Legislation & Regulation

Trying to Sidestep Off-Label Dance-Around

The FDA’s work to redefine ‘truthful and non-misleading’ communication may preempt state efforts.

Richard Mark Kirkner
Contributing Editor

The privilege of a medical license has long meant that physicians could prescribe drugs in ways that they think are best for their patients, not necessarily just for their FDA-approved indications.

Where a license is a privilege, free speech is a right. Drug companies have long claimed the FDA has been trampling on their free speech rights by keeping clamps on what they can tell doctors about using their drugs for indications beyond those the agency has approved. Now, after years of court challenges, agency-imposed fines, and drugmaker lobbying, those restrictions on off-label marketing are loosening up. The agency is working on revisions to rules that govern how drug companies and their sales representatives can communicate with doctors and payers about off-label use.

Those FDA rules have given rise to dance-arounds like drug company reps passively giving physicians reprints of peer-reviewed articles that describe off-label uses. On a higher level, drugmakers have had to be even more discreet in talking to formulary committees about off-label uses. Opponents of looser regulations say they would expose the public and doctors to even more drug company marketing of medications for uses with dubious supporting evidence.

Landscape shifts

A series of events have aimed at easing restrictions on communications about off-label uses. A couple of significant, if not landmark, federal court rulings in 2012 and 2015 upheld the free-speech rights of drug reps when talking with doctors about off-label drug use.

Then, in the final two weeks of the Obama administration, the FDA came out with new proposed rules for off-label communication. The comments swarmed in, prompting FDA Commissioner Scott Gottlieb last January to indefinitely delay releasing new proposed rules.

It’s not because Gottlieb is a prude about loosening off-label restrictions; he is anything but. In 2007, Gottlieb wrote a Health Affairs article that said the FDA is interfering in medical practice by limiting off-label prescribing. “Scott always believed that more responsible sharing of truthful, accurate and non-misleading information is a good thing,” says Peter Pitts, president and cofounder of the Center for Medicine in the Public Interest, a think tank that favors market solutions for health care.

States are also starting to get into the act. This may sound familiar: Following a playbook the conservative Goldwater Institute used to advance state and federal right-to-try legislation that led to President Trump signing federal legislation last month, two states—Arizona and Tennessee—have adopted laws easing off-label communications. A third, Missouri, is taking up similar legislation.

But, as with the right-to-try laws, where states fit in legally here is a head-scratcher. “I’m not really quite sure why the states are spending their energy on it,” says Allison Zieve, director of the litigation group at Public Citizen, the consumer group started by Ralph Nader. FDA authority supersedes state regulations of drugs; Pitts calls state legislation “interesting but useless.”

The latest federal legislation, which Virginia Republican Rep. Morgan Griffith put forth last year, is stuck in committee. The 21st Century Cures Act, passed in 2016, gives drug companies flexibility to provide payers and formulary committees economic analysis information on off-label uses—again, pending regulations.

Going back further, the ACA, as Pitts points out, directed the FDA to draft regulations on off-label drug use.

The momentum to ease off-label restrictions should not lull people into thinking this is a harmless practice, says Zieve. “The term off-label is a sort of technical term and a way to avoid saying unapproved,” she says. “What industry is asking for is permission to market a product for a use when it has not been proven safe and effective for that use.”

She notes the FDA regulatory structure evolved because of a “series of public health tragedies over the years” that resulted from use of drugs marketed without preapproval review. As an example of the risks of companies’ marketing for unapproved uses, she points to the drug Risperdal (risperidone), approved for treatment of schizophrenia. In 2013, Johnson & Johnson paid $2.2 billion in penalties to settle Justice Department charges that it marketed the drug off-label for treatment of dementia in the elderly, downplaying the risks of dangerous adverse effects, including stroke.

But proponents of revised FDA regulations say they will make it easier to approach formulary committees with medical evidence about off-label uses and potentially lower drug costs by reducing drugmakers’ research and development spending (provided the pharmacy benefit managers pass along those savings).

‘Truthful and non-misleading’

Any communication a drugmaker or its reps engage in about off-label uses must be “truthful and non-misleading,” according to the FDA. The meaning of that phrase may be undergoing some alterations.

The Caronia ruling might have a “chilling effect” on the FDA’s enforcement of off-label regulations, says Michael S. Sinha, MD, of the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital in Boston.

Drug manufacturers’ First Amendment right to provide “truthful and non-misleading” information was the key to court challenges of the FDA’s authority. In United States v. Caronia, the federal appeals court rejected the FDA’s effort to essentially criminalize accurate speech about off-label uses. A few years later, Amarin Pharmaceuticals took the FDA to court, claiming the agency was preventing it from communicating “truthful and non-misleading” information about its drug, Vascepa, for lowering triglycerides. Amarin won a preliminary injunction based on court-sanctioned promotional language.

The Caronia ruling, however, lacks national scope and is applicable only in the region covered by the Second Circuit Court of Appeals says Michael S. Sinha, MD, a postdoctoral fellow in the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital in Boston. “However, it did show that at least one appellate court was convinced to expand commercial speech rights to cover off-label marketing rules.” He adds that the ruling may have had a “chilling effect” on the FDA’s enforcement of off-label regulations.

More explicit regulation needed

Essentially, says Pitts, the court ruled in both the Caronia and Amarin cases that the FDA could not prohibit the sharing of “truthful non-­misleading” information, “which was really quite earth shattering from a regulatory perspective.” However, without more explicit regulations, those rulings amount to regulation by lawsuit.

Until the FDA rolls out new rules regarding how drugmakers can pitch their products, expect the agency to take a more casual approach to enforcement, says Peter Pitts of the Center for Medicine in the Public Interest.

The Pharmaceutical Research and Manufacturers Association (PhRMA) and the Biotechnology Innovation Organization (BIO) released joint guidelines in 2016 titled “Principles on Responsible Sharing of Truthful and Non-Misleading Information about Medicines with Health Care Professionals and Payers.” The document spells out scenarios for sharing information with physicians on a personal level and with pharmacy benefit managers on a higher level.

PhRMA itself would like to see more explicit FDA regulations. “A regulatory framework that allows biopharmaceutical manufacturers to responsibly share such information is essential to fostering innovative approaches such as value-based arrangements and other efforts to improve patient care,” says PhRMA public affairs director Andrew Powaleny. The PhRMA–BIO principles would do that, he says.

In an editorial he coauthored in May for the online journal PLOS Medicine, Sinha noted revised regulations need to define beneficial off-label uses versus those that lack evidence.

That’s a tall task for the agency. “The FDA certainly isn’t staffed up to do that,” Pitts says. A panel that former FDA Commissioner Mark McClellan led at the Duke-Margolis Center for Health Policy recommended that the FDA and the pharmaceutical industry create a third-party entity of some kind to do that work.

That work would include figuring out what exactly “truthful non-misleading” means. “One of the important things when talking about the sharing of good versus bad information is, who decides what is truthful, accurate, and non-misleading and in what context?” Pitts says.

That can be difficult when it comes to medications—and many, many other things.

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