A recent court ruling inhibiting the FDA from punishing Amarin ($AMRN) for off-label promotion deemed truthful and non-misleading shook up the pharma world. The ruling was made for reasons "totally extrinsic to the definition of a drug," and its principles "definitely apply to medical devices," said attorney Coleen Klasmeier in an interview. She heads the food, drug and medical device regulatory practice team at Sidley Austin LLP.
In particular, Klasmeier said drugs and devices that meet a surrogate endpoint will now have to be able promote themselves off-label with greater confidence, as long as the claims made are true, even if the FDA has doubts about the endpoint's relationship to a clinical outcome or endpoint--such as a reduction in coronary heart disease, in the case of Amarin's drug Vascepa. That's assuming the preliminary injunction against FDA enforcement action is upheld in the final ruling, which is considered highly likely.
The dispute between Amarin and the FDA arose after the agency rejected Amarin's bid for an expanded indication after it demonstrated in clinical trials that Vascepa can reduce triglyceride levels (the surrogate endpoint) in patients whose levels are "persistently high" because it was uncertain about the link between drug-induced changes in lipid parameters and cardiovascular risk (the clinical endpoint) in patients with triglyceride levels between 200-499 mg/dl. Note that the drug is already approved for patients with "severe" hypertriglyceridemia (levels above 500 mg/dl).
Because it has been proven that Vascepa reduces triglycerides among patients with persistently high levels, Amarin can market that fact in spite of FDA's rejection of the drug in that patient cohort. The company can also distribute a study that summarizes the clinical trial.
In addition, "the Court noted FDA's decision to make approval of the supplemental indication contingent on a further clinical trial designed to generate data on a related endpoint--a point of interest to FDA but not necessary to vindicate the accuracy of the speech," Klasmeier and fellow Sidley partner Dr. Paul Kalb wrote in a news brief.
The precedent applies not only to drugs, but also to devices that make proven claims about, or are approved upon, the basis of surrogate endpoints, or intermediate outcomes believed to be precursors of, or biomarkers to, clinically relevant endpoints or outcomes.
The preliminary injunction's applicability to the marketing of surrogate endpoint takes on greater importance because the FDA is encouraging their use via its new Expedited Access Pathway, as a means of enabling shorter trials and speeding approvals of "breakthrough" devices.
In the EAP final guidance the FDA writes that "when there is strong evidence demonstrating a predictive relationship between a measure and clinical benefit, it may be accepted for use as a 'well-established' surrogate endpoint in a clinical study which will serve as the basis for approval."
But even "well-established" surrogate endpoints can come into question. In the case of Vascepa, new studies caused the FDA to question whether a link between triglyceride levels and cardiovascular disease exists in patients with "persistently high" levels, Klasmeier said, adding that few people doubted the relationship until recently.
Thanks to the injunction, Amarin can still market Vascepa's effectiveness at reducing triglyceride levels even though it did not win approval for reducing cardiovascular risk in patients with "persistently high" levels, though it still has that indication in patients with "severe" levels."
With the FDA now encouraging the use of surrogate endpoints in accelerated device trials, it's certainly possible that a similar conflict could arise in the device world, so companies should take note of the Amarin precedent.
Especially because the FDA says in the EAP guidance that it will generally "require postmarket confirmatory data as a condition of approval" in return for accepting "a greater level of uncertainty about the likelihood that an intermediate or surrogate endpoint predicts the intended clinical benefit for EAP devices than for other PMA devices."
Some attorneys say unanswered questions about scenarios like what would happen if the confirmatory study comes out negative are a barrier to EAP's adoption, but due to the Amarin injunction, companies should at least feel more secure about their marketing privileges in such a scenario. (So far, there is one confirmed device utilizing the pathway.)
Beyond the obscure topic of surrogate endpoints, the Amarin injunction turned on the First Amendment, which, applies to the marketing of drugs and devices. The FDA has a poor record in free speech cases, but Klasmeier said that the agency hasn't changed its behavior toward off-label promotion much as a result.
A former member of the FDA's Office of Chief Counsel, she said there is a decent chance that employees in the Department of Health and Human Services (under which the FDA serves) will dismiss the ongoing legal spat as having an "unusual fact pattern" because it involves claims about surrogate endpoints that both sides accept as fact and decide that "all we have do to is treat these claims as false or misleading and we'll be fine."
If taken to their logical extreme, First Amendment free speech arguments "pose an existential threat" to the agency, "because they would mean that the FDA no longer has a role to play in adjudicating claims" Klasmeier said.
A lack of consensus at HHS is preventing the FDA from reforming its off-label promotion rules, Klasmeier said. In an effort to build that consensus she said there is a working group withinthe FDA that meets to discuss the issue.
Klasmeier said the group includes officials from the FDA's device arm (CDRH), but declined to specify the individuals. The FDA confirmed the existence of the working group, but didn't provide any additional details.
However, an FDA spokeswoman did say that the agency "is working towards a comprehensive guidance that will consolidate the agency's latest thinking on information dissemination regarding unapproved uses of approved medical products."
-- Varun Saxena (email | Twitter)