FDA Law SSRN Reading List – October and November (Part 1 of 2)

Here is what is new and interesting from the last two months.  I’ll start with two articles on off-label promotion and two articles relating to tobacco regulation.

Nathan Cortez, The Statutory Case against Off-Label Promotion, University of Chicago Law Review Online. 

In this paper, Professor Cortez explains and evaluates the statutory theory that FDA uses when it pursues off-label promotion of prescription drugs.  As he notes, FDA’s statutory theory depends on whether the promotion occurs via labeling, advertising, or oral promotion.  It is complex and, in my experience, can be very hard to explain to students and clients.  Take oral statements, by way of example.  A drug is misbranded under section 502(f)(1) if it lacks adequate directions for use.  FDA interprets this to mean adequate directions for lay use, so prescription drugs are automatically misbranded.  Section 502(f)(1) permits the agency to exempt drugs by regulation if those directions are not necessary, so FDA has exempted prescription drugs provided certain conditions are met.  One of those conditions is that the approved physician labeling include adequate information for use, with respect to all purposes for which the drug is intended, including all purposes for which it is advertised or represented.

Now consider the oral statement.

  • FDA reasons that an oral statement about an unapproved use creates a new “intended use” under its intended use regulation.
  • If the approved physician labeling doesn’t contain adequate information about the use, then the drug doesn’t qualify for the regulatory exemption from 502(f)(1).
  • But of course, the approved physician labeling won’t have those instructions — because it’s an unapproved use.
  • So the drug doesn’t qualify for the exemption from section 502(f)(1).  It is subject to 502(f)(1).
  • But it violates this section, because the labeling doesn’t have adequate directions for lay use.
  • BOOM, it’s misbranded.

This is my way of explaining the theory.  Cortez’s article does a nice job laying all this out, too.

In my view, the real contribution is section V of the article, which assesses whether the agency’s position would survive judicial review.  Cortez proceeds to the second step of Chevron and asks whether the agency’s interpretation is reasonable.  He concludes that it is.  Various provisions of the statute, he argues, would make little sense of off-label promotion were widely permissible.  For instance, the new drug approval provisions would not make much sense.  And, he says, prohibiting off-label promotion is key to the integrity of the drug approval scheme. (FDA has made both arguments in court many times.)  Moreover, he says, FDA’s had this position for a very long time, and Congress seems to have acquiesced. Views on the agency’s theory vary , though, and I have always been a bit skeptical.  It would be interesting to see someone publish a robust analysis that reaches the opposite conclusion.

Patricia Zettler, The Indirect Consequences of Expanded Off-Label Promotion, __ Ohio State Law Journal __ (forthcoming). 

This article provides a nice complement to Professor Cortez’s article.  Professor Zettler provides a careful and thoughtful assessment of the impact on FDA of the 2012 decision in United States v. Caronia. This groundbreaking Second Circuit decision overturned a conviction relating to off-label promotion, on First Amendment grounds.  The decision is significant because the majority determined that, FDA’s usual position notwithstanding, Caronia was prosecuted for his speech alone.  That is, the speech was not simply evidence of a new intended use.  Rather, the government’s argument at trial suggested that Caronia’s speech itself was the proscribed conduct.  Professor Zettler notes a robust debate on the impact of this ruling — views that it changes nothing, views that it changes everything (e.g., that it undermines the preapproval system, diminishes incentives to study new uses, and broadly disrupts drug regulation) (precisely the risks that Professor Cortez warns of), and views that it changes some things (for instance by making FDA more cautious in regulation of prescription drug advertising and promotion — witness a drop in warning and untitled letters).  She describes this final impact as the most likely scenario.

Section IV is the pay dirt; here, she describes the indirect consequences of the ruling.  The heart of her argument is that limiting FDA’s regulation of product promotion will increase the risk of products (she argues that most off-label prescriptions are for uses that are associated with significantly higher rates of adverse events than on-label uses).  FDA might attempt to address the increased risk through use of its risk evaluation and mitigation strategy (REMS) authority.  But greater use of REMS comes with trade-offs, she points out, including burdens on patient access and the healthcare system.  It’s also plausible, she argues, that FDA’s benefit-risk calculus would change at the time of drug approval.  The impact could spill over into other categories of regulated products, she notes, and she offers a detailed discussion of tobacco product regulation.  Caronia raises complex issues, and this is a very sophisticated discussion of the impact at FDA, with a lot of new thinking.  It’s well worth reading.

Jonathan Adler, Regulatory Obstacles to Harm-Reduction: The Case of Smoking, 11 NYU Journal of Law & Liberty (forthcoming 2017). 

Although this article focuses on FDA regulation of electronic cigarettes, it makes an interesting contribution to the broader discussion about the relationship between regulation and innovation, by suggesting a concrete example where imposing premarket approval requirements may hamper innovation and thereby harm the public health.  Congress gave FDA formal authority to regulate tobacco products in 2009.  The statute imposes restrictions on certain types of tobacco product and gives the agency authority to “deem” other tobacco products subject to the same provisions.

In May 2016, the agency deemed e-cigarettes to be tobacco products subject to federal regulation.  Professor Adler argues that e-cigarettes have life-saving and harm-reducing potential and notes that some public health advocates urge their use by current smokers.  The “deeming rule” means that these products are subject to adulteration and misbranding rules, limitations on advertising and promotion, sale restrictions, and a premarket approval requirement.  Professor Adler criticizes this as likely to inhibit the development of electronic cigarettes and other less harmful alternatives to cigarettes and other conventional tobacco products.

FDA has also made clear that it plans to police the claims made by e-cigarette manufacturers and retailers about the potential benefits of these products.  For instance, these entities may not claim the products are less dangerous than cigarettes, nor may they inform consumers about the potential benefits of switching, even if these claims are true, without getting FDA’s approval of the e-cigarette as a “modified risk tobacco product.”  Professor Adler criticizes this, noting that consumers benefit when product manufacturers are permitted to make truthful and non-misleading health claims.

In my view, the most interesting part of article is the claim that e-cigarettes are a “disruptive technology” that threaten the established market for traditional tobacco products, that the low barriers to entry ensured a highly competitive market in which producers were free to experiment and innovate, and that the industry itself has been marked by a wide range of participants none of which has a dominant market position.  Professor Adler argues that the new restrictions are likely to advantage larger incumbent firms, like the major tobacco companies, which now make e-cigarettes as well. The preapproval requirement, in particular, is likely to hamper innovation, for instance by precluding vape shops from tinkering and by pricing smaller players out of the market.

Micah Berman et al., Communicating Tobacco Product Information to the Public, 72 Food & Drug Law Journal 386 (2017).   

The 2009 legislation also requires tobacco companies to disclose to FDA information about the harmful and potentially harmful chemicals in their products.  The agency, in turn, must communicate this information to the public in “a format that is understandable and not misleading to a lay person.”  The authors use conventional methods of statutory interpretation — plain language, legislative history, and the like — to propose meanings of the key words in this phase.  Working with these legal conclusions, the researchers also studied how consumers respond to different ways of presenting information about harmful and potentially harmful constituents.  (A full description of this research is being published separately.)

The concern that emerges from their research is that consumers may inappropriately assume that a product is less harmful simply because it has less of a particular harmful constituent or fewer harmful constituents overall.  The information, in other words, may have limited utility to lay people, which means FDA may never be able to satisfy this requirement.  It’s possible, the authors write, that “any presentation of constituent information by brand and subbrand inevitably produces confusion and inaccurate impressions of relative harm.”

Although the authors have provided a legal framework that is intended to help the agency satisfy its statutory obligation (to communicate this information in a format that is “understandable and not misleading to a lay person”), they agree that doing so may be “impossible,” in which case FDA should “limit the amount of information presented.”

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