United States: Potentially, The Mother Of All Off-Label Uses, As FDA Backs Down

Last Updated: June 14 2018
Article by James Beck

Researchers at Temple University here in Philly recently published a scientific article, "Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway," in the scientific journal Molecular Neurobiology. That sounds pretty dense, but what the article concludes is that the generic drug zileuton (branded name Zyflo) has been shown – in a transgenic mouse study – to reduce both physical evidence of Alzheimer's disease, and its mental symptoms. To whit:

[A]ged tau transgenic mice were randomized to receive zileuton . . . starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice.

"Learning Impairments" Article, at Abstract (emphasis added). In lay terms, it might just successfully treat (we hesitate to throw the "c" word around) Alzheimer's disease.

Nothing else works very well at treating Alzheimer's disease.

Zileuton/Zyflo has been on the market since 1996, indicated for treatment of asthma, and is thus available for generic production under Hatch-Waxman.

Since this drug has already been FDA approved, it may also be used off-label, right now, to treat Alzheimer's patients under the therapeutic rationale explained in the "Learning Impairments" article. With the drug's basic safety profile already established by FDA approval and twenty-something years of clinical use, the primary issue in any such off-label use is effectiveness – does it actually benefit Alzheimer's patients – rather than safety.

Let's assume, for the moment, that zileuton/Zyflo actually has therapeutic value for treating Alzheimer's in humans. This is a drug that can be produced generically, so who is going to finance the Phase III human studies necessary to provide the "substantial evidence" that the FDA requires for a label change adding a new indication? If any generic manufacturer can take a "free ride" on studies sponsored – at great expense – by someone else, then there is not much incentive for anyone to spend that money. Thus, this extremely consequential new indication may become a regulatory orphan. Of course, if the drug shows sufficient promise, other sources of funding could become available – third party payers who pay for the medical needs of Alzheimer's patients, or even the research fund that is supported by the recently issued Alzheimer's semipostal stamp.

If this off-label use is truly beneficial, then it would (in the absence of any better treatment option) likely become the medical standard of care despite being off-label. Eventually, the FDA would be forced to engage in some ad hoc, retrospective approach in order to reconcile the label with clinical practice. That's how the FDA finally resolved the regulatory conundrum of so-called "pedicle screws," where regulation fell behind clinical practice – a retrospective study supported the safety and effectiveness of off-label spinal use, but only after manufacturers endured a decade of meritless product liability litigation. See 63 Fed. Reg. 40025-41 (FDA Jul. 27, 1998).

While further studies are being performed, however, what happens to scientific communication? This could be (or it could not be – too early to tell for sure) an historic breakthrough in treatment of Alzheimer's. If it is, does the FDA continue to prohibit any manufacturer of zileuton/Zyflo from informing the medical community of information on the effectiveness of the off-label treatment, such as optimal dosage and administration practices? We've frequently decried the unconstitutionality of such speaker- and topic-based restrictions on manufacturer scientific communications under the First Amendment. However, for the most part the FDA's refusal to conform to current First Amendment norms has flown under the public's radar, allowing the agency to get away with dilatoriness, and the rest of the government to monetize the FDA's unconstitutional stance with through "false" claims litigation that isn't really about falsity.

Alzheimer's, however, is the elephant in the room. Without some sort of effective treatment, our health care system cannot indefinitely support the cost of palliative Alzheimer's care. Almost everybody knows somebody suffering from dementia, or else someone suffering through the heartbreak of caring for someone with dementia. The FDA will run into a political and medical buzz saw if its retrograde attitude towards truthful off-label promotion gets in the way of making information about an effective (we hope) treatment for Alzheimer's available to the public.

And now – but probably not coincidentally – it looks like the FDA is finally getting off the regulatory schneid. A couple of days ago, the agency issued a "statement" from the commissioner about what was billed as a "new effort" "to advance medical product communications to support drug competition and value-based health care." The big news in the statement is rather buried in regulatory-speak, but it is legitimate big news:

Additionally, it's our [FDA's] belief that giving companies clear guidelines for providing payors with truthful and non-misleading information about unapproved products and unapproved uses of approved or cleared products will help facilitate communications that can allow payors to provide coverage for these new products and new uses more quickly after FDA approval or clearance. And our hope is that these communications can also help companies and payors establish pricing structures that benefit patients as well as health plans.

(Emphasis added). That's a reference to (among other things) off-label use. Specifically, the FDA is now approving "truthful and non-misleading" off-label promotion when directed to an audience of third party payors.

The details of this regulatory retreat from Moscow are found in the FDA's new final guidance, "Drug and Device Manufacturer Communications With Payors, Formulary Committees, & Similar Entities − Questions & Answers, available here. That's another mouthful, so we'll call it the "Off-Label Promotion (OLP) Guidance," since that's really what it is.

The FDA is now allowing those who market prescription drugs and medical devices (see id. at 16 explaining the identical treatment of all classes of medical devices) to provide information about off-label uses of these products to "payors, formulary committees, or other similar entities with knowledge and expertise in the area of health care economic analysis." OLP Guidance at 1 (footnote omitted)

This audience includes public and private sector payors, formulary committees (e.g., pharmacy and therapeutics committees), drug information centers, technology assessment committees, pharmacy benefit managers, third party administrators, and other multidisciplinary entities that, on behalf of health care organizations, review scientific and/or technology assessments to make drug or device selection or acquisition, formulary management, and/or coverage and reimbursement decisions on a population basis.

OLP Guidance at 5 (footnotes omitted).

That's the who.

The "what" is just about everything. The kind of information that regulated drug and device manufacturers can now provide to third-party payors about off-label uses is defined as:

"any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug. Such analysis may be comparative to the use of another drug, to another health care intervention, or to no intervention. . . . [Off-label promotion] may include comparative analyses of the economic consequences of a drug's clinical outcomes to alternative options (including the use of another drug) or to no intervention.

[The information] can be presented in a variety of ways that can include, but are not limited to, an evidence dossier, a reprint of a publication from a peer-reviewed journal, a software package comprising a model with a user manual, a budget-impact model, a slide presentation, or a payor brochure.

OLP Guidance at 4-5.

The "when" varies a bit depending on whether what kind of off-label use is at issue. The FDA has drawn what we believe to be a new distinction between "material differences" from the labeling that "relate[] to an approved indication" and so-called "unapproved indications." Id. at 7. In our experience, the FDA has always considered any variance from labeling limitations to be off-label use. But now, as to approved indications, "material differences from the FDA-approved labeling (e.g., new or increased risks, different dosing/use regimens, different endpoints, more-limited/targeted patient populations)" are treated differently, and somewhat less stringently. Id. at 6. A presentation "should include an accurate overview of the design of the economic analysis, including a statement of the study objectives." Id. at 11 (going into considerable detail).

As to promotion of uses involving such "material differences" from labeling, a basis in "competent and reliable scientific evidence" is sufficient. Id. at 10. In determining the sufficiency of the scientific basis, the FDA will be deferring to "existing current good research practices for substantiation developed by authoritative bodies." Id. The prior FDA requirements of "substantial evidence" is nowhere mentioned. It appears to be gone as a restriction on off-label promotion under the OLP Guidance. Promotion of "material differences" must include a "conspicuous and prominent statement describing" those differences. Id. at 14.

However, off-label promotion "regarding unapproved products and unapproved uses of approved/cleared products" is also now allowed by the FDA. Id. at 18-20. As to this type of what might be considered "true" off-label uses, distribution of the following information to third-party payers is now OK with the FDA:

  • "Product information (e.g., drug class, device description and features)."
  • "Information about the indication(s) sought, such as information from the clinical study protocol(s) about endpoint(s) being studied and the patient population under investigation (e.g., number of subjects enrolled, subject enrollment criteria, subject demographics)."
  • "Anticipated timeline for possible FDA approval/clearance/licensure of the product or of the new use."
  • "Product pricing information."
  • "Patient utilization projections (e.g., epidemiological data projection on incidence and prevalence)."
  • "Product-related programs or services (e.g., patient support programs)."
  • "Factual presentations of results from studies, including clinical studies of drugs or devices or bench tests that describe device performance (i.e., no characterizations or conclusions should be made regarding the safety or effectiveness of the unapproved product or the unapproved use)."

Id. at 18-19.

This kind of off-label promotion should be accompanied by a variety of disclaimers and other information to ensure that the off-label nature of the uses involved is understood:

  • "A clear statement that the product or use is not approved/cleared/licensed, and that the safety or effectiveness of the product or use has not been established."
  • "Information related to the stage of product development" and "whether a marketing application for the product or new use has been submitted to FDA or when such a submission is planned."
  • "[M]aterial aspects of study design and methodology and . . . material limitations related to the study design, methodology, and results. Firms should also ensure that results are not selectively presented."
  • "A prominent statement disclosing the indication(s) for which FDA has approved, cleared, or licensed the product and a copy of the most current FDA-required labeling."

Id. at 19. Significantly, there is no prerequisite that an FDA application for marketing be either pending or contemplated, although if this is the case, it should be disclosed.

As to off-label promotion of these so-called "unapproved uses" (and also drugs and devices that have not yet received any FDA regulatory OK), the FDA tries to salvage what it can of the justifications it used to advance in opposition to our side's First Amendment arguments about truthful off-label promotion:

FDA believes that the categories of information . . . are, on the one hand, broad enough to encompass the information that payors may need to make informed coverage and reimbursement decisions and, on the other hand, limited enough to maintain appropriate incentives for firms to conduct robust studies to evaluate the safety and efficacy of unapproved products and unapproved uses of approved/cleared/licensed medical products. . . . FDA believes that the risk that payors will be misled is relatively low. Payors are a sophisticated audience with established procedures to carefully consider the full range of relevant evidence about new uses of medical products.

OLP Guidance 21-22.

Finally, the OLP Guidance reminds us that "[f]irms' communications to other audiences about unapproved products or unapproved uses of approved/cleared/licensed products could raise additional or different considerations and are beyond the scope of this guidance." Id. at 22.

In conclusion, let's look at that last point a bit. The OLP Guidance punches another huge hole in the FDA's previous attempts to ban regulated entities from distributing truthful information about off-label uses to anybody. As discussed at some length in Greater New Orleans Broadcasting Ass'n, Inc. v. United States, 527 U.S. 173, 192-94 (1999), the number and nature of exceptions to a speech prohibition adversely affect both the prohibition's rationality and its ability to advance the governmental interest that motivates it. We fail to see how any constitutionally valid distinction can exist between providing the identical information, with identical disclaimers and limitations, to one "sophisticated" audience (third-party payors) while prohibiting that information's distribution to another "sophisticated" audience – that being medical doctors that directly prescribe these drugs and devices.

And that's just within the rubric of commercial speech. Greater New Orleans also cautioned, "decisions that select among speakers conveying virtually identical messages are in serious tension with the principles undergirding the First Amendment." Id. at 194. We now have Sorrell v. IMS Health, Inc., 564 U.S. 552 (2011), for the proposition that, with respect to pharmaceutical detailing, we're not just dealing with commercial speech.

Thus, we believe that, as a practical matter, the OLP Guidance effectively dooms any First Amendment defensibility of an FDA ban on the same truthful information being distributed, in the same fashion, to the rest of the medical community beyond third-party payors. Conversely, to those regulated entities that seek to inform physicians of truthful scientific information about their products, we believe that the OLP Guidance can serve as a roadmap to success in an Amarin Pharma, Inc. v. FDA, 119 F. Supp.3d 196 (S.D.N.Y. 2015), situation by establishing that off-label promotion is "truthful," "not misleading," and therefore protected against governmental enforcement activity. After all, just as third-party payers are sophisticated professionals interested in possible effective treatments for Alzheimer's disease, so are the doctors directly involved in treating Alzheimer's patients.

This article is presented for informational purposes only and is not intended to constitute legal advice.

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