FDA Law SSRN Reading List – February and March 2018, 2/3

Continuing with FDA-related scholarship posted on SSRN in February and March:  Professor Noah explores the possibility of “reverse switches” from over-the-counter (OTC) status back to prescription status (or perhaps, he suggests “behind the counter” status) in response to new safety information.  Professor Paradise explains the provisions of the 21st Century Cures Act that contemplate greater patient involvement in medical product development, and Professors Evans and Ossorio evaluate the 21st Century Cures Act exclusion of clinical decision software from the agency’s medical device authority.

Lars Noah, Reversal of Fortune: Moving Pharmaceuticals from Over-the-Counter to Prescription Status?

Many secondary sources explore the grounds and procedures for switching a drug from prescription status to non-prescription (over-the-counter, or OTC) status.  This article, forthcoming in the Villanova Law Review, contributes by exploring the possibility of “reverse” switches — moving back from OTC to prescription status or, perhaps, from OTC to a new third class of drugs controlled by pharmacists (“behind-the-counter” or BTC drugs).  I like this article mainly for the richness of the footnotes, many of which detail historical examples for the points that Noah makes, or draw analogies from other areas of FDA law.

Noah seems motivated by two considerations  — first, his sense that serious safety issues emerge after drugs are switched from Rx to OTC status, and second, the fact that FDA generally responds to emerging safety signals by requiring labeling changes.  Sections II and III of the article explore these points in detail.  Section II tells the “cautionary tale” of nonnarcotic painkillers, pointing to the gastrointestinal risks of nonsteroidal anti-inflammatories (such as ibuprofen), the link between Reye syndrome and aspirin, and the association between acetaminophen and liver toxicity.  Section III argues that internal analgesics are not outliers and provides a litany of serious risks associated with a variety of OTC drugs such as proton pump inhibitors and first generation antihistamines.  Woven throughout are descriptions of FDA’s responses to the safety issues in question, which Noah argues demonstrate reluctance to revisit decisions of OTC availability.

Noah attributes the lack of switchbacks to “skewed incentives” — for instance noting the procedural hurdles FDA would face with a reverse switch (such as the possibility of a hearing requirement if it were to force a change over the NDA holder’s objection), the notion that manufacturers have little inclination to switch back (in part because they would prefer FTC’s authority over OTC drug advertising to FDA’s authority over prescription drug advertising), and the fact that payers would not support the switchback.  Perhaps most interesting, he suggests that the prospect of tort liability could be “harnessed” to drive manufacturers to switch back to prescription status.  As new safety risks emerge, he argues, a manufacturer might prefer the “shelter from expansive products liability” that attaches to prescription status (through the learned intermediary doctrine).  In the end, though, “judicial resistance to negligent marketing claims coupled with receptivity to the preemption defense” mean that the specter of tort liability is not enough to prompt switchbacks.  He concludes in the end that the dangers associated with OTC access to “powerful pharmaceutical agents” have become “intractable.”

Jordan Paradise, 21st Century Citizen Pharma: The FDA & Patient-Focused Product Development

This article, forthcoming in the American Journal of Law and Medicine, describes the provisions of the recent 21st Century Cures Act that support the broader engagement of patients in FDA regulatory decision making, linking these provisions to the emergence of patient advocacy and increased public engagement in scientific issues.

Section I describes patient-focused initiatives at FDA in the recent past, mainly focusing on steps taken by the agency in response to mandates in the Food and Drug Administration Safety and Innovation  Act of 2012 (FDASIA) — such as the creation of a Patient Engagement Advisory Committee in the medical device center, and the issuance of guidance regarding patient preference information in certain medical device submissions.

Section II describes the emergence of a patient advocacy movement in the United States, which Professor Paradise characterizes as a response to the “failures of the legal system to recognize patient rights, autonomy, and perspectives in the scientific process.”  Thus, for instance, she describes several examples from the bioethics literature relating to removal and use of human samples without consent for financial gain.  Section II also invokes a large literature tying the emergence of the patient advocate with “citizen science,” which she defines as public participation and collaboration in scientific endeavors involving legitimate research questions.  According to Paradise, patient advocacy groups led the charge on legislative reform to increase patient involvement in drug and device research, leading to the patient-focused provisions of the 21st Century Cures Act.

The balance of Professor Paradise’s article summarizes the provisions of the 21st Century Cures Act that relate to patient-focused product involvement as well as the implementation steps FDA has taken to date, concluding that the agency has “successfully delivered” on various directives in the statute.  The conclusion’s extended discussion of Exondys-51 (eteplirsen) in 2016 struck me as significant because, unlike many commentators, Paradise does not criticize the agency for approving the drug on the basis of a 12-patient trial without a placebo control.  Rather, it serves as an example of intense patient involvement in regulatory decision making.  Putting aside Exondys-51, as she notes in the ultimate paragraph it remains to be seen how FDA will handle the combination of patient perspectives and its own long-standing requirements for product approval.

Barbara Evans & Pilar Ossorio, The Challenge of Regulating Clinical Decision Support Software after 21st Century Cures

In this brief paper published in the American Journal of Law and Medicine, Professors Evans and Ossorio take up a different aspect of the 21st Century Cures Act: section 3060, which removed five categories of software from FDA’s jurisdiction by excluding them from the statutory definition of “medical device.”

This included a subset of “clinical decision support” (CDS) software.  In plain English, this software combines patient-specific medical information with external knowledge in order to generate a recommendation for a healthcare professional.  To be exempt the software must “enable” the healthcare professional to independently review the basis for its recommendations “so that it is not the intent” that the healthcare professional rely primarily on the recommendation to make a clinical diagnosis or treatment decision for any given patient.

The authors express concern that a manufacturer could simply assert the requisite intent (i.e., that the software is intended to enable independent review and not intended for use as the primary basis of a treatment decision) even if physicians cannot actually understand the basis for the software’s recommendations.  But they suggest that FDA could make a circumstantial case that this software is intended for use as the primary basis of a treatment decision in this situation, under the agency’s intended use regulation.  They also raise the specter of a machine-learning algorithm that cannot explain the basis for its recommendation in terms understandable to a healthcare professional.  In its recent guidance on clinical decision software, they note, FDA did not address machine-learning algorithms.

Perhaps the agency means to exclude machine-learning algorithms altogether.  But, they point out, innovation and patients could suffer if FDA limits the exemption to simple systems. In this scenario, sophisticated systems could face long regulatory delays, which would deprive patients of their benefits and might even deter the development of those systems.  Subjecting all CDS systems with machine-learning algorithms to regulatory scrutiny was, they write, “not necessarily” the balance between innovation and safety that Congress sought to strike. Instead, FDA should require transparency about the basis for the algorithm’s recommendations as well as physician access to the underlying data used by the algorithm, before the CDS exemption applies.

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