While COVID-19 and monkeypox may be the public health emergencies garnering much of our current attention, we have been in the midst of another declared public health emergency for nearly 5 years: the opioid crisis.  FDA recently issued a Guidance (Exemption and Exclusion From Certain Requirements of the Drug Supply Chain Security Act for the Distribution of FDA-Approved Naloxone Products During the Opioid Public Health Emergency) that is narrowly tailored, but it is intended to increase access to naloxone—a prescription drug critical in the rapid treatment of opioid overdoses—by harm reduction programs that often serve the most at-risk populations.  In light of the urgent public health need to facilitate and expedite access to naloxone, FDA is implementing this Guidance immediately without prior public comment.

As background, naloxone hydrochloride (“naloxone”) is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdoses and is available in three FDA-approved forms (injectable, auto-injector, and nasal spray).  Naloxone is a prescription drug, but unlike some other prescription drugs used in the treatment of opioid addiction such as buprenorphine, it is not a controlled substance.  Most states have some form of naloxone standing order that allows a healthcare provider to write a prescription that covers a large group of people rather than just an individual patient.  For example, the Maryland standing order allows all Maryland licensed pharmacists to dispense naloxone, including any necessary sup​​plies for administration (e.g., syringes), to any individual without a patient-specific prescription.

Despite the state standing orders, “harm reduction programs” that provide products and services to individuals at risk of experiencing an opioid overdose or those who might respond to an overdose, still face logistical difficulties in acquiring naloxone, as was the subject of a March 2022 workshop on Naloxone Access hosted by the Reagan-Udall Foundation for the FDA.  Because naloxone is a prescription drug, its distribution is subject to the requirements of the Drug Supply Chain Security Act (DSCSA).  One of the DSCSA requirements is that the trading partners of a manufacturer, wholesale distributor, repackager, or dispenser must be “authorized,” which generally requires they hold a valid FDA registration or applicable state license.  Harm reduction programs typically aren’t medical clinics or pharmacies and would not hold any state licenses that would allow them to purchase prescription drugs; although, at least one state (Rhode Island) has created a licensure category for harm reduction centers.   As described by Dr. Nabarun Dasgupta in the Naloxone Access workshop, wholesale distributors often treat harm reduction programs like pharmacies because naloxone is a prescription drug.  Because many harm reduction programs don’t have a pharmacy or medical license, wholesale distributors may determine that they are ineligible to purchase prescription drugs.

By statute, certain activities are automatically excluded from particular DSCSA requirements upon the declaration of a public health emergency under section 319 of the PHS Act.  Specifically, the distribution of a product for emergency medical reasons (including a public health emergency declaration), is exempted from the definition of a “transaction” and excluded from the definition of “wholesale distribution” under the DSCSA.  The purpose of the recent Guidance is to clarify FDA’s interpretation that the exemption and exclusion apply to the distribution of FDA-approved naloxone products to harm reduction programs and to harm reduction suppliers.  The Guidance is intentionally narrow and only remains in effect for the duration of the declared public health emergency which currently must be renewed by the HHS Secretary every 90 days.

During the declared opioid public health emergency, trading partners engaged in the distribution of FDA-approved naloxone products to harm reduction programs and harm reduction suppliers, and the harm reduction programs and harm reduction suppliers obtaining naloxone through such distribution, are not required to comply with the DSCSA product tracing and product identification requirements that are triggered by a “transaction.”  Additionally, FDA does not intend to take enforcement action against trading partners for the distribution of naloxone to harm reduction suppliers and harm reduction programs that are not “authorized trading partners.”

While it is clear that FDA intends to provide clarity and increase access to naloxone for harm reduction programs in particular, we see two potential impediments that can hopefully be easily resolved:

1. Wholesale distributors that sell naloxone to harm reduction programs—particularly the individuals responsible for onboarding new customers—need to be aware of the DSCSA exemption and exclusion provided by the Guidance or else the administrative roadblocks described by Dr. Dasgupta will persist.
2. It may not be clear to supply chain stakeholders which entities may be considered “harm reduction programs” for the purposes of this Guidance. While certain states do define “harm reduction programs” (e.g., West Virginia), there is no such definition in FDA regulations or in the DSCSA.  When ordering from a new supplier, harm reduction programs should be prepared to provide an explanation of how then intend to dispense or otherwise use the products.

We note that the clearest (but certainly not fastest) way to reduce barriers to naloxone access for harm reduction programs and other stakeholders is for naloxone to be available as an OTC drug, which remains an ongoing effort and is well beyond the scope of the particular Guidance.  If naloxone were available for OTC use, the patchwork of state standing orders would no longer be necessary and the transactions would not be within the scope of the DSCSA, which only applies to the distribution of prescription drug products.

As we begin the final quarter of 2022 and the leaves here on the east coast begin to turn and fall, it seems the clock may be running out on FDA and the Center for Drug Evaluation and Research (CDER) to meet its goal of publishing a draft guidance on confirmatory evidence this year.  For the past two years, CDER’s Guidance Agenda has included a spot for this eagerly anticipated guidance, tentatively titled ‘Meeting the Substantial Evidence Standard Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence’.  To be fair, the annual guidance agenda consistently presents a lengthy and somewhat aspirational to do list, and it is not surprising when one slips through the cracks.  However, we wonder whether recent and ongoing approval decisions are shaping FDA’s thinking, possibly pushing back issuance of a draft.

The two previous FDA guidance documents on meeting the patient benefit part of the statutory standard for drug approval – substantial evidence of effectiveness – were released in May 1998 (Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, available here) and December 2019 (Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, available here), just over two decades apart!  Additional guidance on confirmatory evidence is sorely needed as the December 2019 draft guidance spends just two of its 18 pages telling us what FDA thinks of such a key piece of statutory language.  Moreover, the draft guidance is the first time FDA tried to explicitly describe its position on such a key phrase (“confirmatory evidence”) that was made a part of the plain language of the statutory standard for drug approval in 1997, a 22-year interval of near public silence.

Even in the absence of a guidance document dedicated to explaining FDA’s views on interpreting the statutory construct of “confirmatory evidence,” a number of drug approvals over the past few years give us a great deal of insight into FDA’s current thinking and how FDA is applying this standard.  These illuminating drug approvals include FDA’s September 29th approval of Amylyx Pharmaceutical’s therapy for amyotrophic lateral sclerosis (ALS), Relyvrio (see additional recent coverage from HPM’s FDA Law Blog, here, and the Pink Sheet, here).  While Relyvrio’s approval is just the most recent and perhaps high-profile application of this single study approval standard, we think confirmatory evidence is having a moment all its own through such FDA actions.

We use the term “confirmatory evidence” as short-hand for one of the two ways explicitly defined in the Federal Food Drug & Cosmetic Act (“FD&C Act”) for demonstrating substantial evidence of effectiveness.  Since 1962, the Act has given FDA authority to reject a drug application that fails to provide substantial evidence of effectiveness.  The Act defines substantial evidence as that consisting of “adequate and well-controlled [clinical] investigations” upon which qualified scientific experts could conclude that a drug will have its purported effect.  In 1997, the Food and Drug Administration Modernization Act (“FDAMA”) amended the definition to make clear that substantial evidence could alternatively be demonstrated by “one adequate and well-controlled clinical investigation plus confirmatory evidence” (emphasis added).  However, the Act does not define what may constitute such confirmatory evidence other than to say FDA’s interpretation is to be “based on relevant science.”

In the December 2019 draft guidance, FDA describes the rationale behind confirmatory evidence by drawing an analogy to its interpretation of the original 1962 evidentiary bar.  In prevalent conditions, FDA nearly universally requires that substantial evidence be demonstrated via two adequate and well-controlled clinical investigations, for example, two Phase 2 or 3 trials (as long as they have the characteristics delineated at 21 CFR § 314.126).  Some may confuse this requirement for two studies as a need for replication.  Those who do should be forgiven as we often think of replication as the appropriate means to demonstrate that the results of a scientific study are not due to chance.  But replication implies identical repetition of the first study and thus may be prone to any flaws inherent to the first study.  More importantly, replication is but one means to substantiate the results of a clinical investigation or scientific study.

Conducting a second investigation that tests the same fundamental principles (e.g., that drug A can treat disease X) but with some variation in its design (e.g., different endpoints, populations, or durations) may provide more compelling substantiation that a drug has the effect it purports to have.  Showing that the drug has consistent effects across two slightly different patient populations with the same disease reinforces the evidence that the drug has a beneficial effect.  However, both the FD&C Act and FDA acknowledge that running two adequate and well-controlled investigations may not be necessary to provide assurance that the drug will have the effect it is purported to have.  Rather, confirmatory evidence can be a means to substantiate the effects observed in a single pivotal trial.

Even so, FDA does not make the decision to rely upon a single adequate and well-controlled trial plus confirmatory evidence lightly.  Several factors may influence FDA’s determination, such as the persuasiveness of the single trial, the robustness of the confirmatory evidence, and the public health need due to the seriousness of the disease, an unmet medical need, or a combination of both, and the feasibility of enrolling two clinical trials.  The infeasibility of a second clinical trial more commonly manifests in orphan conditions because they offer limited pools for recruiting patients.  Therefore, we have more commonly encountered use of the confirmatory evidence pathway in rare disease drug approvals.  However, this statutory standard is not restricted to use in rare disease settings.  The confirmatory evidence standard is applicable in any condition, especially in those where the clinical context warrants expedited development as a result of having a serious or life-threatening unmet medical need.

Notably, the single study approval pathway using the “confirmatory evidence” standard is just one approach that allows FDA to use its expert judgment to determine that an application meets the substantial evidence of effectiveness standard.  FDA’s Subpart E regulations and the December 2019 draft guidance also provide for broader application of scientific judgement in review of new drugs, mainly through the acceptance of greater uncertainty based on what can constitute an adequate and well-controlled trial (e.g., a study designed to be externally-controlled).  Such expert judgment should be considered on top of use of the “confirmatory evidence” standard in rare, serious diseases with an unmet medical need.

All of this brings us back to where we started – FDA’s interpretation of “confirmatory evidence.”  In the December 2019 draft guidance, FDA provides four examples of what may constitute such evidence – (1) supportive evidence from existing adequate and well-controlled clinical investigation(s) in a closely related approved indication, (2) evidence from data that provide strong mechanistic support, (3) compelling results from the single adequate and well-controlled clinical investigation supported by additional data from the natural history of the disease, and (4) support from scientific knowledge about the effectiveness of other drugs in the same pharmacological class.  While the guidance clearly describes these as just four illustrations of confirmatory evidence, it has been our experience that individual review divisions within FDA have not always shared this view.  We have at times encountered not only a reluctance to apply the “confirmatory evidence” standard but even experienced refusal to recognize other sources of evidence not explicitly mentioned in the guidance (but equally capable of substantiating a single pivotal trial’s results).

Despite these experiences, we have been involved with several “confirmatory evidence” approvals, especially for rare serious conditions, in the past few years that suggest that the FDA may be taking confirmatory evidence more seriously.  Many of these approvals have been variations of the guidance’s mechanistic confirmatory evidence example.  These examples have often taken a similar form whereby the positive findings on a clinical endpoint in the single adequate and well-controlled trial are supported by an effect on a biomarker, another pharmacodynamic endpoint, or even a drug mechanism of action that fits squarely within the disease’s pathogenic pathway(s).  In these examples, we have seen everything from data from the same clinical trial to data collected during in vitro and in vivo experiments cited as confirmatory evidence.  These variations on the mechanistic confirmatory evidence example provide some indication that the December 2019 draft guidance’s language is intended to illustrate just a portion of what may be possible sources of confirmatory evidence rather than provide a rigid framework to be followed.

In other precedents, we have seen FDA cite to consistent clinical findings in earlier phase (i.e., phase 1 and 2) studies, randomized trials of higher or lower doses of the same drug, and data from the open-label cross-over portion of a single pivotal trial.  Notably, none of these latter examples are mentioned in the December 2019 draft guidance.  Further, FDA notes in that draft guidance that the strength of evidence from the clinical trial and the robustness of the confirmatory evidence are two additional factors to consider when deciding whether a single adequate and well-controlled trial plus confirmatory evidence demonstrates substantial evidence of effectiveness.

All of this is why we find FDA’s application of the “confirmatory evidence” standard in the case of Relyvrio so interesting.  In this example, FDA explained that Relyvrio’s primary finding, a slowing of disease progression as measured by the ALSFRS-R clinical rating scale, was supported by long-term survival benefit observed in the open-label extension and by vital status census of all those originally randomized in the clinical trial.  Here, FDA cited to survival data from the same clinical trial population as confirmatory evidence.  The FDA noted that the ALS functional rating scale and survival were distinct aspects of the disease.  In other words, these two types of data represented phenomena that were sufficiently distinct that a survival effect could substantiate, or confirm, a functional one.

Relyvrio may be just the latest and perhaps most high-profile confirmatory evidence approval precedent to date, but it reinforces the interpretation that FDA’s discussion of confirmatory evidence in the December 2019 draft guidance was meant to illustrate what is possible and was not intended to set rigid bounds or limitations on the nature or scope of types of confirmatory evidence.  We would be remiss not to mention that our extensive analyses of FDA’s rare disease approvals lead us to believe that a substantial number of FDA’s orphan drug approvals have been based on this “confirmatory evidence” standard since its enactment in 1997 even when FDA has not explicitly cited to this part of the law.

However, we also see Relyvrio and other confirmatory evidence approvals as indicia of FDA’s emerging, explicit interest in this 25-year old portion of the FD&C Act.  Even in the absence of a stand-alone guidance, we sense that confirmatory evidence may be having a moment all its own.

On September 28, 2022, the FDA issued the long anticipated final Clinical Decision Support Software Guidance (CDS Guidance), which replaces the revised draft guidance document from 2019.  The CDS Guidance interprets the “medical software” carve-out of the 21st Century Cures Act (2016) as it pertains to Clinical Decision Support (CDS) software functions.  Specifically, the guidance interprets the Cures Act’s four criteria for exclusion of CDS software functions from FDA’s medical device jurisdiction (so-called “Non-Device CDS”).  You can find our preliminary blog post on the release of this guidance here, and our blog posts on the draft CDS guidances here and here.

The final CDS Guidance represents a marked change in approach from prior drafts and foreseeably will result in the regulation of many types of CDS that were previously considered to be Non-Device CDS or low-risk Device CDS under enforcement discretion.  The final guidance therefore may have significant implications for a wide range of stakeholders, including not only software developers but also health care providers, hospitals, patients and payors.

Interpretation of Statutory Criteria Under the Final Guidance

The CDS Guidance interprets the Cures Act’s definition of “medical software” that is excluded from the statutory “device” definition, as it relates to CDS software.  As a refresher, the Cures Act established the following four criteria for Non-Device CDS software:

• Criterion 1: Non-Device CDS software functions do not acquire, process, or analyze medical images, signals from an in vitro diagnostic (IVD) device, or patterns or signals from a signal acquisition system.
• Criterion 2: Non-Device CDS software functions display, analyze or print medical information about a patient or other medical information.
• Criterion 3: Non-Device CDS software functions are intended for the purpose of supporting or providing recommendations about a patient’s care to a health care professional (HCP) user.
• Criterion 4: Non-Device CDS software functions provide sufficient information about the basis for the recommendations to the HCP user, so that the HCP user does not rely primarily on any of the recommendations to make a clinical decision about an individual patient.

Criterion 1: The first criterion describes the type of data inputs that are not permissible for Non-Device CDS (inputs that would render CDS software ineligible for the statutory medical software exclusion).  While the final guidance includes the same definition of “signal” as that used in the draft guidance—i.e., signals that typically require the use of either an IVD or a signal acquisition system—it revises the definition for “medical image” and provides a definition for “pattern” for the first time.  As newly defined, the terms “medical image” and “pattern” would appear to narrow the scope of Non-Device CDS.

“Medical image” is defined as including “those images generated by the use of medical imaging systems to view any parts of the body or images acquired for a medical purpose,” even if the images were not “originally acquired for a medical purpose but are being processed or analyzed for a medical purpose.” FDA interprets the term “pattern” to mean “multiple, sequential, or repeated measurements of a signal or from a signal acquisition system.”  As these definitions were not proposed in the draft guidance, stakeholders have not previously had an opportunity to weigh in on the impact of these changes.  Furthermore, the examples of software functions that fail Criterion 1 that are included in the final guidance do little to illustrate the application of these new definitions in practice, as the examples are limited to software products that have been regulated as medical devices for years.

Criterion 2: The second criterion describes the type of data inputs that are permissible for use in Non-Device CDS.  Here again, FDA’s novel interpretation of statutory terms effectively narrows the scope of information that a software product can display, analyze, or print and still be considered Non-Device CDS.  FDA gives no rationale for interpreting the apparently broad statutory term “medical information” in such a restrictive manner.

Medical information about a patient

The 2019 draft guidance interpreted “medical information about a patient” to mean the “kind of information used by the intended user to make decisions.”  In contrast, the final guidance interprets this phrase to mean the “type of information that normally is, and generally can be, communicated between HCPs in a clinical conversation or between HCPs and the patient in the context of a clinical decision, meaning that the relevance of the information to the clinical decision being made is well understood and accepted.”

The CDS Guidance lists four general types of medical information that would meet the definition of “medical information about a patient”—a radiology study report, an ECG report, a blood pressure result, and a lab test result—but these examples shed little insight on how to apply the interpretation in practice.  Furthermore, the subjective terminology in the revised definition gives rise to many questions, including what other types of information “normally” are or “generally can be” exchanged during a clinical conversation, who can determine that the relevance of the information is “well understood and accepted,” and what kind of objective documentation a software developer must collect to document that software inputs meet these conditions.

The CDS Guidance also adds a novel limitation to patient-specific medical information that may be used under Criterion 2, stating that the information must be a “single discrete test or measurement result.”  In contrast, a “continuous sampling” of the same information would constitute a “pattern” or “signal” and therefore fail Criterion 1. The guidance provides no rationale for hinging the device status of CDS software on the frequency with which medical information is collected.  Certainly we would expect clinical communications, as well as HCP-patient communications, to include discussions of test results over time as these would seem highly relevant to clinical decision making.

Other medical information

FDA interprets “other medical information” to include items such as “peer-reviewed clinical studies, clinical practice guidelines, and information that is similarly independently verified and validated as accurate, reliable, not omitting material information, and supported by evidence.”  Consistent with the 2019 draft guidance, the final guidance also includes textbooks, approved drug or medical device labeling, and government agency recommendations as other permissible types of medical information.  The final guidance does not provide further insight as to what other types of information would be considered “similar” in their level of independent verification and validation, but could be read to exclude any reports, such as sponsor white papers, that have not undergone third-party peer review.

Criterion 3: The third criterion defines the scope of permissible intended uses for Non-Device CDS; namely, to support or provide recommendations about a patient’s care to the HCP.  FDA’s 2019 draft guidance explicitly tied its interpretation of Criterion 3 to the International Medical Device Regulators Forum (IMDRF) risk-based categorization scheme, such that Non-Device CDS could only “inform” but not “drive” clinical management.  While the final guidance continues to borrow some IMDRF concepts, it no longer limits Non-Device CDS to software that informs clinical management (per the IMDRF guidelines).  Instead, the final guidance states that, to satisfy Criterion 3, Non-Device CDS must satisfy the following four conditions:

1. Provide condition-, disease-, and/or patient-specific information and options to an HCP to enhance, inform, and/or influence a health care decision;
2. Not provide a specific preventive, diagnostic, or treatment output or directive;
3. Not be intended to support time-critical decision-making; and
4. Not be intended to replace or direct the HCP’s judgment.

FDA justifies these new conditions as intended to prevent clinical errors caused by “automation bias,” i.e., the human propensity to over-rely on a suggestion from an automated system.  The final guidance raises the concern that software that provides single, specific outputs or that is intended to support time-critical decisions will tend to replace or direct HCP judgment even if the software is not explicitly intended to do so.  Thus, to meet Criterion 3 software functions must be designed to prevent automation bias by providing lists of options or follow up for the HCP to consider, and must not be intended to support time-critical decision making.

While the four new conditions on their face would appear to provide more flexibility than the 2019 draft guidance’s binary “inform vs. drive” standard, as interpreted by FDA these conditions appear to limit the scope of Non-Device CDS functions to an even greater extent, as the examples below illustrate.

Risk Scores Off the Table

The final guidance takes the position that software that informs an HCP that a patient “may exhibit signs” of a disease or condition, or that identifies a “risk probability or risk score” for a specific disease or condition, necessarily provides a “specific preventive, diagnostic or treatment output” and therefore is inconsistent with condition 2 and categorically excluded under Criterion 3.  This interpretation of Criterion 3 does not clearly align with the statutory language and could cause more software to be regulated as a device than Congress intended in the Cures Act.  Software providing a risk score for a specific disease could, plausibly, be intended to “support or provide recommendations” to HCPs and it therefore seems a stretch for the agency to categorically determine that such software, just because its output includes a risk probability or risk score, could never meet Criterion 3.  FDA’s novel reading of Criterion 3 may dramatically affect the regulatory status of CDS software that includes risk probabilities or risk scores as outputs.

Criterion 4: The fourth criterion seeks to ensure that Non-Device CDS does not supplant an HCP’s independent clinical judgment.  The statute achieves this through disclosure of information by the software manufacturer about the “basis for” the recommendations made by the software.  The final guidance focuses on labeling as a means to effectuate Criterion 4.  To that end, FDA recommends that:

• software output explains how the logic was applied to the patient and identify other variables to consider when interpreting the recommendation; and that
• software or labeling
  • include the intended use, user, and intended patient population,
  • a summary of the algorithm’s logic or methods (e.g., AI/ML techniques), a description of the datasets used, and clinical studies conducted to validate the algorithm/recommendations, and
  • identification of required inputs, how the inputs are obtained and quality of inputs.

The final guidance stresses the importance of ensuring that an HCP can understand the “strength/limitations of the CDS software recommendations.”

A focus on information disclosure through labeling is generally consistent with the 2019 draft guidance and appears, at least on paper, a reasonable approach to interpreting Criterion 4.  Software developers will need to carefully review their current software and labeling to ensure they provide adequate and understandable information concerning the intended use, inputs, algorithms, datasets and validation.

In addition to labeling, the final guidance adds that software developers “may need to perform usability testing to evaluate if their implementation meets Criterion 4.”  Although not phrased as a requirement for demonstrating compliance with Criterion 4, it is possible that FDA in practice may expect software developers to perform usability studies to demonstrate HCP comprehension, which would add new burdens not clearly supported by the statute.

The Demise of Enforcement Discretion

The final guidance notably eliminates the category of low risk “Device CDS” subject to enforcement discretion that had been included in draft guidance.  Under the draft guidance documents, FDA had provided numerous examples of HCP- and patient-directed CDS software that the agency did not intend to regulate as matter of policy.  The final guidance instead suggests that the regulatory status of such software should be evaluated under FDA’s Policy for Device Software Functions and Mobile Medical Applications and Software as a Medical Device (SaMD): Clinical Evaluation; Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices—revised versions of which were released concurrently with the CDS Guidance—as well as under the 2019 General Wellness: Policy for Low Risk Devices.

Takeaways for Stakeholders:

Overall, this long-anticipated CDS Guidance includes a number of dramatic changes from past iterations, many of which would appear to limit the statutory exclusions for CDS software provided under the Cures Act.  The final guidance foreseeably will lead to more CDS software needing to comply with FDA medical device requirements, including in some cases the requirement for premarket authorization, i.e., 510(k) clearance, de novo classification, or Premarket Approval.  Developers and users of CDS software currently in distribution should carefully evaluate the effect of this guidance on their continued distribution and use of such software, respectively, as well as the impact on regulatory strategy for and timeline for availability of software currently in development.  We expect this guidance will generate concerns not only from software developers but also from HCPs, health care institutions, payors, and patients.  Stakeholders with such concerns may consider expressing them through the submission of public comments to the guidance document’s docket at regulations.gov, filing of Citizen Petitions, or legislative engagement.

On October 6, President Joe Biden issued a brief but sweeping three-step statement towards reforming Federal marijuana law.  The president’s first step was a pardon of all prior federal offenses of simple marijuana possession and a direction to the Attorney General to develop an administrative process to issue certificates of pardon to eligible individuals.  Possession by an individual of a small amount of a drug for personal use without intent to distribute constitutes “simple possession.”  It is important to note that the president’s pardon is limited to simple possession and he made clear that “important limitations on [marijuana] trafficking, marketing and underage-sales should stay in place.”  The president’s pardon is estimated to affect over 6,500 persons with prior federal convictions and thousands of others convicted under District of Columbia law.

Because the vast majority of marijuana-related convictions are at the state level, President Biden’s second step encouraged governors to follow his lead and issue similar pardons.  The President cannot compel governors to act, but their issuing such pardons would be largely consistent with the wave of decriminalization and authorized use of marijuana that has occurred across the country in recent years.  As of earlier this year, 37 states and the District of Columbia have legalized marijuana for medical use and 19 states and the District of Columbia have legalized cannabis for adult recreational use.  Additionally, marijuana legalization measures are on the ballots for the upcoming midterm elections in Arkansas, Maryland, Missouri,  North Dakota, and South Dakota.  We also note there are states where marijuana remains the equivalent of a schedule I controlled substance.

Separate and apart from the loosening of marijuana restrictions by these states, marijuana remains a schedule I controlled substance under federal law.  In his third step, President Biden asked Secretary of Health and Human Services (“HHS”) Xavier Becerra and Attorney General Merrick Garland to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  The Controlled Substance Act (“CSA”) authorizes the Attorney General to reschedule (or deschedule) substances of abuse after consideration of the drug’s potential for abuse and dependence as well as its acceptance for medical use for treatment in the United States.  Before the Attorney General and the Drug Enforcement Administration (“DEA”) can initiate proceedings to reschedule a substance, they must request a scientific and medical evaluation of the substance from HHS.  HHS has undertaken scientific and medical evaluations of marijuana in recent years.  In 2016, DEA denied two petitions — originally filed in 2011 and 2009— after HHS concluded that marijuana continued to meet schedule I criteria by having a high potential for abuse, no accepted medical use in the United States, and lacking an acceptable level of safety for use even under medical supervision.

The CSA requires DEA to seek an opinion from HHS and determine whether the “scheduling recommendation, scientific and medical evaluation, and ‘all other relevant data’ constitute substantial evidence that the drug should be rescheduled as proposed.”  HHS’ recommendations are binding on DEA as to scientific and medical matters.  This “eight factor analysis” requires consideration of:

1. The drug’s actual or relative potential for abuse;
2. The drug’s scientific evidence of its pharmacologic effect, if known;
3. The state of current scientific knowledge regarding the drug;
4. The drug’s history and current pattern of abuse;
5. The drug’s scope, duration, and significance of abuse;
6. The risk, if any, to public health;
7. The drug’s psychic or physiological dependence liability; and
8. Whether the drug is an immediate precursor of a controlled substance.

Again, HHS concluded in 2016 upon considering the eight factors, that marijuana met the scheduling criteria for remaining in schedule I because marijuana does not have a currently accepted medical use in the United States.  While DEA also made specific findings relative to these factors, in effect, DEA’s hands were tied because without a finding from HHS that marijuana has an accepted medical use, DEA had to deny any petition to reschedule the drug.  In summary, the key to any future rescheduling of marijuana remains a finding, specifically by HHS, and supported by DEA, that marijuana does have an accepted medical use in the United States.

President Biden’s statement and requests are no doubt significant.  The federal pardon will have a near-term effect on the lives of those who have been charged and convicted with simple possession of marijuana.  However, only time will tell whether governors will follow President Biden’s lead and issue similar pardons for offenses under state law.  The rescheduling or descheduling of marijuana would be the most monumental and President Biden has clearly signaled his support of this goal.  This is not something we expect will occur quickly.

On September 29, 2022, FDA’s Center for Biologics Evaluation and Research (CBER) and the Office of Tissues and Advanced Therapies (OTAT) held a town hall to answer questions related to gene therapy chemistry, manufacturing, and controls.  Wilson Bryan opened this new forum for direct agency feedback by describing the transformation of OTAT into the Office of Therapeutic Products (OTP).  The restructuring of OTAT into a “super-office” will increase its review capabilities, and enhance expertise on new cell and gene therapies.

When on the bleeding edge of new product development, it can be hard to know ahead of time what the agency is looking for in terms of CMC information.  The standard practice is for FDA to engage with companies on an individual basis through formal meetings and deliver directed feedback to specific sponsor questions.  With the explosion of new gene therapy investigations in recent years, these meetings with industry have become a proverbial black-hole of OTP’s time, energy, and reviewer resources.  OTP has spent years communicating industry-wide problems on an individual basis.

The solution that OTP has reached is to address what are very likely to be common industry problems in a public setting. This move is likely to ease the pressure on their overburdened review staff by creating an organic reference Q&A for industry without having to create and iterate a new series of guidance documents.  Town Hall forums have been used to great success since the start of the pandemic in CDRH to accelerate the development of new IVD products.  Sponsors can interact with FDA in the town hall by submitting questions in advance or by asking a question live during the meeting.  It is important to keep in mind that this meeting is for general CMC feedback and sponsors are informed that “FDA is not able to comment on or answer questions regarding specific investigational products or drug applications during the town hall.”

The major theme underpinning their commentary for this first meeting was the need for cell and gene therapy product developers to think ahead to the long term and plan accordingly.  While the transcript of the town hall will be posted for a healthy dose of science-filled pleasure reading, we highlight a few key points that hopefully set the tone for what to expect from future meetings:

Comparability

OTP acknowledged the elephant in the room that their expectations for comparability assessment is a “hot topic”, and that to address this complex question, they are developing a specific guidance document (i.e., “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products”) that should be released “sometime in the near future.”  At this time, they recommend developers follow ICH Q5e when assessing comparability.  The Agency’s recommendation is that developers implement changes in product manufacturing as early as possible to reduce the risk in the development program.  Depending on the change (e.g., change from an adherent to a suspension cell product system), the Agency might expect both comparability assessments and developmental studies to support that the change does not adversely affect product quality.  The Agency emphasized that release testing alone is not sufficient to assess comparability and that additional characterization testing or in process testing be conducted based on risk assessment and developmental studies.  In some cases, the effect on the final drug product should also be assessed (e.g., vector manufacturing for a transgene vector).

Process Control and Potency

The Agency recommends determining the process requirements early in the development process because late changes in the development program will introduce uncertainty later that may result in a clinical hold.  Product developers should have a robust understanding of their process and process controls. In addition, they should know how to control for analytical method variability prior to starting the clinical trial.  The Agency recognized that sponsors may have difficulties establishing a single suitable test for products with complex mechanisms of action, which is why they recommend developers think about characterizing the product and potency assay development during pre-clinical development.  The Agency expects that the quantitative test to measure biological function of the product is expected prior to initiating clinical studies.  As the product advances in clinical development, expectations are that the potency test be refined to measure biological activity of the product.  If developers want to use a surrogate test(s) for function they must comply with product specific considerations, such as whether the test(s) is specific to the product, provides meaningful measure of activity, and contributes to the overall potency assessment.  The Agency considers early qualification of assays to characterize the product as critical to the success of the program.  The Agency stressed to “think in advance and work hard to getting the data you need to support whatever potency test you submit” as many comments in pre-INDs are regarding inadequate potency tests.

Release Criteria

To determine lot release criteria and to ensure product consistency and quality, OTP recommended that gene therapy product developers use multiple lots during the clinical study, even if one lot is enough to treat everyone in the pivotal study.  Use of multiple lots will help developers set commercial specifications and understand the variability in the product and how it affects the clinical trial results.  One way to facilitate this strategy would be to conduct PPQ runs and use those few runs during the pivotal study.  OTP recognized that this strategy may not be possible for all products (e.g., rare diseases) and recommended developers either leverage data they have from similar products they’ve manufactured from pre-clinical lots, engineering lots, and small-scale development studies, or to design the manufacturing process to allow for more drug product to be used during the clinical study.  They recommended product developers to meet the OTP review team if there are still concerns that there will not be enough data to set the commercial lot release criteria.

We look forward to the next town hall and will be sitting in the virtual front-row.

It is with great excitement that we share CDRH’s announcement that now anyone may submit premarket submissions directly to the Center through the Customer Collaboration Portal (CCP).  We heard from a number of readers after our prior post (here) asking how they could get access to the CCP.  Up until now, access was limited to pilot users who had been granted access during the last year.  On October 3, 2022, CDRH announced the expansion of this program.  Now, according to the Center’s announcement, anyone may request access to the CCP and begin filing premarket submissions electronically.  CDRH’s website provides a link to request access to the CCP (here).  We are certain this will be welcome news for those of you who were not part of the pilot program.

There also appears to be another exciting expansion to the CCP—the ability to track all types of 510(k) submissions.  As discussed in our prior post (here), the CCP has allowed, since its inception, the ability for pilot users to track Traditional 510(k) submissions only.  According to CDRH’s website, “When you send a CDRH 510(k) submission (traditional, special, and abbreviated 510(k)s) for review, your official correspondent can monitor the FDA’s progress online in a simple, concise format.”  The tracking feature is useful to sponsors during the review process to ensure alignment with the Center on timelines and review status, and it will only grow in its utility now that all 510(k) types can be tracked.

We hope others are as excited about the CCP as we are!

Nearly one year after FDA published a draft guidance on its Electronic Submission Template for Medical Device Submissions (see our blog post here), the Agency is back to formally introduce the widespread implementation of the electronic Submission Template And Resource (eSTAR) electronic submission template for 510(k) submissions. eSTAR will be mandatory October 1, 2023 for all 510(k) submissions and subsequent supplements and amendments (e.g. add-to-files).

As its name implies, eSTAR is intended to be a guided submission preparation tool for industry (see here for the FDA’s website for eSTAR). It is designed to improve consistency and enhance efficiency in the review process with data and content that are captured in fields, dropdown boxes, checkboxes, etc. that align with the content of the SMART 510(k) review memo template used by CDRH reviewers (see here for the details of the SMART memo template).

The development of an electronic submission template for 510(k) submissions is significant in that:

1. eSTAR submissions are not expected to go through the refuse to accept (RTA) process. Instead, it will go through a virus scanning and technical screening process to verify that eSTAR responses accurately describe the device and there is at least one applicable attachment per relevant attachment-type question. Although this screening is anticipated to occur within 15 days (the same time as the RTA process), given the electronic nature, we hope this means a shorter administrative turnaround time compared to the RTA process. (A submitter has 180 days to submit a replacement eSTAR upon receipt of a technical screening deficiency notification; failure to do so will result in the 510(k) being withdrawn just like the RTA process.)
2. eSTAR submissions are automated (e.g., form construction, auto filling). eSTAR will prompt for attachments when necessary; this includes financial certifications and disclosure statements for the section of clinical testing. This is a welcome benefit as failure to include these items can result in an RTA designation, stop the review clock, and require time and attention to address with the traditional eCopy submission method. Even if it did not result in an RTA designation, time spent chasing down purportedly missing items (when they were included) could be better spent on substantive review.
3. eSTAR employs targeted questions to collect specific data and information and includes applicable links to regulations, relevant guidance documents, and other resources. (For additional information on the structure and referenced guidance documents, please refer to Table 1 of the Electronic Submission Template for Medical Device 510(k) Submissions guidance document.) This has the potential to make the FDA’s review efficient as relevant information is collected upfront.
4. eSTAR uses the widely available Adobe Acrobat Pro and is compatible with mobile devices for certain PDF features. In response to feedback from users of eSubmitter (software that contained electronic submission templates, including one for preparing a 510(k) submission, and was available from September 2018 through May 2021), eSTAR allows comments to be added to the submission PDF for the purposes of preparing a submission. Comments could include reminders to fill in specific data or call attention to a section of the submission that requires additional review. This is helpful especially when collaborating with teammates on the review and revision process. Users will see a pop-up window appear during the flattening process (i.e., printing to PDF) that states comments will not be sent to FDA.
5. eSTAR allows for responses to additional information (AI) requests. eSTAR guides the submitter in modifying the original submission so that the requests can be addressed. The submitter would select “Additional Information” in eSTAR and see a pop up that provides information on next steps. This development is noteworthy because it aids reviewers in easily identifying where and how submitters have addressed each of FDA’s AI requests. This could, however, become limiting for more complex or innovative device submissions where various elements are connected and/or information needs to be contextualized.

With the exception of points 1 and 5 above, these are not different from when the draft guidance came out in September 2021. However, they are worth reiterating for their potential downstream effect.

On October 3, 2022, FDA announced that eSTAR and eCopy submissions can be submitted through the CDRH Customer Collaboration Portal (CDRH Portal). This builds on the progress tracker launched in 2021 for 510(k) submissions and allows anyone to register for a CDRH Portal account to send their eSTAR and eCopy submissions.

Exemptions from the electronic submission requirements apply to interactive review responses and some amendments (e.g., appeals, substantive summary requests, change in correspondent, and amendments after final decision). FDA does not intend to grant waiver requests. In the meantime, use of eSTAR is voluntary and may be good practice to ensure familiarity with the template before the practice becomes official.  With limited experience using eSTAR, to date, while it seems promising and certainly streamlined for FDA, it is possible there could be drawbacks to users once widespread adoption begins.  We look forward to using the new format and will certainly report back to our readers with both the good and bad.

On September 28, 2022, FDA announced the availability of the proposed rule for the implied nutrient content claim “healthy.”  The healthy claim has been the topic of much discussion and challenged in consumer class actions.  The term healthy, as an implied nutrient claim, was first defined by FDA in 1994.  It is focused on the nutrients in the food product rather than on it overall nutritional “quality.”

In 2015, FDA issued a Warning Letter to Kind LLC because, among other things, the company labeled products as healthy whereas these products provided more saturated fat per serving than permitted by the regulatory definition.  In response to this Warning Letter, Kind LLC with support of nutrition experts) submitted a Citizen Petition asking that FDA update its healthy definition to better reflect the nutritional quality of a product.  The existing regulation for healthy, includes specific criteria for individual nutrients that must be met in the food for it to bear the claim, including limits on total fat, saturated fat, cholesterol, and sodium, and minimum amounts of nutrients for which consumption is encouraged, such as vitamin A, vitamin C, calcium, iron, protein, and dietary fiber.  Under this rule, several foods emphasized in current nutrition science and Federal dietary guidance as key elements of a healthy dietary pattern are not able to bear the “healthy” claim; for example, salmon due to fat levels.

In 2016, FDA reversed its position on the healthy claim for Kind’s products and issued a final guidance informing industry that FDA would exercise enforcement discretion for certain products that did not meet the requirements of the current definition because of their fat (or saturated fat) content but have a fat profile makeup of predominantly mono and polyunsaturated fats.  (The guidance also advised food manufacturers of FDA’s intent to exercise enforcement discretion for foods that are a good source of potassium, and vitamin D, as these two nutrients had been designated nutrients of public health concern in the 2016 final nutrition labeling regulation).  FDA also announced it would be re-evaluating the regulatory criteria for use of the “healthy” claim.

Since then, FDA has undertaken several actions to get input on a revised definition of healthy culminating in the proposed rule.  The proposed rule is intended to align with current nutrition science, the Dietary Guidelines for Americans 2020-2025 and the 2016 nutrition labeling regulation (which also was intended to align with the Dietary Guidelines for Americans).

Some notable aspects of the proposed rule:

• Likely the biggest change is that the proposed definition no longer focuses on presence of specific beneficial nutrients, e.g., minerals or vitamins, to qualify for a healthy claim, but instead focuses on the presence of a defined meaningful amount of food from at least one of the food groups or subgroups recommended by the Dietary Guidelines 2020-2025, such as dairy, fruit, or vegetable.  As a result, there  generally will be no incentive to fortify foods with certain beneficial nutrients.
• Vegetable, fruit, and grain products and other food group definitions are based on food group 1 cup (1 c) or 1 oz equivalents (eqs) as discussed in the Dietary Guidelines 2020-2025. The preamble to the proposal provides further clarification:
  • For vegetables and fruits, a 1 c-eq is: 1 cup raw or cooked vegetable or fruit, 1 cup 100 percent vegetable or fruit juice, 2 cups leafy salad greens, or ½ cup dried fruit or vegetable.
  • For grains, a 1 oz-eq is: ½ cup cooked whole grain rice, whole grain pasta, or cereal; 1 oz dry whole grain pasta or rice; 1 medium (1 oz) slice whole grain bread, tortilla, or flatbread; 1 oz of ready-to-eat whole grain cereal.
  • For dairy, a 1 c-eq is: 1 cup fat-free or low-fat milk, yogurt or lactose-free versions, or fortified soy beverage or yogurt alternatives; 1 ½ oz natural cheese or 1 oz processed cheese.
  • For protein foods, a 1 oz-eq is: 1 oz game meat or seafood; 1 egg; ¼ cup cooked beans or tofu; 1 tbsp nut or seed butter; ½ oz nuts or seeds.

This information is not included in the proposed codified language for the regulation.

• The criteria for nutrients to avoid vary for different food categories. In fact, for fresh fruit or vegetables, FDA does not define nutrients that must be avoided; all raw, whole fruits and vegetables may bear the healthy claim.
  • Individual food products: Must include at least one food group equivalent per RACC from one food group and meet specified limits on the amount of added sugars, saturated fat, and sodium.
  • Mixed products: Must include at least ½ food group equivalent each from at least two different food groups and must meet specified limits on the amount of added sugars, saturated fat, and sodium.
  • Main dish: Must include at least one food group equivalent each from at least two different food groups, and must meet specified limits on the amount of added sugars, saturated fat, and sodium
  • Meal: Must include at least one food group equivalent each from at least three different food groups and must meet limits on the amount of added sugars, saturated fat, and sodium.
  • Water: Plain water and plain, carbonated water may bear the healthy claim.

• The proposed definition lowers the limits on the sodium content from 480 mg to 230 mg per RACC  (which is 10% of the DV) for certain food products. For example, most cheeses will no longer be  eligible for the healthy claim because they contain too much sodium.
• The proposed definition no longer includes a limit on the total fat because, as discussed in the preamble, there is a shift in emphasizing total fat content of a food.  The proposed rule does, however, limit the amount of saturated fat per RACC to 5% of the Daily Value (DV) for vegetable, fruit, and grain product foods, for protein foods that are bean, peas, or soy products, and for protein products that are nuts and seeds (except if the saturated fat is derived from the nuts and seeds), and to 10% of the DV for dairy products and the protein foods game meat, seafood, egg and for oils.  The proposed rule does not include a separate limit on cholesterol content.
• Because it may not be possible to determine if processed foods meet the healthy claim criteria by analysis of the products, companies wishing to use a healthy claim may need to prepare documents to support the claim.  Consequently, the proposed rule includes recordkeeping requirements for foods bearing the claim where compliance cannot be verified through analysis or information on the product label.

Plant-based alternatives to milk yogurt will be evaluated as dairy products; products whose overall nutritional content is similar to dairy (e.g., provide similar amounts of protein, calcium, potassium, magnesium, vitamin D, and vitamin A) and are used as alternatives to milk or yogurt will be evaluated against the dairy criteria for the purposes of the ‘‘healthy’’ nutrient content claim.

FDA is conducting research on a symbol to represent the claim “healthy.” The symbol on the front of a package would function as a quick signal to allow consumers to identify foods that will help build healthy dietary patterns.

FDA proposes a compliance data of 3 years after the effective date. These three years are intended to provide industry with sufficient time to revise labeling (if needed) and, according to FDA, balance the time that industry needs to revise labeling and or reformulate certain products against the need for consumers to have the updated rule (and information) in a timely manner.

FDA seeks comments on many of the aspects of its proposal (the term seek comments occurs 22 times).  Comments must be submitted by December 28, 2022.

Allegations of regulatory misconduct are claims that a medical device manufacturer or marketers of medical devices operate in such a way that violates the law. Allegations may include failure to register and list a medical device, promotion of a device outside the scope of its clearance or approval, and marketing a device without an appropriate clearance of approval. Reporting these allegations to FDA is important as the Agency may be unaware of the actions of these manufacturers and marketers, thus creating potential risks to patients.

FDA reviews allegations submitted through the Allegation of Regulatory Misconduct Form, by email, or by regular mail to determine whether an investigation and any follow up activity is justified. Although these allegations can be submitted anonymously, FDA encourages the submitter to provide contact information in case additional background is needed. When reporting an allegation of regulatory misconduct, FDA advises on identifying the medical device at issue as well as its model number, serial/lot/part numbers, and the name of the company, its location and telephone.

If contact information is provided, FDA will respond with an acknowledgment from the Allegation of Regulatory Misconduct Team at FDA. This acknowledgment will include an FDA-assigned identification number for the allegation report. The acknowledgment also states that “[w]hile FDA does not provide information on ongoing investigations, information can be obtained through a Freedom of Information Act (FOIA) Request.” FOIA requests can be submitted online. FDA encourages waiting at least 6 months to make such a request for related records; FDA cites this as the average time to complete an investigation. If the request pertains to 510(k)s, PMAs, or De Novos, FOIA requests can “take approximately 18 – 24 months to process.”

Without constant vigilance of the warning letter, inspection, or recall databases, learning the outcome of any regulatory action can be sluggish and inconclusive. We analyzed FOIA logs from the last five years for allegations of regulatory misconduct. While we know who submitted FOIA requests, the subject of these requests, and the control number for each request, the status of these reports is largely listed as “pending action” or altogether absent from FOIA logs for FY 2017 – FY 2021. When reviewing each month’s FOIA logs from September 2018 to August 2022, the status is “closed” or “withdrawn[,] closed w/o [without] charges.” The time in which these requests were completed ranged from months to years. Any specific action as a result of the allegations are not publicly disclosed.

This means there needs to be a better way to understand the outcomes of urgent issues. If the original complainant of the allegations of regulatory misconduct is to wait at least 6 months to submit a FOIA request and then at least another 18 – 24 months for it to process, years will have gone by without any insight on the assessment and resulting actions undertaken by FDA. This is unproductive. We recommend FDA engage with the complainant and keep them abreast of any investigation and subsequent efforts to bring the offending party back in line.

On September 26, 2022, Biogen Inc. agreed to pay $900 million to the United States and various states to settle a False Claims Act (FCA) lawsuit.  This lawsuit was brought to the U.S. district court of Massachusetts by former employee and whistleblower Michael Bawduniak in April 2012 as a qui tam action. See United States ex rel. Bawduniak v. Biogen Idec, Inc., No. 12-cv-10601-IT (D. Mass.). Mr. Bawduniak alleged that, between 2009 and 2014, Biogen paid illegal kickbacks to its largest prescribers to induce them to prescribe the company’s multiple sclerosis drugs, Avonex, Tysabri and Tecfidera, and discourage them from prescribing newer competitor products. This settlement is the largest ever FCA settlement secured without the intervention of the United States.

Biogen first disclosed this tentative agreement in a quarterly earnings report in July of this year. In a statement, the company denied all allegations raised in the case, saying that it believed its intent and conduct to be at all times lawful and appropriate. The company did not accept any admission of liability as part of the settlement.

For several years now, the U.S. Department of Health and Human Services (HHS) and the Department of Justice (DOJ) have aggressively pursued antikickback cases in the healthcare industry. As many of our readers know, the federal antikickback statute prohibits offering or paying healthcare professionals (HCPs) anything of value as an inducement or reward for ordering or prescribing an item or service reimbursable by federal health care programs. See 42 U.S.C. § 1320a-7b(b). HHS noticed an increasing trend of illegal kickbacks in connection with speaker programs and in November 2020, the Office of Inspector General issued a Special Fraud Alert on the topic. The Alert described several factors that could potentially violate the antikickback statute. For example, the government closely scrutinizes speaker programs or trainings that involve lavish venues or meals and free alcohol, invite attendees with no legitimate business reason to attend, and present little substantive information to them.  The government also suspects violative conduct if the speakers, attendees, or consultants are selected based on the volume of their past prescriptions of the company’s products or their expected future prescriptions.

Biogen allegedly paid kickbacks in the form of honoraria, speaker training fees, consulting fees, and for meals to HCPs who spoke at or attended Biogen’s speaker programs, speaker trainings, or consulting programs.  The relator claimed that his secretly recorded conversations confirmed that Biogen deliberately compensated some of its most important prescribers “to influence their prescribing and to ensure that they remained loyal Biogen customers.” Mr. Bawduniak claimed that these events were held at “sumptuous resorts and restaurants” and involved “lavish meals and free alcohol.” Biogen supposedly paid doctors for services that had no legitimate business purpose and no demand from doctors, and were unlikely to be conducted. For example, he claimed that Biogen paid “hundreds of customers” and HCPs for consulting advice on topics that the company did not need, never intended to use, could not use, or for which Biogen already had all the information it required. The company also allegedly paid its speakers and consultants above the fair market value for their services by, for example, automatically adding compensation for three hours of travel time even when an HCP did not have to travel to get to a speaking event.

After the OIG Special Fraud Alert, the Pharmaceutical Research and Manufacturers of America (PhRMA) updated its Code on Interactions with Health Care Professionals to offer updated guidance on speaker trainings, speaker programs, meals, and gifts. Today, these two documents are key in navigating speaker programs in the industry.

On September 28, 2022, FDA published its long-awaited final guidance document entitled “Clinical Decision Support Software,” which interprets the medical software provisions of the 21st Century Cures Act (Cures Act). The final guidance was preceded by two iterations of draft guidance—one in 2017 and one in 2019—each of which garnered extensive public comment. We discussed the evolution of FDA’s CDS guidance, in previous blog posts here, here, and here.

The Cures Act excluded from FDA oversight certain software functions, including those that are intended to “support or provide recommendations to a healthcare professional (HCP) about prevention, diagnosis, or treatment of a disease or condition,” i.e., “clinical decision support” functions, subject to specified conditions. FDA’s draft guidance documents sought to establish criteria for three categories of CDS, those that: (i) did not meet the statutory device definition (Non-Device CDS); (ii) while technically devices, would be subject to enforcement discretion; and (iii) would be actively regulated (Device CDS).  In contrast, the final guidance focuses solely on Non-Device CDS. Consequently, the final guidance no longer articulates a policy of enforcement discretion for any CDS software, although the guidance notes that certain CDS software “may” fall under enforcement discretion policies found in FDA’s other guidance documents related to low risk software products. See Policy for Device Software Functions and Mobile Medical Applications; Software as a Medical Device (SaMD): Clinical Evaluation; Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices; and General Wellness: Policy for Low Risk Devices (HPM has written about several of these policies and their past iterations here, here, here, and here).

The final guidance also seeks to shed light on a key statutory condition for exclusion from FDA regulation, namely, that the software enables a health care provider “to independently review the basis for” the software’s recommendations.  This prong of the statutory exemption has led to much uncertainty among stakeholders about the regulatory status of particular CDS software products. The final guidance makes recommendations about software and labeling that will provide the requisite independence, which are “based on FDA’s experience” evaluating CDS functions but acknowledges that “sponsors may use alternative approaches.”

There is much to unpack in the final guidance, and it will undoubtedly have significant implications for stakeholders in the burgeoning CDS software sector.  Stay tuned for an in-depth analysis on the blog in the coming week!

On September 29, 2022, FDA approved Amylyx’s NDA for its drug, Relyvrio (sodium phenylbutyrate/taurursodiol), for treatment of patients with amyotrophic lateral sclerosis (ALS) (see FDA announcement here).  This approval decision charts a path for the exercise of appropriate flexibility in regulatory decisions for other rare conditions where there is a serious and/or life-threatening unmet medical need, as is very often the case.  As articulated by Dr. Billy Dunn, the Director of CDER’s Office of Neuroscience, at the September 7, 2022 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, applying the statutory standard in approval decisions in these clinical contexts warrants the “broadest possible” flexibility.  These remarks by Dr. Dunn and his Summary Review offer insights into the practical application of the FDA’s December 2019 draft guidance on substantial evidence of effectiveness (as we will discuss further below).  Hyman, Phelps & McNamara, P.C.’s Frank Sasinowski and James Valentine are honored to have aided Amylyx in this development program and approval.

This approval is a testament to FDA drug officials in the Office of Neuroscience and Division of Neurology 1 (see their Summary Review here).  We would like to acknowledge FDA for its efforts on this devastating condition, ALS.  The Office and Division have paid special attention to the Voice of the ALS Patient as witnessed by the historic engagement with the ALS community to craft disease-specific drug development guidance, ongoing engagement through FDA-hosted and community-led meetings (see, e.g., ALS Association We Can’t Wait Action Meeting), and efforts to understand patients’ continued unmet medical needs (see ALS Voice of the Patient Report).  This is evidence of FDA’s embrace of patient-focused drug development.

However, this approval has implication for the development and review of drugs for all rare diseases, not just ALS.  While the concept of “flexibility” has been in FDA regulations for decades, the Agency’s first fulsome articulation of how this should be manifested when reviewing evidence of effectiveness came in 2019, when FDA issued draft guidance on the substantial evidence of effectiveness standard.  This guidance, for the first time, offered insights into where and how a single adequate and well-controlled (A&WC) study with confirmatory evidence could meet this standard.  The guidance went further to describe how, in certain circumstances, less traditional study designs that introduce greater uncertainty (e.g., due to being historically-controlled) can still be considered an A&WC study.  Yet, in our view, Dr. Dunn’s opening presentation at the September 7^th Advisory Committee meeting is FDA’s most eloquent description of how to apply appropriate regulatory “flexibility,” which we know can be like asking regulators to color outside of the lines.  In these remarks, notably, Dr. Dunn suggested that we look to FDA’s previous approval decisions to understand just how much uncertainty can be accepted, sighting in ALS to previous approval decisions that did not provide traditional efficacy evidence. This is what these authors worked to do in 2010 and 2015 when we catalogued and characterized the application of appropriate flexibility in FDA approvals of orphan drugs, shedding light on these important issues (see coverage of here).

This flexibility by FDA manifested itself ultimately in the approval of Relyvrio, where FDA in its Summary Review concluded:

Overall, Study AMX3500 demonstrated a statistically significant treatment benefit of AMX0035 compared to placebo on the prespecified primary endpoint, the rate of decline of ALSFRS-R. In post hoc long-term analyses, an overall survival benefit was observed for those patients who were originally randomized to AMX0035 compared to those originally randomized to placebo. Supplemental post hoc exploratory analyses comparing the overall survival to natural history databases provided consistent results. There are limitations to these findings that result in a degree of residual uncertainty about the evidence of effectiveness that exceeds that which might typically remain following a conclusion that substantial evidence of effectiveness has been demonstrated; however, given the serious and life-threatening nature of ALS and the substantial unmet need, this level of uncertainty is acceptable in this instance and consideration of these results in the context of regulatory flexibility is appropriate. Exercising regulatory flexibility, the single study with positive results on a clinically meaningful primary outcome accompanied by confirmatory evidence of an observed survival benefit provides substantial evidence of effectiveness. (emphasis added)

In November 2020, we blogged about a decision by the Federal District Court of Maryland dismissing a Federal False Claims Act (FCA) qui tam suit alleging that Forest Laboratories knowingly reported inflated best prices under the Medicaid Drug Rebate Program (MDRP), resulting in underpayment of rebates.  The relator claimed that Forrest knowingly failed to combine (“stack”) discounts on the same drug unit to two different customers when determining best price.  As we reported, on November 5, 2020, the District Court held that the relator could not plausibly plead the requisite scienter because Forest’s interpretation of the ambiguous statute was objectively reasonable and CMS did not warn Forest away from that interpretation through authoritative guidance.

The relator subsequently appealed to the 4th Circuit Court of Appeals but was unsuccessful.  In a January 25, 2022 decision, a three-judge panel upheld the District Court’s decision under a similar rationale.  Still undeterred, the relator requested and obtained en banc review.  Last Friday, September 23, the 4th Circuit issued an en banc per curiam judgment vacating the panel’s decision, and affirming the District Court’s decision by an equally divided court.  (The three-judge panel’s decision was vacated because, under the 4th Circuit’s appellate procedures, the granting of rehearing en banc vacates the previous panel judgment and the rehearing is a review of the lower court’s decision.)  The relator has until December 22, 2022 to petition for certiorari to the Supreme Court.

Apart from its importance in connection with best price stacking, the Sheldon case has been cited in a larger controversy about the intent standard under the FCA.  The 4th Circuit three-judge panel decision relied heavily on the Supreme Court’s decision in Safeco Insurance Co. of America v. Burr, 551 U.S. 47 (2007), which addressed the intent standard under the Fair Credit Reporting Act.  In Safeco, the Supreme Court set forth a two-step analysis for determining whether a defendant exhibited reckless disregard where a statute is ambiguous:  (1) was the defendant’s interpretation objectively reasonable; and (2) was there authoritative guidance that might have warned defendant away from that reading.  Id. at 69-70.  The three-judge panel in Sheldon held that the Safeco test should apply in determining whether a defendant had “knowing” intent under the FCA.  Other circuit courts have disagreed, holding that the defendant’s subjective understanding of an ambiguous statute at the time of the violation can support scienter, regardless of the objective reasonableness of a post-hoc interpretation.  See, e.g., United States ex rel. Phalp v. Lincare Holdings, Inc., 857 F.3d 1148, 1155 (11th Cir. 2017).

In a certiorari petition appealing a 7th Circuit case that also applied Safeco to the FCA, U.S. ex rel. Schutte et al. v. SuperValu Inc., the Petitioner’s reply brief cited the Sheldon case as evidence of a circuit split.  The petitioner wrote:  [T]he Fourth Circuit has now changed positions. That court previously agreed with the [7th Circuit’s] decision below. . . .  The relator, however, sought rehearing en banc, and . . .  the Fourth Circuit granted the petition and vacated the panel opinion pending rehearing.”  The Supreme Court has sought the views of the Department of Justice on this issue.

The controversy over the FCA’s intent standard where the applicable statute or regulation is ambiguous has special relevance when the FCA is used to target inaccurate government price calculations.  The AMP, best price, and ASP statute and regulations are complex and full of gaps and ambiguities.  CMS itself has recognized this by repeatedly inviting manufacturers to use reasonable assumptions where a question is not addressed in the statute, regulations, or CMS guidance.  We are closely following the SuperValu cert. petition, and will post updates in this blog.

As we  previously reported, about two years ago, the Natural Grocers, Citizens for GMO Labeling, Label GMOs, Rural Vermont, Good Earth Natural Foods, Puget Consumers Co-op, and the Center for Food Safety (“Plaintiffs”) filed a complaint against USDA challenging USDA’s the final rule implementing the National Bioengineered Food Disclosure Standard (NBFDS), also known as the BE labeling rule.  Plaintiffs challenged the use of the term bioengineered (rather than GMO or genetically engineered), the limitation of the mandatory disclosure being required only if the food contains detectable modified genetic material and the options of using a QR code disclosure or a text message for the disclosure statement.

On September 14, 2022, the U.S. District Court for the Northern District of California ruled on a motion for summary judgement filed by the plaintiffs.

The Court denied the motion on the points of the use of the term bioengineered and the limitation of a mandatory requirement to foods that contain detectable BE material as, according to the Court, these provisions were consistent with the statute.

However, the Court did grant the motion on the issue of the disclosure options.  As readers may recall, the current regulation provides for four options for a disclosure statement, i.e., text disclosure, symbol disclosure, electronic disclosure (QR code with a phone number for further information), and a text message disclosure. The statute itself – the National Bioengineered Food Disclosure Standard – requires use of one of three forms of disclosure: on-package text, a symbol, or an electronic or digital link.

USDA’s final rule includes the option for a QR code plus phone number even though a study (mandated by the statute) revealed significant access problems with this option.  To “fix” the potential problem of access, USDA added a fourth disclosure option of a text message.  The Court’s order explains that the text message “did nothing to fix the problem of the inaccessible electronic disclosure”.  USDA should have improved the electronic disclosure statement by “providing additional and comparable options to access the [electronic] bioengineering disclosure,” rather than adding a fourth option for a stand-alone text message. Thus, the Court concluded that addition of the standalone text message disclosure options was inconsistent with the statute’s mandate. The Court remanded to USDA, the BE labeling regulation provisions regarding these disclosure options without vacatur; in other words, the status quo is maintained (products using these disclosure options need not be revised immediately) while USDA revisits these two disclosure provisions of the BE labeling rule.

The New Jersey Supreme Court, in its August 25, 2022 opinion in Mirian Rivera v. Valley Hospital, Inc., 2022 N.J. LEXIS 679 (NJ Aug. 25, 2022), https://www.njcourts.gov/attorneys/assets/opinions/supreme/a_25_26_27_21.pdf?c=lmL, considered whether a provider’s use of a medical device that is the subject of an FDA safety communication constitutes per se evidence of wanton disregard, which would warrant punitive damages. The Court found that in this case it did not, although it left open that it could be evidence of negligence, which could result in compensatory damages.  The Court’s analysis also leaves open the possibility that other FDA communications could result in punitive damages.

Case Summary

Plaintiffs (heirs and executor) in this case filed complaints seeking compensatory and punitive damages on numerous counts after a patient’s death from leimyosarcoma, a rare cancer that cannot be reliably diagnosed preoperatively, following the hysterectomy the patient underwent at defendant Valley Hospital with the use of a power morcellation device by defendant Dr. Howard Jones. Approximately six months before the patient’s surgery, the FDA issued a Safety Communication discouraging the use of power morcellation due to the risk that the procedure could spread cancerous tissue in patients with undiagnosed uterine sarcoma.

The New Jersey Punitive Damages Act (PDA) provides that “punitive damages may be awarded . . . only if plaintiff proves, by clear and convincing evidence,” both “that the harm suffered was the result of defendant’s acts or omissions,” and that defendant’s acts or omissions were either “actuated by actual malice” or were “accompanied by wanton and willful disregard of persons who foreseeably might be harmed.”  Id. at 2; N.J.S.A. 2A:15-5.12(a). The PDA further defines “wanton and willful disregard” as “a deliberate act or omission with knowledge of a high degree of probability of harm to another and reckless indifference to the consequences of such act or omission.”  N.J.S.A. 2A:15-5.10. This is a higher standard than that required to prove ordinary or gross negligence.

The Court found that plaintiffs’ claims did not meet this standard for punitive damages. Notably, the Court found “the FDA Communication was purely advisory in nature, so the use of the power morcellator after that communication does not constitute per se evidence of wanton disregard” for plaintiff’s safety.  Rivera v. Valley Hosp., Inc., at 3. The Court also found that “nothing in the facts before the Court suggests that [Dr. Jones] acted with actual malice or with wanton and willful disregard of” the plaintiff’s health and, in fact, there was evidence he informed the patient of the procedure’s risks.  Id.  Specifically, the Court did not agree that FDA’s communication of a less than 1% risk that patients undergoing this treatment would have undiagnosed uterine sarcoma constituted the defendant’s “knowledge of a high degree of probability of harm.”  Id. The Court was even more persuaded that defendant Valley Hospital’s conduct did not constitute wanton and willful disregard, as it took proactive steps shortly after the issuance of the FDA Communication to respond to the advised risk of power morcellation.

The Court was careful to state that although defendants’ actions and omissions after the FDA Safety Communication did not demonstrate a wanton and willful disregard, a jury could still find those actions establish defendants’ negligence.  Thus, the Safety Communication could play a role in further proceedings in the case.

Why this Case Matters

This case demonstrates that a court can consider a provider’s actions taken in response to public FDA safety notices when determining whether a patient’s harm resulted from that provider’s negligence or recklessness, as well as the form of the communication.  Here, the court deemed FDA’s communication to be advisory and that it left ample room for provider discretion.  Depending on the wording of other FDA notices, that may not always be the case.

The specific actions a provider takes with regard to a safety communication could still provide evidence of actual malice or wanton and willful disregard, even though that standard was not met in this particular case. Additionally, providers could also be subject to ordinary negligence where, as here, an FDA Safety Communication discourages a certain type of product or procedure and directs providers to inform patients of the specific risk involved but the provider fails to properly inform patients (e.g., by obtaining appropriate informed consent). Thus, this decision serves as a reminder that the issuance and wording of FDA safety notices can potentially impact the civil liability exposure of the customers of medical device manufacturers.