Big Pharma Objects to New Hurdles for Off-Label Drug, Device Promotion

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By Bronwyn Mixter

Big Pharma is challenging a final rule that affects the off-label promotion of drugs and devices.

The Food and Drug Administration in the final rule revised the definition of “intended use” to include a new “totality of the evidence” standard that wasn’t in the proposed rule.

Because stakeholders weren’t given fair notice of the revision and opportunity to comment, the FDA violated the Administrative Procedure Act (APA), three industry groups—the Pharmaceutical Research and Manufacturers of America (PhRMA), the Biotechnology Industry Organization (BIO) and the Medical Information Working Group (MIWG)—said in a Feb. 8 citizen petition to the agency.

The intended uses of a product determine whether the product is regulated as a drug or device by the FDA, and they are described in the product’s labeling. Doctors can prescribe products for off-label uses, but manufacturers can’t promote their products for off-label uses. If they do, they can face enforcement action by the agency.

Some attorneys agree the FDA violated the APA when it made the change to the final rule. But a consumer group says the change wasn’t a violation and the final rule is consistent with existing regulation and the proposed rule.

Stay of Rule Requested

The industry groups said in the petition the FDA should indefinitely stay the final rule, reconsider it and use a final definition of “intended use” that is consistent with the proposed rule issued in 2015.

The final rule (RIN:0910-AH19), published in the Jan. 7 Federal Register (82 Fed. Reg. 2,193), also describes when a product made or derived from tobacco intended for human consumption will be subject to regulation as a drug, device or a combination drug/device product under the Federal Food, Drug and Cosmetic Act. The rule’s effective date was Feb. 8, but the FDA postponed it until March 21 in a Feb. 7 Federal Register notice.

The FDA has 180 days to respond to a citizen petition, but the agency can respond by saying it is still considering the issue, Bradley Merrill Thompson, a Washington-based attorney with Epstein Becker & Green PC, told Bloomberg BNA in a Feb. 10 e-mail. “So the deadline really isn’t terribly effective,” he said. Thompson counsels medical device, drug and combination-product companies on a wide range of FDA issues.

Totality of the Evidence

In the proposed rule, the FDA deleted from the “intended use” definition a provision that said if a manufacturer has knowledge that a drug or device is used for off-label conditions, the manufacturer is required to provide adequate labeling for that use. But in the final rule, the FDA replaced that provision with languages saying it would consider “the totality of the evidence” when deciding whether a company needs to provide labeling for an off-label use.

The petition said that under a totality of evidence standard, “everything may be considered to establish a product’s intended use. This standard would allow FDA to rely even on non-promotional scientific exchange as evidence of intended use” and could include clinical practice guidelines and a company’s response to unsolicited requests for information about off-label uses.

“There is no support in existing law for the totality standard, and it would represent a substantial change with significant constitutional and public health ramifications,” the petition said.

Anne K. Walsh, an attorney with Hyman, Phelps & McNamara PC in Washington, told Bloomberg BNA Feb. 13 the totality of evidence standard “it’s clear to me that FDA tried to avoid the notice and comment requirements of the APA,” Walsh said.

Walsh said the petitioner’s APA argument “is certainly strong enough that they could have filed directly with the court and challenged it on an APA basis.” Walsh counsels clients on compliance and enforcement issues, including FDA inspections, seizure and injunction actions, warning letters and recalls.

Deborah M. Shelton, a partner in the FDA Practice Group of McCarter & English in Washington, told Bloomberg BNA Feb. 13 the FDA “is saying [in the final rule] it’s not the knowledge in and of itself that would inform the ‘intended use,’ but that could be part of the equation and could go into the totality of evidence.”

“The petitioners have a very strong argument that this is actually a change in position from the proposed rule. To do that in the final rule without providing an opportunity for comment, is arguably violative of the APA,” Shelton said.

Shelton said “whatever the standard is, it’s certainly not what was in the proposed rule and it’s certainly not what stakeholders had an opportunity to comment on in 2015. And then you have to add to that the complications due to the fact that FDA and industry are in the middle of this dialogue about off-label communications and what all that looks like.”

“So, it’s inappropriate content-wise and timing-wise,” and “I think it makes good sense for FDA to stay the final rule,” Shelton said.

In November 2016, the FDA held a public hearing to obtain input about its policies on manufacturer communications concerning communication about off-label uses of their products ( 10 LSLR, 11/11/16 ). The agency also opened a docket to obtain written comments after the hearing (Docket No. FDA-2016-N-1149). Comments to the docket were initially due Jan. 9, and the FDA extended the comment period 90 days until April 10.

Consumer Group Supports New Definition

Michael Carome, director of Public Citizen’s Health Research Group, told Bloomberg BNA Feb. 13 that he doesn’t think the FDA violated the APA in making the change in the final rule.

“We don’t think there’s anything unique there that’s inconsistent with the existing regulation or what was proposed in 2015,” Carome said.

The proposed rule struck the last sentence of the definition of “intended use,” which said “that if a manufacturer knows that a drug or device is being used for off-label uses such knowledge would require the manufacturer to update the labeling for that use,” Carome said. “And when we saw that proposal, we agreed that change seemed reasonable.”

Manufacturers shouldn’t have to update the labeling of their products just because they knew about off-label prescribing, Carome said.

Carome said the final rule still basically deletes what was in the last sentence of the definition and replaces it with something else that just clarifies what the FDA states in the beginning of these provisions.

“So we think that new last sentence [in the final rule] addresses the concern that was originally raised about the sentence and simply clarifies in a different way language that was already stated in these provisions,” he said.

To contact the reporter on this story: Bronwyn Mixter in Washington at

To contact the editor responsible for this story: Brian Broderick at

For More Information

The citizen petition is at

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