Updated: Off-Label Promotion: Are FDA’s Rules About to Unravel?

Regulatory NewsRegulatory News | 09 May 2018 |  By 

State and federal legislators are prepping changes that would give wider latitude to pharmaceutical manufacturers and unravel FDA rules on off-label promotion, according to a new editorial in PLOS Medicine from Drs. Michael Sinha and Aaron Kesselheim of the Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School.

The editorial coincides with a new push from the libertarian Goldwater Institute, which has already sought to undermine FDA with its “Right-to-Try” state and federal legislation, and is now targeting off-label promotion, as it said in a press release Wednesday that the government is “censoring the communication of valuable information.”

Most recently, Goldwater has made inroads in Arizona and Tennessee, which have established new laws on the “truthful promotion” of medicines for off-label uses.

Tennessee’s law, which takes effect 1 July, says, “No state regulatory board may revoke, fail, or renew or take any other action against a pharmaceutical manufacturer's or representative's, healthcare institution's, or physician's license solely for engaging in truthful promotion of off-label uses.”

Sinha told Focus: "The content of these laws is focused primarily on lifting restrictions on pharmaceutical manufacturers' interactions with physicians and payors, entities that have the power to prescribe and pay for medications. This is a problem because decades of evidence and experience shows how effective pharmaceutical marketing is at driving physician prescribing and payor coverage practices in ways that are not always consistent with data or optimal benefit for patients."

But FDA has pushed back on the idea of opening up off-label promotions further.

Former FDA Commissioner Robert Califf said in a hearing on the issue in November 2016 at the agency’s campus that there is a fine line between helpful information and information that could harm patients.

"Of course, not all communications about unapproved uses would help support public health or the specific health of individual patients,” Califf explained. “For example, communications that are not based on sound science, or otherwise mislead audiences about the benefits or risks of the product, or about the strength of the evidence that supports the use of the product can inappropriately influence prescribing or use decisions in a way that harms patients."

Similarly, the authors of the PLOS editorial, published Tuesday, note that the Caronia decision has permitted manufacturers to engage in off-label promotion under a standard that is “far less rigorous than the FDA’s current standards for determining a drug’s efficacy and safety for a particular indication. For example, a single study (such as a poorly controlled trial or badly done observational study) may have some ‘truth’ to it about a drug’s possible effectiveness or safety but may badly misrepresent the totality of the evidence that the FDA considers, which may point in an opposite direction.”

And the expansion of off-label promotion may also reduce the odds that companies would submit a second indication for approval once a treatment is already approved by FDA.

Sinha adds: "Expanded off-label promotion may not directly reduce the number of published, peer-reviewed studies, but it could reduce the likelihood of FDA review of secondary uses of approved drugs. This is important because it might incentivize manufacturers to bring a drug to market using the easiest, most narrow indication available and then promote the drug widely for any number of off-label uses for which evidence would not similarly pass FDA muster."

FDA in January 2017 also put out two draft guidances and a memo on the issue of truthful and non-misleading communications, noting that recent studies have found that most unapproved uses for which drugs are prescribed lack adequate evidence of effectiveness, and the risk of adverse events is higher for unapproved versus approved uses, and even higher when the unapproved use is not supported by reliable scientific data.

“Buoyed by a narrow victory in one appeals court, advocates have turned to state and federal legislatures to unravel current FDA rules relating to off-label promotion. But these rules are essential for the ability of the FDA to fulfill its public health mission by defining what uses of drugs have benefits that outweigh their risks versus those that lack sufficient evidence to warrant such use. These distinctions are crucial for individual physicians—who do not have the time or expertise to perform the same critical data evaluation conducted by the scores of highly trained scientists at the FDA—and for patients, who could be exposed to more non–evidence-based and potentially dangerous off-label uses of high-cost drugs,” the editorial says.

Sinha added: "Pharmaceutical manufacturers spend 20-30% of their revenues on marketing and administration and have developed substantial skill at marketing over the years. And a busy physician may be swayed over a 10-minute lunch break, just as a patient may be while watching a thirty-second television advertisement. We depend on the FDA to objectively review clinical trial data, carefully weigh risks and benefits, and make approval decisions accordingly."  

Editor's note: Updated with comment from Dr. Sinha.


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