Off-Label Debate Between FDA, Industry To Formally Begin After Election

After years of industry prodding, FDA schedules a two-day public meeting in November to establish direction for off-label regulation, but the agency is already being pulled in multiple directions.

Stakeholders applauded FDA's announcement that it would hold a two-day public hearing to gather input on off-label medical product issues, but they are already pulling the agency in several different directions in terms of a desired policy approach.

FDA is finally jumping into the minefield of off-label prescribing with its Nov. 9-10 meeting, following years of push from industry to establish a clear position. The agency has a rocky track record on regulating the issue, falling short on its enforcement bids in several court cases.

In a settlement with Amarin Corp. PLC, FDA agreed to be bound by a district court's ruling that Amarin may engage in truthful and non-misleading speech promoting the off-label use of Vascepa (icosapent ethyl) in patients with persistently high triglycerides. The agency also agreed to adhere to the appellate court ruling in US v Caronia, where that speech may not form the basis of a misbranding prosecution. (Also see "Consumer-Focused Off-Label Promotion Seems Possible After Amarin Settlement" - Pink Sheet, 14 Mar, 2016.)

The drug lobby previously made a pitch to FDA to update its regulations on the subject, amid a shift toward more real-world and health economic data aimed at both prescribers and payers. The Pharmaceutical Research and Manufacturers of America and Biotechnology Innovation Organization July 27 released Principles on Responsible Sharing of Truthful and Non-Misleading Information About Medicines with Health Care Professionals and Payers with the goal "to establish responsible, science-based parameters for accurate and trusted information sharing." (Also see "Off-Label Communication Principles From PhRMA, BIO Aim For Reg Changes" - Pink Sheet, 27 Jul, 2016.)

The principles aimed to allow drugmakers to provide information on off-label uses, and also addressed pre-approval communication with payers and sharing real-world evidence and pharmacoeconomic information with formulary managers, and BIO followed up with a list of ethical principles that should be followed in policy development. (Also see "Off-Label Communications: BIO Lays Ethical Foundation For Change" - Pink Sheet, 9 Aug, 2016.)

FDA said in its most recent regulatory agenda in early 2016 that it plans to release two drug information-sharing guidances this year. (Also see "US FDA Sets Goal For Biosimilar, Drug Promotion Guidances" - Pink Sheet, 26 Jan, 2016.)

A Look At FDA's Questions

Health providers already have the ability to access scientific information about off-label uses for drugs, such as through scientific journals, clinical practice guidelines or by requesting that information from firms.

FDA is therefore seeking comment "on the extent to which additional communications from firms about unapproved uses can provide access to information that is relevant, scientifically sound, responsibly presented, and provides as full an understanding as possible about the limitations of the available evidence, as well as comment on the extent to which health care professionals," according to agency's meeting announcement, scheduled to be published in the Federal Register on Sept. 1.

The agency is also soliciting comments as to the ways communications from drugmakers regarding off-label use information are distinct, and whether they provide unique benefits compared to other sources. The announcement lays out eight lengthy sets of questions. Some specific ones are:

• What are the benefits for clinical decision making, research, coverage, reimbursement or other purposes if firms communicate to health care professionals, payers, researchers and patients information about off-label uses? Are there risks, and ways to mitigate these risks?
• To what extent do changes occurring in the health care system that give payers and formulary committees more influence on prescribing decisions provide incentives for firms to generate the necessary high-quality data demonstrate safety and effectiveness for off-label uses?
• What processes do firms use to determine whether information is scientifically appropriate to communicate to health care professionals about a product?
• What information should firms communicate to make audiences aware that the medical product is not indicated for a certain use and to distinguish between the approved uses of the medical product and the unapproved use?

Regulatory Clarity Atop Industry Concerns

PhRMA VP and Senior Counsel Jeff Francer applauded the meeting announcement. He said in a statement that FDA’s current federal regulations governing information-sharing about medicines have not kept up with the new reality of patients, payers and providers seeking more science-based information about the safety, effectiveness and value of treatments.

"PhRMA is pleased that FDA has recognized that ‘relevant, truthful, and non-misleading scientific or medical information regarding unapproved uses of approved medical products may help health care professionals make better individual patient decisions," Francer said. "Given our increasingly data-driven, value-based health care system, we hope that FDA will act quickly to define new and clearer regulatory standards to permit responsible sharing of information and data about medicines with other parties in the health care system."

More First Amendment, Please

Richard Samp, chief counsel at the Washington Legal Foundation, told the Pink Sheet in an interview that FDA is right to be taking a closer look at this issue, adding that he had not seen until the meeting notice a summary of the off-label issues that FDA is examining. He described the summary as "excellent," but was disappointed that there was no explicit reference to the First Amendment in the notice, calling FDA's previous standards for judging what is truthful and non-misleading "inappropriately strict."

"In general in the past, FDA has taken the position that something is not truthful unless it is supported by two well-controlled clinical studies, Samp said. "I don't believe that is the way science operates. I believe that science will generally accept the studies that don't meet the strict standards that would be necessary to get a product approved for on-label FDA marketing."

Samp said, for example, that information from an open study from the New England Journal of Medicine is the kind of information that reasonable scientists would deem more likely to be accurate than inaccurate, and should therefore qualify as truthful.

"I'm hoping that FDA comes to realize that things can be truthful even though FDA has not certified the information on the basis of two well-controlled studies," Samp said.

A Place For Tighter Regulations?

Samp was pleased that the FDA's questions appear to recognize the distinction in communications based on who the audience is. The concern, Samp says, is that even if information is technically true, is that it has potential to mislead the audience, especially if the audience is consumers rather than trained medical professional. He noted the standards that FDA applies to off-label communications ought to account for this difference.

Michael Carome, director of Public Citizen’s Health Research Group, called on the agency to "strongly regulate manufacturer communications regarding unapproved uses of approved or cleared medical products to protect public health."

"Without strong limits on such industry communications, our country’s long-standing regulatory framework for ensuring that drugs and medical devices are safe and effective for their intended uses would be undermined, threatening patient health," Carome said in a statement to the Pink Sheet.

Former FDAer Questions Timing Of Meeting

A former FDAer called into question of the scheduling of the November meeting, which falls just days after the 2016 presidential election.

Peter Pitts, president of the Center for Medicine in the Public Interest and a former FDA associate commissioner, said the timing shows that there will be no guidance on the topic until well after a new president takes office, which could have "profound implications on the direction of both agency thinking and timing."

"If the folks at White Oak think this will deter attention, they are mistaken," Pitts told the Pink Sheet. "The agency is asking a lot of excellent questions, but they've had a lot of time to ponder all of them already."