Off-Label Communications: Industry, FDA Debate Role Of Peer Review

Allowing manufacturers to share research on unapproved uses that has not been formally vetted and published raises transparency concerns, US FDA commissioner says; industry attorney counters that many useful data sources 'would never see the light of day' under current peer review approaches.

Pharmaceutical manufacturer communications about research on unapproved uses that has not undergone peer review and publication raises transparency and monitoring concerns, US FDA Commissioner Robert Califf suggested Nov. 9.

During the first day of a widely anticipated two-day hearing on manufacturer communications, representatives from the biopharmaceutical and medical device industries urged FDA to modernize its regulations so that companies can share truthful, non-misleading information about unapproved uses, or information on approved uses that extend beyond the product label, with health care providers and payers.

However, Califf suggested there could be a transparency problem if such communications extend beyond publicly available peer-reviewed research.

The commissioner’s repeated questions on this point, coupled with other agency officials' concerns about how such communications would be judged for their appropriateness and by whom, highlight some key issues the agency will have to work through as it re-evaluates its regulatory oversight of off-label communications. (Also see "‘Who Is The Arbiter?’ US FDA Asks As It Mulls Loosening Off-Label Reins" - Pink Sheet, 9 Nov, 2016.)

PhRMA/BIO Principles Apply To Unpublished Data

The pharmaceutical industry should be able to discuss and share data that are either publicly available or not in the public domain, said Michael Labson, a partner at Covington and Burling who appeared on behalf of the Pharmaceutical Research and Manufacturers of America (PhRMA).

PhRMA has advocated for a step-wise approach to relaxing existing constraints on what information manufacturers can share, starting with the "low hanging fruit" of communications between manufacturers and payers, including in the pre-approval setting. (Also see "FDA's Off-Label Communication Changes Should Start With Payers – PhRMA" - Pink Sheet, 20 Sep, 2016.)

Under the current regulatory system, companies face "severe legal constraints and enforcement and compliance risks" in communicating about findings from clinical trials and emerging data sources, such as claims databases and electronic health records, Labson said.

"In some instances, some other participant in the health care system or in the public might be talking about it, say a payer, and the biopharmaceutical company may feel that they can't respond or engage comparably in the dialogue because of the worry about violating the FDA rules," Labson said. In such instances, a company "may have unique data and just not be able to share it for fear of violating FDA rules."

"In other situations, it may be that there's public discourse about the issue, but the company has its hands tied in being able to participate in that, which both is a legal problem under the First Amendment and I think a policy concern because they have a lot of data obviously and should have an equal voice in that discussion," Labson said.

Following presentations from PhRMA and the Biotechnology Innovation Organization (BIO), Califf said he recognized there is a pathway for leveraging data sources other than randomized, controlled trials that involves "publication, consideration of peer review [and] incorporation into clinical practice guidelines by professionals."

"Are you proposing that there should be no requirement for peer review? That the company could go directly to physicians, for example, and show the results of observational studies and case studies?" – FDA Commissioner Califf

"If I understand you correctly, you're suggesting another pathway would be for the company to basically keep the information to itself and promote it without going through those steps of peer review, in a way that some people might regard as not being transparent with the information," Califf said to Cartier Esham, BIO’s ‎executive vice president for emerging companies and vice president of science and regulatory affairs.

While Esham said BIO would respond on this point in written comments to the public docket, she pointed to the information-sharing principles jointly developed by BIO and PhRMA. The principles call for providing adequate, scientific substantiation of shared information that is not included in product labeling, such as limitations in the study methodology or statistical results. (Also see "Off-Label Communication Principles From PhRMA, BIO Aim For Reg Changes" - Pink Sheet, 27 Jul, 2016.)

"When companies have scientifically substantiated information on health outcomes and economic research, for example, what our principles propose is the ability to share that information but ensure that it is shared in a manner that describes the study plans, describes the limitations, describes the statistical analysis," Esham said.

After a presentation by the medical device trade group Advanced Medical Technology Association (AdvaMed), Califf asked: "Are you proposing that there should be no requirement for peer review? That the company could go directly to physicians, for example, and show the results of observational studies and case studies and all that?"

"There is certainly absolutely value in peer review," responded Khatereh Calleja, AdvaMed senior vice president of technology and regulatory affairs. Peer review is the "gold standard in terms of where we want to move." However, "it's just important to look at the host of types of information that's out there," she added.

Peer Review Is No Panacea

One industry representative suggested a requirement for peer review would be too limiting a remedy.

Coleen Klasmeier, a partner in the law firm Sidley Austin, spoke on behalf of the Medical Information Working Group. MIWG is a coalition of biopharmaceutical and medical device manufacturers that has twice petitioned FDA to reform its regulatory framework governing manufacturer communications.

In a June 2014 response to those petitions, FDA said it was engaged in a comprehensive review of its regulations and planned to issue several guidance documents by the end of 2014. (Also see "FDA Promises More Off-label Guidances As Part Of First Amendment Harmonization" - Pink Sheet, 10 Jun, 2014.). The agency has yet to release those documents.

"Peer review has its own internal logic, and there are many sources of data that are incredibly useful that will never see the light of day under prevailing approaches to peer review and publication." – MIWG attorney Klasmeier

In an exchange with Califf following her formal presentation, Klasmeier revisited the commissioner's concerns about sharing off-label information that does not go through the peer review process.

"I recognize that there's a great temptation to treat peer review as a panacea," Klasmeier said. "I think that is a temptation that this policy conversation ought to try to resist, because peer review has its own internal logic, and there are many sources of data that are incredibly useful that will never see the light of day under prevailing approaches to peer review and publication."

"I fully accept peer review has many flaws," Califf responded. "How do you feel about nontransparent transmission of information from one person to another versus full transparency of making it available to the public if one is going to transmit it?"

The MIWG's positions "have always been based on the idea that the informational needs of this evolving system can and should be satisfied by providing scientific data and analysis of the type that … enables prescribers and population-level decision-makers to reach their own conclusions," Klasmeier said.

"Our positions have never sought to preempt that," she continued. "We are not interested in revisiting scenarios that I know are on the forefront of everyone's minds in which there were rampant, unjustified claims being made without regard to data."

"This is a very different discussion and it's about providing data and analysis of the type that would inform very informed decision-making," Klasmeier said. "It's not about rampant, old school Wild West claims."

Publications alone are an insufficient means for ensuring that health care providers are informed of important data, said Edith Perez, vice president and head of the US BioOncology Medical Unit at Genentech Inc.

"There are hundreds of publications for any particular disease, essentially on a weekly basis, so it's very difficult for health care professionals to read everything or to have access to everything," Perez said.

'Sufficient Vetting' Needed

However, one industry consultant suggested that limiting communications about unapproved uses to peer-reviewed evidence would be appropriate.

"The best type of data that we're looking at is data that is peer reviewed and published," said Nicodemo Fiorentino, manager of research and compliance at G&M Health.

"I don't think we would want to see manufacturers go out and just say, 'Here's our data. Take it at face value, doctor.' I think there needs to be sufficient vetting and that's done through the peer review process."