they are a good source of information," said Dr. Rita Redberg, professor of medicine at the University of California, San Francisco, and editor of the medical journal JAMA Internal Medicine. "You don't ask the barber if you need a haircut."
Off-label use already accounts for 10 percent to 20 percent of prescribing, with that figure rising in oncology and pediatric rare diseases, according to the AMA, which said it "supports the important need for physicians to have access to accurate and unbiased information about off-label uses of drugs and devices, while ensuring that manufacturer-sponsored promotions remain under FDA regulation."
REPUTABLE JOURNALS
The FDA does allow companies to provide doctors with data from well-controlled clinical trials from reputable medical journals and reference texts (but not from early clinical trials or letters to editors) and they can talk about off-label use at medical conferences. They can also respond to unsolicited questions from physicians as long as the responses do not tout the benefits of a product without disclosing its risks.
Companies want to be able to discuss data that does not come from randomized clinical trials. They also want to be able to provide economic analyses to insurance companies showing why a drug should be covered.
"Let's say a drug is very expensive and very effective and doesn't have many side effects," Klasmeier said. "If you're a health plan and you are trying to decide whether to pay for the drug you want to know how it stacks up against others."
Industry pressure has "forced the FDA to think harder about this topic," said Peter Pitts, a former FDA associate commissioner for external relations, who is now president of the Center for Medicine in the Public Interest, a think-tank that receives funding from drug companies.
In response to petitions from the coalition, the FDA noted that its regulatory framework was developed "in response to public health tragedies" but said it "recognized the evolving legal landscape in the area of the First Amendment" and promised to review its policies.
It has proposed adding clinical practice guidelines to the list of material companies can circulate. These are often developed by professional associations and may include treatment and dosing regimens that differ from what is on a drug's label.
It has also proposed allowing companies to distribute medical literature showing a product's side effects to be less than described in the label. Comments from the public in response to the proposal were overwhelmingly opposed, according to documents obtained and made public by the consumer watchdog Public Citizen.
TRUTHFUL BUT NOT MEANINGFUL
Those moves have not been enough to appease the industry. Yet public health advocates fear that if the FDA yields further, companies may be able to circulate data which is truthful under the Caronia definition without being meaningful for patient health.
A 2012 study showed that up to 75 percent of published pre-clinical trial results could not be reproduced in subsequent trials. An earlier one showed that when scientists attempted to corroborate 34 claims from frequently cited published trials they were unable to do so 41 percent of the time.
"People do not realize that the consequences of this new ideological approach to the First Amendment will be measured in lives," Dr. Joshua Sharfstein, a former principal deputy commissioner at the FDA who is now associate dean at Johns Hopkins Bloomberg School of Public Health.
For example, doctors prescribed schizophrenia and bipolar disorder drugs for years to control behavior in elderly patients with dementia. Studies later showed they increased the rate of death in the elderly.
Premarin and Prempro, drugs to treat symptoms of menopause, were prescribed extensively to women for years on the assumption they would prevent increased coronary disease. The hypothesis was supported by some data but not by randomized, controlled clinical trials. When the drugs were eventually analyzed in a large government-sponsored trial they were found to increase the risk of stroke and heart attack.
If companies can market drugs for off-label uses there will be no incentive for them to conduct the clinical trials needed to show the products work and are safe, critics say.
"If off-label marketing is allowed then drugs will come to be used for a wide variety of conditions for which there has not been developed evidence of safety and efficacy," said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. "You take away those checks and balances and it's the wild, wild west."