This guest post is from Liz Minerd, an associate at Reed Smith. She previously wrote the post on the FDA’s off-label promotion meeting last November, so when she indicated that she’d like to write about the FDA’s “Midnight Memo” on the same topic, we were only too happy to say “yes.” So here is some in-depth analysis of the FDA’s rather unusual decision to, in effect, comment on its own meeting. As always, our guest posters deserve all the credit, and any blame, for their efforts.

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As this blog reported here, last week—two days before the change in administrations—the FDA released a memorandum entitled “Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products” available here. The Agency characterizes this 12th hour memorandum as a follow up to the two-day public meeting it held on November 9-10 regarding off-label promotion (or what the Agency refers to as “communications regarding unapproved uses of approved/cleared medical products”). In particular, the Agency claims that it is issuing this memorandum to provide “additional background” in response to frustrations expressed by certain speakers during the November meeting regarding the Agency’s failure to adequately address the First Amendment in the public hearing notice.

However, the real purpose of the memorandum appears to be to set forth the Agency’s justification for their current restrictions on off-label promotion before a new administration and a new FDA commissioner could have a chance to revisit them. Indeed, after briefly noting the First Amendment concerns raised at the November meeting, the Agency spends the first twenty pages of the memorandum detailing its oft-repeated policy justifications for its current restrictions before addressing any of the First Amendment jurisprudence that has called those restrictions into question. Its attitude is reflected in the memorandum’s first case citation—to the dissent in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012). [Memorandum, at p. 2. fn. 3] The Agency’s lengthy policy discussion demonstrates that the outgoing policymakers at the FDA find very little benefit in communications from manufacturers regarding off-label uses even, though it recites that off-label uses can be the standard of care in some circumstances. This attitude, that only the Agency can keep the public sufficiently safe, is classic governmental paternalism of the sort that the United States Supreme Court has repeatedly condemned in its First Amendment decisions over the past several decades.

For example, the Agency asserts that it seeks to “motivate” the creation of “robust scientific data” about the safety and effectiveness of drugs. [Memorandum at 4-5] However, the current prohibitions only do so prior to approval of a product. After approval—a time period usually much longer than the approval process itself—the current prohibitions prevent the same manufacturers from providing the same sorts of scientific data to the same audience. Thus, the Agency’s current prohibitions actually interfere with the continued creation of robust scientific data after approval. For example, a manufacturer can be required to post clinical trial results concerning an off-label use [Memorandum at 17-18], but is prohibited from informing doctors that they can view the results on ClinicalTrials.gov and decide whether their patients might benefit from the studied use.

The Agency’s remaining policy justifications for the current restrictions on non-misleading, truthful scientific speech about drug or device benefits and risks are all subject to similar flaws, such as conflating unapproved drugs or devices with off-label use, failing to distinguish between what is truthful and what is “false and misleading,” and emphasizing off-label risks (two appendices consisting of over 20% of the memorandum) while ignoring corresponding benefits (no appendices, and only passing mention in the memorandum), but to dwell on them would make this post as long as the memorandum itself. Some of the complaints are with state law [Memorandum at 14]; others apply to only specialized subsets of products [Memorandum at 15-16] and thus cannot support the Agency’s current overbroad prohibition. Suffice it to say that there is nothing new here. The Agency raises no issues beyond those already considered and rejected by most courts since the Supreme Court’s landmark decisions in Sorrell v. IMS Health Inc., 564 U.S. 552 (2011), and Thompson v. Western States Medical Center, 535 U.S. 357 (2002), the second of which the Agency’s memorandum does not even deign to mention.

When the memorandum does finally address the First Amendment jurisprudence, the Agency concludes that the restrictions on off-label promotion advance substantial government interests—which it expounded on at length in the first twenty pages of the memorandum—and are therefore constitutional under Central Hudson Gas & Elect. Corp. v. Pub. Serv. Comm’n, 447 U.S. 557 (1980). The Agency dismisses the Second Circuit’s contrary analysis of the off-label promotion restrictions under the Central Hudson framework in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), because the Agency seemingly asserts that the case was poorly briefed—noting that “multiple components of public health interests advanced by” the off-label promotion restrictions were not considered by the Second Circuit. [Memorandum at 23] This attack on the briefing in Caronia is particularly puzzling because Caronia was handled by the Department of Justice and, as this blog reported at the time, the Second Circuit ordered a second extraordinary set of First Amendment- related briefing after Sorrell was decided.

The Agency further argues, as it has argued in the past, that the scope of Caronia should be limited to barring only the direct criminalization of off-label promotion and not the use of off-label promotion as evidence of intent. [Memorandum at 23] With good reason, courts have been rejecting this argument, because in the usual case, the “intent” of a company to promote off label is not in dispute. The relevant question is, or should be, not “intent” to promote off label, but rather whether the information was accurate and unbiased.

The Agency dismisses any concerns raised by Amarin Pharma, Inc. v. FDA, 119 F. Supp. 3d 196 (S.D.N.Y. 2015), arguing that Amarin wrongly interprets Caronia as foreclosing reliance on the use of truthful, off-label promotion as evidence of intended use for misbranding and citing a footnote from United States ex rel. Polansky v. Pfizer, Inc., 822 F.3d 613, which this blog addressed here. [Memorandum at 22] The Agency notably argues that Amarin wrongly interpreted Caronia even though, as this blog previously discussed, the Agency agreed in settling that case to be bound by the Amarin Court’s conclusion that truthful and non-misleading off-label promotion may not form the basis for a prosecution for misbranding. Notwithstanding the Agency’s settlement in Amarin, as this blog has noted, the government also continues to prosecute manufacturers in circumstances where truthful and non-misleading off-label promotion appears to form the basis of the prosecution.

The Agency then rejects arguments that its restrictions on off-label promotion are content- and speaker-based restrictions subject to heightened scrutiny under Sorrell v. IMS Health Inc., 564 U.S. 552 (2011). The Agency argues that when speech is used as evidence of intent, it will often necessarily appear to be speaker and content-based because whether the speech is relevant evidence depends on the speaker and the content. The Agency alternatively argues that its content- and speaker-based restrictions meet the heightened scrutiny standard because “it makes sense for these restrictions to apply only to [manufacturers], who have an economic motivation related to product distribution.” [Memorandum at 25] Notably, in another decision that the Agency’s memorandum nowhere mentions, the same six justices that decided Sorrell held in Reed v. Town of Gilbert, 135 S. Ct. 2218 (2015) (not a drug case, but neither was Central Hudson) that content- and speaker-based speech prohibitions are subject not just to Central Hudson intermediate scrutiny, but to strict scrutiny.

After the Agency’s brief analysis of (and dismissal of) the First Amendment jurisprudence, the Agency then examines a variety of alternative policies that it could enact, many of which appear to be straw man policies. Specifically, the Agency suggests the following policy alternatives before quickly rejecting each one:

  • Prohibiting altogether the use and/or prescribing of an approved/cleared medical product for an unapproved new use. But this is the quintessential straw man argument. The FDCA does not give the Agency the authority to regulate the practice of medicine, so this was never a possible alternative.
  • Barring approval of generics and other affected products until all periods of exclusivity on the reference product have expired.
  • Creating ceilings or caps on the number of prescriptions for an unapproved use. But again, the Agency does not have the authority to regulate the practice of medicine.
  • Limiting Medicare and Medicaid reimbursement to approved uses. This is also outside the Agency’s authority.
  • Prohibiting specific unapproved uses that are exceptionally concerning or developing tiers based on level of safety concerns with greater regulatory controls for the relatively higher risk products.
  • Requiring manufacturers to list all potential indications for a product in the initial premarket application.
  • Allowing manufacturers to actively promote an unapproved use as long as they disclose that the use is unapproved and include other appropriate warnings.
  • Educating health care providers and patients to differentiate false and misleading promotion from truthful and non-misleading information.
  • Reminding health care providers of potential malpractice liability.
  • Taxing manufacturers more heavily for sales of products for unapproved uses than for approved uses.
  • Permit promotion of unapproved uses listed in medical compendia.
  • Limiting evidence that could be considered relevant to intended use to speech that the government can prove is false or misleading

Notably, the Agency’s memorandum does not consider the alternatives that this blog has discussed, such as permitting off-label promotion subject to the same requirements that the Agency created for textbooks and medical journal articles, or establishing ceilings beyond which it would be mandatory to submit promoted off-label uses for Agency evaluation.

It is unclear at this time how these policies may change under the new administration. The FDA’s memorandum is not an advisory opinion, or a “guidance,” and has no status under administrative law. It is essentially a comment by the outgoing administration. The comment period for the rest of us regarding the Agency’s regulations of off-label promotion has been re-opened until April 19, 2017. Instructions for submitting comments are available here.