Just over two years ago, I wrote about the challenges with implementation of the contraceptive mandate in the Patient Protection and Affordable Care Act (ACA).  You will recall that, despite the ACA, a 2019 HRSA Guideline, and guidance from the federal agencies responsible for enforcing the contraceptive coverage requirement of the ACA (the Departments), women seeking contraceptives that were not specifically identified on an FDA Birth Control Guide were encountering roadblocks to accessing the contraceptive of their choice.

Since that blog post, an important step forward was the decoupling of the coverage requirement from the FDA Birth Control Guide in the guidance provided by the Department to plans and issuers.  This occurred in January 2022 when the Departments issued additional guidance, which discussed reports of denial of coverage in violation of the ACA requirement and provided a reminder to plans and issuers of their responsibilities under the statute and 2019 HRSA Guideline (FAQ Part 51, Q9).  Regarding the latter, the guidance made clear for the first time that “if an individual and their attending provider determine that a particular service or FDA-approved, cleared, or granted contraceptive product is medically appropriate for the individual (whether or not the item or service is identified in the current FDA Birth Control Guide), the plan or issuer must cover that service or product without cost sharing” (FAQ Part 51, Q9, emphasis added).  This guidance was based on stakeholder feedback that the current FDA Birth Control Guide may not identify all and/or newer contraceptive products approved, cleared, or granted by FDA.

Regarding the reports of noncompliance, the guidance provided examples, including denial of coverage for brand name contraceptives, even after the individual’s healthcare provider determines and communicates to the plan or issuer that a particular contraceptive product is medically necessary for that individual; requiring individuals to fail other numerous products within the same contraceptive method before approving coverage for the product that is medically necessary for the individual as determined by their healthcare provider; requiring individuals to fail products in other contraceptive methods before approving coverage for the product that was medically necessary for the individual as determined by their healthcare provider; and failing to provide an easily accessible, transparent, and sufficiently expedient except ion process that is not unduly burdensome.

In July 2022, the Departments issued further guidance in response to reports that individuals continued to experience difficulty in accessing contraceptive coverage without cost sharing.  With this guidance, the Departments decided to reference the 2019 HRSA Guideline rather than the FDA Birth Control Guide for the range of identified categories of contraception (FAQ Part 54, Q2), stating that plans and issuers must cover without cost sharing at least one form of contraception in each category.  The guidance also reiterated prior guidance that plans and issuers are required to “cover without cost sharing any contraceptive services and FDA-approved, cleared, or granted contraceptive products that an individual and their attending provider have determined to be medically appropriate for the individual, whether or not those services or products are specifically identified in the categories listed in the HRSA-Supported Guidelines, including contraceptive products more recently approved, cleared, or granted by FDA” (FAQ Part 54, Q2).

The Departments also reiterated that, while reasonable medical management techniques can be utilized to determine which specific products to cover without cost sharing, “[t]he plan or issuer must defer to the determination of the attending provider, and make available an easily accessible, transparent, and sufficiently expedient exceptions process that is not unduly burdensome so the individual or their provider (or other individual acting as the individual’s authorized representative) can obtain coverage for the medically necessary service or product without cost sharing” (FAQ Part 54, Q3).

While the Departments were updating their guidance, the House Committee on Oversight and Reform was investigating contraceptive coverage for individuals enrolled in private health plans by seeking information from five of the nation’s largest health insurers and four of the largest pharmacy benefit managers (PBMs) to assess how companies provided patients with access to FDA-approved birth control.  In October 2022, the Committee issued a report titled “Barriers to Birth Control: An Analysis of Contraceptive coverage and Costs for Patients with Private insurance,” which determined that:

• health plans and PBMs have coverage exclusions or cost-sharing requirements for at least 34 different contraceptive products;
• insurers and PBMs disproportionately impose cost-sharing or coverage exclusions for newer contraceptive products;
• many contraceptive products used by patients with distinct healthcare needs or disproportionately used by people with lower incomes are subject to cost-sharing or exclusions;
• health insurers and PBMs deny an average of at least 40% of exception requests with one denying up to almost 80% per year; and
• exceptions processes are inadequate.

The report recommend that Departments consider issuing further guidance to (1) clarify requirements regarding “appropriate medical management” for coverage of contraceptives, which could include providing guidance that “all FDA-approved contraceptive products that do not have a therapeutic equivalent should be covered without cost-sharing as part of every plan or formulary,” which would allow health plans and PBMs to use medical management techniques to prioritize the use of generic pharmaceuticals where possible, while ensuring that patients have access without cost-sharing to products that do not yet have a generic version; and (2) encourage exceptions processes that are automatic at the point of prescribing.

Shortly thereafter in December 2022, HRSA updated its Women’s Preventive Services Guidelines to make it more explicit that the full range of contraceptives  approved, granted, or cleared by FDA be available as part of contraceptive care.

Most recently, in June of this year, the Biden administration issued an Executive Order focused on protecting and expanding access to contraception.  Specifically, Section 2 of this executive order directs the Secretaries of the Treasury, Labor, and Health and Human Services (Secretaries) to

consider issuing guidance, consistent with applicable law, to further improve Americans’ ability to access contraception, without out-of-pocket expenses, under the Affordable Care Act.  In doing so, the Secretaries shall consider actions that would, to the greatest extent permitted by law:

• ensure coverage of comprehensive contraceptive care, including all contraceptives approved, granted, or cleared by the Food and Drug Administration, without cost sharing for enrollees, participants, and beneficiaries; and
• streamline the process for patients and healthcare providers to request coverage, without cost sharing, of medically necessary contraception.

While progress has been made in terms of the Departments’ guidance no longer depending on whether a product is identified in FDA’s Birth Control Guide, the new Executive Order makes it clear that the Biden administration believes that additional guidance is needed to ensure that full effect is given to the ACA contraceptive mandate.  It will be interesting to see what new tactics may be employed by the Departments to implement the Executive Order.

In our June blog post, we reported on FDA’s request for comments about its program to receive information from the public alleging misconduct by other companies.  FDA uses this program to help it identify risks and to determine whether further investigation is needed.  Because this program requires information collection from the public, the Paperwork Reduction Act (PRA) of 1995 (44 U.S.C. 3501) and its implementing regulations at 5 CFR 1320, requires federal agencies to minimize paperwork burden and ensure quality of information, amongst other objectives. On October 12, 2023, FDA published a notice reporting on several comments about its information collection activities under this program, and the changes FDA made to address those concerns.

One comment FDA received had noted that existing procedures do not allow for complete anonymity, specifically when requiring that attachments be sent via email. While changes have not been made to allow for attachments to the Allegations of Regulatory Misconduct Form, which would address this comment in part, FDA did acknowledge confidentiality as “an important concern” and cited that under the Freedom of Information Act (FOIA) (5 U.S.C. 552), there are exemptions from mandatory disclosure. While we would encourage providing contact information so that FDA may follow up, if need be, we appreciate the value of being able to submit information anonymously.

Another comment questioned FDA’s process to verify the accuracy and validity of the allegations. In response, FDA noted that it reviews allegations of regulatory misconduct and prioritizes taking action based on risk level, but did not address any specifics on how or whether it decides when to follow-up with subsequent questions about an allegation. We renew our comment from June that transparency on FDA’s activities in response to allegations would make the program much more meaningful to industry.

In response to comments on improving the submission form, FDA already has implemented a notable change by adding asterisks on the Allegations of Regulatory Misconduct Form, to identify the fields that are required (e.g. name and model of medical device and detailed description of the allegation with any supporting documentation) versus non-required. This will help streamline the submission for those complaints that may not have all the information to complete the fields. We also note that an assistant director for allegations has now been identified in the CDRH management directory. We hope to be surprised with more changes that result in transparency on the process and progress of all investigations FDA undertakes when reviewing allegations of regulatory misconduct.

Yesterday, FDA published a new Draft Guidance, “Communications from Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers” (SIUU Guidance or Draft Guidance).  Previous iterations of this guidance from 2009 and 2014 (blogged on here and here) were known as Good Reprint Practices (GRP).  These guidances focused on the types of scientific publications (journal articles, reference texts, and in 2014, clinical practice guidelines) and necessary accompanying information that firms could proactively provide in a manner that would not, on its own, constitute evidence of a new intended use.  The SIUU Guidance, which supersedes the 2014 Draft GRP Guidance, is not substantially different in that regard and contains similar information as to the types of disclosures previously recommended.  However, there’s a clear shift in FDA’s approach that is noticeable from the title of the Draft Guidance, alone.

The SIUU Guidance introduces two new concepts that are of note to industry regarding information it may choose to disseminate under this “safe harbor:” 1) application to firm-generated presentations of scientific information; and 2) material that meets a new evidentiary standard – scientifically sound and clinically relevant.

Creation of a “Safe Harbor” for Firm-Generated Presentations of Scientific Information

FDA acknowledges that firms may develop presentations of scientific information from an accompanying reprint.  Firm-generated communications must meet the general recommendations in the Draft Guidance and “should be truthful, non-misleading, factual and unbiased and provide all information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the presented information . . .”  The presentation should be accompanied by the reprint and the reprint, itself, must meet the criteria articulated in the SIUU Guidance for reprints.  FDA recommends that firm-generated portions of an SIUU communication should use “plain language,” as despite having specialized training, “research indicates that HCPs may nonetheless have difficulty understanding some types of scientific information, including clinical trial data, and the design and methodological limitations of studies.”

Creation of a New Evidentiary Standard

FDA’s new standard, scientifically sound and clinically relevant, is a departure from its decades-long approach under GRP that articles about unapproved uses of approved products must describe adequate and well-controlled clinical investigations.  Throughout the SIUU Guidance, FDA refers to studies and analyses, suggesting that publications may cover more than a description of an adequate and well-controlled clinical trial.  FDA notes that real-world data and associated real-world evidence may be scientifically sound and clinically relevant depending on the circumstances.

Other Topics of Note

In addition to the two concepts above, FDA also discusses the use of dedicated vehicles, channels, and venues to distinguish SIUU communications from promotional communications to reduce the risk of HCPs confusing approved and unapproved use information.  FDA also addresses social media platforms, providing advice for firms seeking to communicate on platforms that may impose character-space limitations that would hinder a firm from including all recommended disclosures (hint:  keep the communication unbranded, linking out to a fully formed SIUU communication).

FDA repeatedly references that in creating the SIUU Guidance, it has sought to balance HCP interests in scientific information with mitigating the potential that government interests in motivating firms to comply with premarket requirements will be undermined.  While the information in the SIUU Guidance is a welcome departure from FDA’s more restrictive approaches under GRP, it may not go far enough.   For example, FDA’s references to firm-generated communications appear inextricably linked to an underlying reprint publication, which seems arbitrary, as firms can generate truthful and non-misleading information about studies and analyses that have not been published.  The SIUU Guidance may leave industry with the feeling that it still hasn’t found what it is looking for in terms of FDA’s attempts to strike the right balance.

As of October 1, 2023, all 510(k) submissions, unless exempted, must be submitted to FDA using the electronic Submission Template And Resource (eSTAR).  The same template can also be used for De Novo submissions.  Currently, eSTAR is voluntary for medical device De Novo submissions, but FDA has initiated the process of requiring De Novos to be submitted using eSTAR.  On September 29, 2023, FDA released a draft guidance on Electronic Submission Template for Medical Device De Novo Requests.

Recap of eSTAR

eSTAR is an interactive PDF form designed to assist users in creating a “complete” submission.  It includes questions, text, logic, and prompts, and integrates databases such as FDA product codes and FDA-recognized voluntary consensus standards.  It also presents specific questions to collect data from the submitter and provides links to relevant regulations and guidance documents.   For 510(k) and De Novo submissions, FDA’s eSTAR Program website offers two different types of eSTAR templates: Non-In Vitro Diagnostic devices and In Vitro Diagnostic devices.  There is also a third template for Pre-Submissions for Non-In Vitro and In Vitro Diagnostic devices.  Make sure you submit your application using the most up-to-date version of eSTAR, as FDA frequently updates eSTAR templates.  To learn more about our experience with the eSTAR for 510(k)s, check out our previous blogs (here, here).

Structure of the eSTAR for De Novos

The draft guidance provides a table that offers a high-level overview of the structure of the eSTAR for De Novos, including elements such as the cover letter, device description, proposed indications for use, classification, benefits, risks, mitigation measures, labeling, and supporting data.  These content elements precisely follow the De Novo request content described in 21 C.F.R. § 860.220, meaning that using eSTAR does not necessarily change the type and amount of information required in a De Novo submission.

Acceptance Review

eSTAR helps submitters prepare a “complete” 510(k) or De Novo submission.  The Refuse To Accept (RTA) process is an acceptance review of 510(k) submissions, aiming to assess whether a submission is administratively complete, and includes all the necessary information within 15 calendar days of FDA receiving a 510(k) submission.  One key benefit for the industry in using the eSTAR for 510(k)s is that 510(k) eSTAR submissions do not undergo an RTA process.  This is beneficial to industry because at times the RTA review is not purely administrative and crosses into substantive issues.  Note, however, that there is a virus scanning and technical screening process that will still happen.  During the technical review, FDA will check to ensure that the attachments to a question are relevant to the question and there are no inaccurate responses provided to any question.

In contrast, for De Novos, the equivalent of a 510(k) RTA review is an acceptance review of De Novos, codified in 21 C.F.R. § 860.230.  Unlike 510(k)s, using eSTAR for De Novos does not eliminate the acceptance review process, which must be conducted and completed within 15 calendar days of FDA receiving a De Novo request.  The draft guidance notes that “[i]f the eSTAR is not complete when submitted, FDA will notify the submitter via email and identify the incomplete information, and the De Novo will be placed on hold.”  This statement appears consistent with the technical review that is being done for the 510(k) eSTAR submissions.

Timeline

FDA notes that when this draft guidance is finalized, it will specify the corresponding timetable(s) for the implementation of De Novo electronic submissions.  The draft guidance indicates that this timetable will be announced by September 30, 2025.  There will be a transition period before requiring all De Novo requests to be submitted electronically.

We can gain insights into the potential timetable from the FDA’s process for eSTAR for 510(k) submissions.  In September 2021, FDA released a draft guidance on Electronic Submission Template for Medical Device 510(k) Submissions (see our blog).  As of October 1, 2023, approximately two years after the release of that draft guidance, all 510(k) submissions are now required to be submitted using eSTAR.  If FDA follows a similar timeline, it is possible that, in approximately two years, FDA may require that all De Novo submissions must be submitted using eSTAR.  For those with experience in using eSTAR for 510(k) submissions, we anticipate that the learning curve for eSTAR for De Novo submissions may not be as steep when FDA mandates that all De Novo submissions must be submitted using eSTAR.  But, for those who do not have any experience with eSTAR, the learning curve may be more significant.

Medicine cabinet, stuffed to the gills
Capsules, liquid, patches, and pills
Expired oxy, hydro, benzos, and more
All kind of meds flowing out the door

We will, we will, clear you
We will, we will, clear you

Were the Drug Enforcement Administration (“DEA”) a rock band, it might promote the upcoming National Prescription Drug Take Back Day by setting the lyrics above to a catchy tune.  DEA is not a band, but along with its law enforcement partners, the agency will host thousands of local drop-off locations nationwide for clearing out and proper disposal of expired and unneeded medication from medicine cabinets between 10:00 am to 2:00 p.m. local time on Saturday, October 28, 2023.

DEA has held Drug Take Back Days each spring and autumn since 2010.  The events have led to the removal of more than 17 million pounds of unwanted medication across the country.  Last April’s Drug Take Back Day alone removed 663,725 pounds (332 tons) of medication at almost 5,000 collection sites hosted by 4,500 law enforcement agencies.

Additional information about DEA’s National Prescription Drug Take Back Day, including local disposal locations, can be found here.

So, clear out that stuffed medicine cabinet.

Although it seems not widely known outside of the medical device industry, FDA can require sponsors to include clinical data as part of a 510(k) submission.  Such data may be needed to demonstrate substantial equivalence to a previously-marketed predicate device or, less frequently, to show that new or modified indications for use fall within the same intended use as the predicate device.

Despite previous efforts by FDA to shed light on this issue (see The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (510(k) Program Guidance), sponsors still often find there is disagreement with FDA when it comes to determining if clinical data are needed, especially when the sponsor believes there is a reasonable justification that non-clinical data are sufficient to reach a substantial equivalence determination.

As part of a multipronged effort to strengthen and modernize the 510(k) program (see our recent blog post here), FDA recently issued a draft guidance, Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions (Draft Guidance), describing situations in which clinical data may be necessary to demonstrate substantial equivalence in a 510(k) submission.  When necessary, data from clinical studies is submitted in addition to standard non-clinical data such as bench performance testing; sterilization and shelf-life testing; biocompatibility testing; animal studies; electrical, mechanical, and thermal safety testing; electromagnetic compatibility testing; software testing; and cybersecurity testing.

The 510(k) Program Guidance provides several scenarios that illustrate the most common situations in which clinical data may be needed to demonstrate substantial equivalence. The Draft Guidance provides additional context and clarity to these three scenarios and adds a new scenario in which clinical data may be needed.  The scenarios are intended “to provide broad considerations to be used by industry and FDA to help determine whether clinical data may be necessary to demonstrate that a new device is substantially equivalent to a predicate device.”

The four scenarios, described in the new Draft Guidance, in which clinical data may be needed in a 510(k) include:

1. There are differences between the indications for use of the new device and the predicate device;
2. There are differences between technological characteristics of the new device and the predicate device;
3. SE between the new device and the predicate device cannot be determined by non-clinical testing (analytical, bench, and/or animal); and
4. A newly identified or increased risk for the predicate device suggests clinical data may be needed for the new device.

The Draft Guidance provides specific examples illustrating the application of each scenario.  The examples include both diagnostic (including in vitro diagnostic) devices and therapeutic devices, since there are significant differences in the types of clinical data that may be needed for these two categories of devices.

While the first three scenarios, and the accompanying examples, seem fairly straightforward and reasonable, the newly-added fourth scenario is perplexing, as it describes a situation where clinical data may be needed for a new device even though no clinical data were needed for the predicate device. This situation is where most surprises arise as a sponsor reviews the 510(k) summary for the predicate device, sees that clinical data were not needed for clearance, and assumes that clinical data will not be needed for their similar device.

The Draft Guidance suggests not using predicate devices with newly identified risks but acknowledges that there may be some cases where there is not a more recently cleared predicate device that does not share the newly identified risk.  FDA’s examples for this scenario show a good faith attempt for a level playing field between new devices and existing devices by describing situations where new device submissions will require clinical data while the currently marketed devices with newly identified risks may be subject to postmarket surveillance studies or recalls with new submissions for modifications to the recalled device that include clinical data.  However, we can envision situations where clinical studies of the previously cleared devices with the new risk have not yet occurred and a sponsor with a new, similar device may be surprised at the need for clinical data.

Although there is some discussion in the examples that relates to whether the predicate device required clinical data for 510(k) clearance, we found that the Draft Guidance does not explicitly address the question of whether or not inclusion of clinical data in the predicate device 510(k) provides any bearing on whether clinical data will be needed for a new device.

The Draft Guidance also describes the types of data that may constitute clinical data supporting a 510(k), drawing on previous recommendations of the International Medical Device Regulators Forum  (see “Clinical Evidence – Key Definitions and Concepts”).  These include:  results of pre- and post-market clinical investigation(s) of the device (i.e., traditional clinical trials); results of pre- and post-market clinical investigation(s) or other studies reported in the scientific literature of a comparable device; published and/or unpublished reports on clinical experience of either the device in question or a comparable device; and other sources of clinical experience such as registries, adverse event databases, and medical records (e.g., electronic health records, claims).

When considering whether data from a comparable device can be used, the Draft Guidance indicates that “adequate justification regarding the applicability of such data should be provided demonstrating why such data would be representative of the new device.”  Given FDA’s current emphasis on data being collected on the final, finished device, it may be beneficial to use the pre-submission process to discuss the applicability of data collected with a comparable device with FDA to allow time for a new clinical study, if they do not agree that the justification is adequate.

Finally, it is not surprising that the Draft Guidance notes that there may be other scenarios not described where clinical data may be necessary and that the need for clinical data may also change as information on the device type is accrued.  We think that the Draft Guidance may prove helpful, especially in situations where the sponsor concludes that clinical data are necessary, at which time they can engage with FDA via the pre-submission process to discuss clinical study design.  However, sponsors should be cautious when review of the Draft Guidance suggests that clinical data are not necessary.  If there are differences in indications for use, novel technology, or the potential for differences in risk profile, a pre-submission may be warranted to confirm FDA agrees with the sponsor’s application of the scenario to the specific circumstances and the conclusion that no clinical data are needed to support substantial equivalence.

On September 15, 2023, FDA released a final guidance document titled “Breakthrough Devices Program.”  Compared to the previous version, the new guidance document highlights that the Breakthrough Devices Program may also be applicable to certain devices that benefit populations impacted by health and/or healthcare disparities and to certain non-addictive medical products to treat pain or addiction.  If you are developing such products, now may be the time to explore the opportunities presented by the Breakthrough Devices Program.

Background

The Breakthrough Devices Program, established under section 515B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), is a voluntary program for certain medical devices and device-led combination products.  FDA previously released the final guidance document in December 2018 outlining the program’s principles, features, designation criteria, and other considerations.  The designation criteria, as defined in section 515B(b) of the FD&C Act, have remained unchanged and continue to govern the program for devices as follows:

(1) that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions; and

(2)(A) that represent breakthrough technologies;

(B) for which no approved or cleared alternatives exist;

(C) that offer significant advantages over existing approved or cleared alternatives, including the potential, compared to existing approved alternatives, to reduce or eliminate the need for hospitalization, improve patient quality of life, facilitate patients’ ability to manage their own care (such as through self-directed personal assistance), or establish long-term clinical efficiencies; or

(D) the availability of which is in the best interest of patients.

In October 2022, FDA released the draft guidance entitled “Select Updates for the Breakthrough Devices Program Guidance: Reducing Disparities in Health and Healthcare,” as previously discussed in our blog.  This 2022 draft guidance proposed that certain non-addictive medical products for pain or addiction treatment could be eligible for breakthrough designation, aligning with the Agency’s obligations under the Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act.  Additionally, the 2022 draft guidance suggested the addition of a new section to the 2018 guidance on reducing disparities in health and healthcare.  The new guidance does not surprise us as the scope of the changes is limited to the select updates, but it is certainly exciting that FDA expands product areas for the Breakthrough Devices Program.

Non-Addictive Medical Products to Treat Pain or Addiction

The SUPPORT Act (Public Law 115-271) mandated that FDA issue a guidance document to provide information on how the Agency can apply section 515B of the FD&C Act to non-addictive medical products intended to treat pain or addiction.  As suggested in the 2022 draft guidance, FDA included a statement in the introduction section of the guidance, indicating that “the Breakthrough Devices Program may be available for certain non-addictive medical products to treat pain or addiction (FD&C Act section 515B (21 U.S.C. 360e-3)).”  Apart from this statement in the introduction section, the new guidance document does not offer any further guidance related to non-addictive medical products for pain or addiction treatment.  This may be because FDA has already been granting breakthrough designation to devices intended to treat pain (e.g., Wysa, see here) and addiction (e.g., reSET-O, see here, here).

The readers may be wondering what kind of devices would be able to leverage the new guidance to receive breakthrough designations.  Although not directly relevant, the FDA Innovation Challenge program called “Devices to Prevent and Treat Opioid Use Disorder” may provide you with an idea.  FDA launched this challenge in 2018 to foster the development of medical devices aimed at addressing the opioid crisis, preventing, and treating Opioid Use Disorder (OUD).  FDA selected and posted eight challenge participants, which included monitoring, OUD therapy, pain therapy, medication dispensing, overdose therapy, and diagnostic devices.  FDA notes “Breakthrough Device designation will be granted to those devices that meet the statutory criteria for designation without submission of a separate application.”  It appears that the devices selected for the challenge may align with the type of non-addictive medical products for pain or addiction treatment that the new breakthrough guidance targets.

Reducing Disparities in Health and Health Care

FDA introduced a new section in the guidance document focused on reducing disparities in health and healthcare.  In this section, FDA acknowledged that treatment outcomes might vary based on factors such as race, ethnicity, sex, age, disability, and others.  Consequently, FDA underscores the importance of considering “technologies and device features tailored to address characteristic differences” such as social factors, phenotypic variations, pathophysiology, and response to treatment when evaluating the first designation criterion.  This implies that if device technologies and features can produce a clinically meaningful impact for the treatment or diagnosis of a condition in certain populations, such data could support the case that the device satisfies the first designation criterion.

The new guidance also presents an opportunity for device manufacturers working for patient populations affected by rare life-threatening or irreversibly debilitating diseases or conditions, such as sickle cell disease.  FDA will consider if technologies and device features “address unmet needs in these populations” when evaluating criterion one.  In addition, criterion one can also apply to technologies and device features aimed at improving accessibility, defined as “an individual or group’s capacity to benefit from a medical device or procedure.”  FDA recognizes the existence of barriers that may hinder underserved populations from receiving medical treatment or diagnosis.  To address these barriers, FDA promotes the development of impactful devices that can enhance accessibility for patient populations with limited or no available options.  This might include “user features that are adaptable or more easily used by diverse populations or allow for use in more diverse settings.”  With improved accessibility, one can make the argument that there is a “reasonable expectation that the device may provide for more effective treatment or diagnosis as compared to the standard of care.”

Other Updates

With respect to the first part of the first criterion (i.e., whether a device provides for more effective treatment or diagnosis), FDA introduced a paragraph explaining that “[t]he level and type of evidence needed to determine whether a device is reasonably expected to “provide for more effective treatment or diagnosis” may vary depending on the intended use of the device, its technology and features, and the available standard of care alternatives.” (Emphasis added.)  While the reasonable expectation standard remains unchanged, FDA emphasizes that it will consider the totality of information regarding the proposed device, its function, potential for technical success, potential for clinical success, potential for a clinically meaningful impact, and its potential benefits and risks.

Remaining Questions

We perceive the new guidance as an expansion rather than a restriction of the types of products that may qualify for Breakthrough Device designation.  However, the new guidance does not address certain questions that the industry may encounter when seeking the breakthrough designation.

For example, it remains uncertain whether devices indicated for addiction or pain treatment would be considered to satisfy the second part of the first criterion (i.e., whether a disease or condition is life-threatening or irreversibly debilitating), regardless of the type or severity of the underlying diseases or conditions causing pain.  Furthermore, the new guidance does not provide any indication of the level of evidence necessary to demonstrate that a candidate device can contribute to reducing disparities in health and healthcare.  There may also be questions about the level of evidence required to demonstrate that a device can address characteristic differences arising from social factors, phenotypic variations, pathophysiology, and/or response to treatment.  Although the new guidance does not explicitly state that clinical data is a mandatory requirement for a breakthrough application, it is our experience that a review division typically expects to review some level of clinical evidence to assess the reasonable expectation of clinical success.

If FDA’s evidentiary expectations are set too high, it could undermine the intent of the new guidance.  FDA has stated that it “considers the totality of available information regarding the device, including its potential for a clinically meaningful impact and its potential benefits and risks.”  We hope that “the totality of available information” that could meet FDA’s expectations will not impose an excessive burden on companies seeking breakthrough designations.

The Wall Street Journal (WSJ) recently published a series of articles as part of its special report “What’s Ahead for Artificial Intelligence.” Three of these articles focus on medical applications of Artificial Intelligence and Machine Learning (AI/ML) and explore FDA’s role in regulating such products.

• The first article—“Is the Eye the Window to Alzheimer’s?”—discusses several approaches that companies are exploring for use of AI in the diagnosis of Alzheimer’s Disease, including AI-enabled software for retinal scans and identification of genetic triggers.
• In the second article—“Why AI is Medicine’s Biggest Moment Since Antibiotics”—Dr. Lloyd Minor, Dean of the Stanford University School of Medicine discusses both the potential promise of increasing use of AI in healthcare settings (e.g., increased access to care in rural areas) and its potential risks (e.g., demographic bias of data fed to algorithms).
• The third article—“Your Medical Devices are Getting Smarter. Can the FDA Keep them Safe”—focuses on FDA’s role in regulating clinical applications of AI/ML technologies and the impact of FDA’s regulatory requirements on the type of products developers choose to bring to market and how quickly they can be improved once there. In particular, the article discusses FDA’s April 2023 draft guidance on pre-determined change control plans (which we previously blogged on here) and whether such plans afford sufficient flexibility for AI/ML developers to innovate and improve products based on new data while also providing sufficient guardrails to ensure patient safety.

Meanwhile, FDA’s AI/ML-focused initiatives continue to expand.  On October 11, 2023 FDA announced the establishment of a new Advisory Committee on Digital Health Technologies that is tasked with, among other responsibilities, helping the Agency navigate complex scientific and technical issues related to AI/ML-enabled devices. Just a day earlier, FDA’s Center for Devices and Radiological Health (CDRH) released a list of the guidance documents the Center intends to publish in the upcoming 2024 fiscal year. Among these are plans to finalize FDA’s guidance on predetermined change control plans for AI/ML-enabled devices and a draft guidance on lifecycle management considerations and premarket submission recommendations for such devices.

With more than 500 devices currently on FDA’s list of cleared AI/ML-enabled devices, these initiatives signal FDA’s recognition that these devices will continue to play a significant and increasing role in the delivery of healthcare in the years to come. We will continue to monitor ongoing developments in this field and are available to assist product developers with their development and regulatory strategies.

For years, submitting a Suitability Petition has been like screaming into a void: You’d be lucky if FDA ever responds.  This has been a big problem because FDA’s inattentiveness can delay entry of certain types of ANDAs for years—often resulting in the ANDA applicant’s abandonment of the Suitability Petition.  Industry has been asking for Suitability Petition reform for years, either by FDA or mandated by Congress, but, other than a few rejected bills, such requests have basically gone nowhere.

Taking a step back, a Suitability Petition is used when an ANDA applicant wants to submit an ANDA that differs from its Reference Listed Drug in strength, dosage form, route of administration, or, in the case of a combination drug, active ingredient.  Under 21 C.F.R. § 314.93, an applicant that wants to submit such an ANDA “must first obtain permission from FDA to submit such an ANDA.”  Such an ANDA therefore can be submitted only upon the submission and approval of a special Citizen Petition, called a Suitability Petition.  Technically, FDA is supposed to review and approve Suitability Petitions within 90 days, but the reality is that it can take years for FDA to respond—if the Agency ever responds at all.

FDA now has committed under GDUFA III to actually reviewing Suitability Petitions.  Like with other types of Reviews, FDA will assign a “goal date” to any Suitability Petition submitted after October 2, 2023.  FDA has contacted applicants with pending Suitability Petitions to confirm continued interest in a response and invited those Petitioners to resubmit Petitions after October 2, 2023 to be assigned a goal date.  For context, before GDUFA III, FDA received 20-30 Suitability Petitions per year and had approximately 170 pending as of July 2021.  To address this backlog and any forthcoming Suitability Petitions, FDA’s GDUFA III commitment letter states that the Agency will review 50% of Suitability Petitions—up to 50 Suitability Petitions—within 6 months after a 21 day completeness review in FY 2024; 70%, or up to 70 Suitability Petitions, in FY 2025; 80%, up to 80 Suitability Petitions, in FY 2026; and 90%, or up to 90 Suitability Petitions, in FY 2027.  Priority is given to Suitability Petitions that could mitigate or resolve a drug shortage; address a public health emergency declared by HHS; mitigate waste by way of new strengths for parenteral products; or subject to special review under the President’s Emergency Plan for Aids Relief.  If FDA misses goal dates, it will prioritize review of those Suitability Petitions with missed goal dates prior to reviewing newly-submitted Suitability Petitions.

In late September 2023, presumably in light of the upcoming goal date assignments, FDA revised MAPP 5240.5 covering ANDA Suitability Petitions.  In the newly-revised MAPP, FDA fully integrates its GDUFA III commitments, including the goal date commitments and the priority list.  FDA also commits to conducting completeness assessments of all submitted Suitability Petitions within 21 days or issue an Information Request as necessary.  All in all, goal dates will be approximately 7 months after submission, or 6 months after completeness assessment.  But we’ll have to wait quite a few years until almost all Suitability Petitions are reviewed within their assigned goal date period.

The MAPP itself adds little new that’s interesting for industry (assuming you’ve read the GDUFA III Commitment Letter), but it reflects that FDA now may be taking seriously its commitment to reforming the Suitability Petition process.  Such a change is welcome, as it not only accelerates and facilitates competition, but it should greatly reduce industry frustration.  It’s too early to tell what kind of traction this effort will get and if FDA will be able to meet its commitments, but it’s promising that FDA has, for the first time, made an actual commitment to trying.  Those of us that have submitted Suitability Petitions after October 2 are waiting with bated breath for FDA’s completeness review and assignment of a Goal Date and to see whether FDA can meet its targets.

On September 18, 2023, FDA published an updated, final iteration of guidance for immediate implementation entitled, “Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies.”  This final guidance replaces and supersedes the March 2020 guidance entitled, “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency.”  The new guidance is meant to expand the earlier’s scope to emergencies outside of the COVID-19 pandemic including but not limited to disasters and public health emergencies such as hurricanes, earthquakes, military conflicts, infectious disease outbreaks, or bioterrorist attacks.

In general, both of these guidances provide recommendations for sponsors to consider and analyze when a disaster (e.g., hurricane) or public health emergency (e.g., pandemic) strikes, causing a major disruption to the conduct of a clinical trial.  For example, a disaster or public health emergency may lead to clinical trial disruptions via population quarantines, travel restrictions, various interruptions to the supply chain, and other logistical issues.  The recommendations provided by the final guidance, and largely included in its previous iteration, center around ensuring the safety of the clinical trial subjects, maintaining adherence with good clinical practice, and limiting the risk to the integrity of the clinical trial (i.e., protecting the clinical trial’s goal of continuing to produce valid data to support eventual regulatory decision-making).

The final guidance largely subsumes the COVID-19-specific guidance with a handful of updates.  First, as previously discussed, FDA broadened the ambit of the final guidance to apply to disasters and public health emergencies generally.  The other major changes come in the appendix which provides a series of questions and answers, including the removal or update of outdated questions (i.e., those specifically related to the COVID-19 public health emergency).  In addition, the final guidance clarifies and expounds upon its previous recommendations, including several potential logistical concerns (e.g., shipment of and charging for investigational product) and a risk-based evaluation for monitoring clinical trial sites and subjects.

While it makes sense for FDA to apply its learnings and considerations to other public health emergencies beyond COVID-19, the shift in focus comes at a time when many medical product programs are still reeling from the effects of the pandemic on their previous or even still-ongoing clinical trials.  Trials that were adapting (or not) in real time due to the emergent nature of the pandemic experienced real, lasting COVID-19 disruptions affecting everything from adherence to study protocols, impacts confounding safety and efficacy evaluation to different degrees at different periods, and less-than-ideal fixes to ongoing protocols and statistical analysis plans in an attempt to protect participants and study personnel.  In our experience, these programs are the ones that seem to be left behind, as FDA has been uncertain of how to handle the results from these COVID-19 era studies.

In the case of trials for orphan drugs, this is particularly concerning because there is often already difficulty in interpreting clinical trial results to establish effectiveness due to the common challenges inherent in rare disease drug development.  Layering on COVID-19 impacts, and the added uncertainty they impart, many of those trials were deemed uninterpretable or negative conclusions of effectiveness were drawn.  This can be the death knell for some rare diseases, as over 95% do not have even a single FDA-approved therapy, so a failure of one program can result in a departure of investment interest by other companies.  While individual sponsors continue to discuss these COVID-19 impacts on orphan drugs in development with FDA, we hope that the Agency will consider the specific impacts on rare disease drug development in future public health emergencies.  There are already enough unique challenges these rare disease drug development programs face, and every patient that participates in clinical trials is precious, so we owe it to them to find a more holistic approach to salvaging clinical trials that are impacted by public health emergencies.

Hyman, Phelps & McNamara, P.C. (“HP&M”), the largest FDA-dedicated law firm, is pleased to announce that Julie Beitz, M.D. has joined the firm as a Principal Drug Regulatory Expert.

Dr. Beitz served in leadership positions in FDA’s Center for Drug Evaluation and Research for nearly three decades.  She is an oncologist/hematologist and at the time she retired from FDA on July 29, 2023, she was the Director of the CDER Office of Immunology and Inflammation (OII) in the Office of New Drugs (OND).

Dr. Beitz was selected by FDA to be the inaugural Director of OII in March 2020 as part of the CDER OND reorganization.  In this position, she had primary oversight for actions taken by the following review divisions:

• Division of Dermatology and Dentistry
• Division of Gastroenterology
• Division of Hepatology and Nutrition
• Division of Rheumatology and Transplant Medicine
• Division of Pulmonology, Allergy and Critical Care
• Division of Pharmacology/Toxicology – Immunology and Inflammation

Prior to the March 2020 creation of OII, Dr. Beitz for 14 years was Director of the Office of Drug Evaluation III (ODE 3) in OND where she oversaw the Division of Gastroenterology and Inborn Errors of Metabolism, the Division of Dermatology and Dental Products, and the Division of Bone, Reproductive and Urology Products.

Other key drug leadership positions that Dr. Beitz served in at FDA include Acting Deputy Director for Clinical Sciences of OND, Director of the Division of Drug Risk Evaluation in the Office of Surveillance and Epidemiology and Acting Deputy Director and Clinical Team Leader in the Division of Oncology Drug Products.

Dr. Beitz earned a Bachelor of Arts (summa cum laude and honors in chemistry) from Barnard College, Columbia University, and a Doctor of Medicine from the College of Physicians and Surgeons, Columbia University.  She completed her residency and a fellowship in medical oncology/hematology at Brown University, Roger Williams Medical Center, and Brown University Affiliated Hospitals.

As a Principal Drug Regulatory Expert, Dr. Beitz joins HP&M’s Drug Development Team, which is comprised of attorneys and regulatory experts who assist companies on a range of drug and biological product legal, regulatory, and policy issues.  Dr. Beitz will be joining fellow former FDA Office Director Dr. Ellis Unger who joined HP&M in February 2022.  “I know Dr. Beitz well from our days as Office Directors at FDA, and I am delighted she is joining Hyman Phelps & McNamara! She made major, and lasting, contributions to public health at FDA. I always found her to be immensely thoughtful, knowledgeable, and insightful, and I am confident our clients will appreciate her approach,” said Dr. Unger.

“HP&M has long respected Dr. Beitz and enjoyed a professional working relationship with her during her distinguished FDA career.  We are thrilled that she is joining the firm and will add her expertise to our already exceptional Drug Development Team,” said JP Ellison, HP&M’s Managing Director.

Drug development attorney Frank Sasinowski commented: “For 20 years I have brought therapies that were needed by patients before Dr. Beitz and her colleagues in OII and ODE 3 and for that long I have admired and respected her sound scientific judgment and regulatory acumen.  Consequently, you can imagine how honored I am that Dr. Beitz would join her former OND Office Director Dr. Ellis Unger and our long-established HP&M drug development regulatory team to assist sponsors and patients in collaboratively working with FDA to bring critical new therapies to those in need.”

As we recently blogged, FDA released three draft guidance documents to help enhance the predictability, consistency, and transparency of the 510(k) program.  One of these documents focuses on “Evidentiary Expectations for 510(k) Implant Devices.”  Implant devices are used in a range of settings such as dental and orthopedic procedures.  Having a clear understanding of FDA’s data expectations for 510(k) applications related to implants is crucial for successful marketing clearance.  In this blog post, we highlight the distinctive data expectations recommended for implant devices in the draft guidance.

Background

The draft guidance addresses the review considerations applicable to all implanted devices undergoing evaluation within the 510(k) program, referred to as “510(k) Implants” in the draft guidance.  Implants subject to premarket approval (PMA), those eligible for the De Novo classification process, or those exempt from the 510(k) requirements fall outside the scope of this draft guidance.  The objectives of the draft guidance are as follows:

• “Serve as a primary resource on expectations for all 510(k) implant devices, generally, while device-specific guidances provide further specificity for a given device type
• Assist industry in design and execution of appropriate performance testing to support 510(k) submissions for implant devices
• Provide recommendations for content and labeling to include in 510(k) submissions for implant devices, and
• Convey that the FDA considers the patient experience to be paramount in improving implant device safety, and encourages the collection, analysis, and integration of patient experience data for implants to support 510(k) submissions for those devices.”

General Considerations: What Makes Implants Unique Compared to Other Device Types?

Implant devices are unique because they are designed for continuous implantation for a period of 30 days or more, as per 21 C.F.R. § 860.3.  This distinct use scenario, combined with new features of such devices, may increase the risks compared to other device types or predicate devices.  For instance, FDA highlights risks associated with everyday activities (e.g., airport security screening), or surgical procedures, as well as the potential for reoperation or revision of the implant.

FDA recommends that applicants of 510(k) devices that are intended to be implanted for fewer than 30 days also consider the recommendations outlined in the draft guidance.

Performance data should be customized to the indications for use, including the specific intended patient population (adult vs. pediatric), disease state, conditions of use, and the target anatomical location.  In the case of 510(k) Implants indicated for use in pediatric patients, FDA recommends consulting two other guidance documents: Pediatrics Guidance and Extrapolation Guidance.

The intended duration of implantation is another crucial factor in performance testing.  Testing should be in line with the device’s intended duration of implantation, but FDA may consider whether testing results for a shorter duration can be extrapolated to provide information about long-term performance.  In cases where devices are expected to be frequently replaced, testing should be guided by the aggregate patient exposure.  Safety and effectiveness evaluations should encompass wear and degradation, taking into account the worst-case implantation conditions.

Non-Clinical Recommendations

The draft guidance highlights non-clinical review areas that are generally relevant across 510(k) Implants and offers recommendations for performance data to include in a 510(k) submission.  It is important to note that the type and amount of performance data required may vary based on the device, device type, and differences from the predicate device.  If a submitter believes that certain testing described in the draft guidance does not apply to their device, they should provide a rationale in the 510(k) submission.

The draft guidance provides an overview of various standard testing areas such as biocompatibility, sterility and shelf life, reprocessing and cleaning, software and cybersecurity, electrical safety and electromagnetic compatibility (EMC), and magnetic resonance (MR) compatibility.  Information about these typical non-clinical tests is generally based on previously released guidance documents for each topic, as linked above.

The draft guidance places emphasis on specific tests, such as acute systematic toxicity and material-mediated pyrogenicity for biocompatibility, pyrogenicity testing for sterility, and the applicability of ISO 14708 for the EMC of certain active implantable medical devices.  For example, the draft guidance outlines a minimum five endpoints for biocompatibility testing (cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute systemic toxicity, and material-mediated pyrogenicity) that should be assessed for 510(k) Implants, plus eight additional endpoints for biocompatibility (e.g., subacute/subchronic toxicity, genotoxicity, implantation, hemocompatibility, chronic toxicity, carcinogenicity, reproductive/developmental toxicity and degradation).  It would be beneficial for the industry to have a clear understanding of which endpoints should be evaluated for specific types of implants and their respective implant locations.

Additionally, FDA has identified eight additional non-clinical performance testing areas unique to 510(k) Implants, as summarized in the table below.  We find that this information is noteworthy for manufacturers to consider.

Animal Testing

When engineering analyses and mechanical tests may not comprehensively address the complexities associated with the clinical use of an implant, the draft guidance suggests that an animal study may be necessary to support SE to the predicate device.  We suggest consulting the draft guidance for a few representative examples of situations in which FDA may recommend animal testing.  FDA encourages manufacturers to submit a pre-submission to discuss the animal study protocol with the Agency before submitting a 510(k) application.

Implant Device Design Considerations

Information regarding raw materials and manufacturing processes can be crucial for certain implants, such as those made of nitinol, implants with unique in vivo wear characteristics, implants composed of degradable materials or biologically-derived materials, and implants manufactured using additive manufacturing processes.  In these cases, it is recommended that a 510(k) submission include details about materials, specifications, design and critical processing information, including reaction parameters and solvents used in processing or cleaning to allow FDA to better understand the final, finished form of the implant and how it compares to the predicate device in evaluating substantial equivalence.

Human Factors/Usability (HF/U) and Clinical Performance Testing

The draft guidance offers general information about HF/U and clinical performance testing.  FDA acknowledges the particular importance of HF/U testing for implant devices with complex interfaces intended for implantation by healthcare practitioners (HCPs) and implants that involve post-implantation management by either the patient or HCP (e.g., programming, monitoring, maintenance).

The FDA notes that, in most 510(k) submissions, clinical data is not typically required to establish SE.  However, there are specific scenarios where clinical data may become necessary to support an SE determination, as explained in another recent draft guidance on clinical data in 510(k), which we will discuss separately in a forthcoming blog post.

Patient Experience Information

As CDRH administers the Patient Science and Engagement Program, the draft guidance includes a separate section to encourage, rather than mandate, submitters to include patient experience data (such as patient preference information and patient-reported outcomes) for implants in a 510(k) submission, if it is relevant to the determination of SE.  Regarding this aspect, FDA refers to three guidance documents: Patient-Reported Outcome Measures, Patient-Reported Outcome Instruments, and Patient Preference Information.

In evaluating substantial equivalence, FDA may consider patient preference information in conjunction with non-clinical and clinical testing.  The totality of information helps inform FDA’s decision when it considers the overall benefit-risk profile of the implant device.  Note that FDA performs a benefit-risk assessment in the 510(k) context when it determines whether the new device is “as safe and effective” as the predicate device after the Agency finds that the intended use of the new device and predicate device are the same and have different technological characteristics that do not raise different questions of safety and effectiveness if there are different technological characteristics.

Labeling and Implant ID Card

Lastly, it is critical that patients are provided with implant information as it pertains to their devices. Manufacturers should create user-friendly instructions for use that facilitate patient understanding of potential risks over the expected lifespan of the implant.  FDA offers a flexible approach to achieve this goal, suggesting that some information may be suitable for inclusion on an implant ID card for the patient or caregiver, while other information may be better communicated in a different format (e.g., separate patient labeling).  Concerning the implant ID card, FDA recommends including basic information such as model name and manufacturer and important details concerning patient contacting materials, including those that may be associated with allergic reactions.  FDA also recommends the implant ID card provide contact information in the event of malfunctions or adverse events.  Finally, for magnetic resonance (MR) conditional implants, FDA recommends identifying those conditions for safe MR use.

Closing Remarks

We encourage sponsors of implant devices to carefully review the draft guidance, participate in the FDA’s webinar scheduled for October 26, 2023, and consider submitting comments on this draft guidance by December 6, 2023, through the provided link.

The U.S. District Court for the District of Columbia has vacated the Notice of Benefits and Payment Parameters (NBPP) rule issued in May 2020 (2020 NBPP Rule) which allowed health insurers and pharmacy benefit managers to use copay accumulators to exclude drug manufacturers’ copay assistance when calculating patients’ out-of-pocket costs and cost-sharing ceilings under the Affordable Care Act (ACA).

We previously blogged about this lawsuit last year.  Three patient advocacy groups sued the Department of Health and Human Services (HHS) and the Centers for Medicare and Medicaid Services (CMS), challenging the agencies’ 2020 NBPP Rule as plainly unlawful on the grounds that it conflicts with the definition of “cost sharing” in both the ACA and the agencies’ existing regulations, and is arbitrary and capricious.

The ACA sets an annual cap on the amount that insurers can require insured individuals to pay out of pocket for their medical expenses.  Once an individual reaches this annual cap, the insurer is solely responsible for covering the individual’s remaining medical expenses that year.  To help patients afford the copays and deductibles for specific medications, some drug manufacturers offer direct financial assistance, often as coupons, to subsidize the patient’s purchase of the drug at the point of sale.  This financial assistance directs the pharmacy to bill all or part of the patient’s copayment obligations to the manufacturer instead of the patient.  Insurers have resisted patient assistance programs using copayment accumulator adjustment programs, whereby insurers do not count manufacturer-provided assistance towards patients’ copay obligations, annual deductible, or out-of-pocket maximum.  The insurer still accepts the manufacturer payment, but also collects the full deductible from the patient.  The patient is left high and dry—no closer to meeting the deductible than before, with full benefits and more affordable drugs the same distance out of reach.

The 2020 NBPP Rule permitted insurers to use copay accumulators.  The ACA defines “cost sharing” to include: “(i) deductibles, coinsurance, copayments, or similar charges; and (ii) any other expenditure required of an insured individual which is a qualified medical expense. . .”  The agencies defined the term by regulation as “any expenditure required by or on behalf of an enrollee with respect to essential health benefits; such term includes deductibles, coinsurance, copayments, or similar charges, but excludes premiums, balance billing amounts for non-network providers, and spending for non-covered services.”  As applied to manufacturer assistance, CMS did not adopt a single interpretation of the statutory or regulatory definition of “cost sharing.”  The 2020 NBPP Rule instead allowed insurers to choose whether to include such assistance toward patients’ annual cost sharing cap, and thus whether to include such assistance in the definition of “cost sharing.”

The Court vacated the rule as arbitrary and capricious “based on its contradictory reading of the same statutory and regulatory language and the fact that the agencies have yet to offer a definitive interpretation of this language that would support the rule.”  The Court specifically concluded that the rule “rests on two contradictory interpretations of the statute” and “conflict[s] with the regulatory definition.”  Noting the “interpretive depths. . .that have yet to be plumbed” in the definition of “cost sharing,” the Court remanded the rule to allow the agencies to interpret the term’s meaning.

The decision does not guarantee that the agencies will adopt plaintiffs’ position and force insurers to change their practices, but it is a necessary first step toward doing so.  As of this summer, 20 states and Puerto Rico have enacted legislation to restrict the use of copay adjustment programs.  It remains to be seen whether the use of such programs will be prohibited nationwide.

On Friday, October 6, 2023, DEA announced a second extension of telemedicine flexibilities concerning the prescribing of controlled substances, which were originally set to expire after the end of the COVID-19 pandemic emergency.  As a reminder, back in February 2023, HPM blogged about DEA’s two proposed rules for prescribing (1) controlled substances generally and (2) for buprenorphine use in opioid treatment.  HPM also conducted a  90-minute webinar addressing the “End of the COVID-19 Emergency and the Ryan Haight Act: Telemedicine and Next Steps.”  HPM’s Presentation Deck and recording of the presentation are here, and here (passcode Bv3*o^i5).  DEA received a whopping 38,000 (!) comments on the two proposed rules.

Next, on May 9, 2023 DEA, jointly with the Substance Abuse and Mental Health Services Administration (SAMHSA), issued the First Temporary Rule, which extended the full set of telemedicine flexibilities regarding the prescribing of controlled medications through November 11, 2023. That First Temporary Rule also provided a one-year grace period, through November 11, 2024, for any practitioner-patient telemedicine relationships established on or before November 11, 2023. Thus, under the First Temporary Rule, if a patient and a practitioner established a telemedicine relationship on or before November 11, 2023, the same telemedicine flexibilities that governed the relationship to that point would continue to apply through November 11, 2024. DEA next hosted Telemedicine Listening Sessions on September 12 and 13, 2023, for which it receive over 180 requests to present. DEA noted that industry will have another opportunity for comment once new proposed rules are promulgated.

Based on industry input, DEA and HHS announced in its Second Temporary Rule a further extension of existing telemedicine flexibilities for new practitioner-patient relationships through December 31, 2024. Unlike the first extension back in May 2023, this time around DEA will not require the practitioner-patient relationship to be one that exists prior to on or before November 11, 2023.  Instead, DEA states:

This extension authorizes all DEA-registered practitioners to prescribe schedule II–V controlled medications via telemedicine through December 31, 2024, whether or not the patient and practitioner established a telemedicine relationship on or before November 11, 2023. In other words, the grace period provided in the First Temporary Rule is effectively subsumed by this Second Temporary Rule, which continues the extension of the current flexibilities for all practitioner-patient relationships— not just those established on or before November 11, 2023—until the end of 2024.

Temporary Rule: Second Temporary Extension of COVID–19 Telemedicine Flexibilities for Prescription of Controlled Medications, 88 Fed. Reg. 69,879, 69,880 (Oct. 10, 2023) (emphasis added).

DEA stated its reasons behind the second extension include the need to spend more time considering industry comments and the input it received during its Listening Sessions.  DEA also stated it intends to “ensure a smooth transition for patients and practitioners that have come to rely on the availability of telemedicine for controlled medication prescriptions, as well as allowing adequate time for providers to come into compliance with any new standards or safeguards.”  Id.  DEA also announced that it is working to promulgate these new telemedicine standards or safeguards by the fall of 2024.  This blogger appreciates DEA’s continued deliberative consideration of these new rules as it works through the unprecedented number of comments and extensive Listening Session input received to date.

As we reported last week, FDA has issued a 26 page, single spaced, tiny-font Proposed Rule of Laboratory Developed Tests (LDTs).  There is much to unpack, and we intend to do so in a series of blog posts. In this post, we focus on the proposed changes themselves, and the many questions the agency leaves unanswered.

Change to the IVD definition

First, the mechanics of the change.  The crux of the proposed rule lies in the addition of ten words: “including when the manufacturer of these products is a laboratory.”   These words would be added to the definition of “in vitro diagnostic [IVD] products” in 21 C.F.R. § 809.3(a).

The amended regulation would read as follows (revisions underlined):

In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products are devices as defined in section 201(h)(1) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section 351 of the Public Health Service Act, including when the manufacturer of these products is a laboratory.

The brevity of this change belies the foreseeably seismic impact of FDA regulation of clinical laboratories on the healthcare system.  The practical consequence of adding these words is that LDTs are expressly defined as a type of IVD device, and subject to device regulations, including registration and listing, premarket review, post-market reporting, and quality system regulation.  As we will explore in a subsequent post, FDA has long claimed these regulations implicitly covered LDTs, but many have questioned the basis for this position.

The end of enforcement discretion

The PR proposes to phase out LDT “enforcement discretion” over a period of four years, after which most LDTs will be subject to all applicable medical device regulatory requirements.

The phase out period applies to LDTs currently on the market in reliance on FDA’s enforcement discretion policy (“affected laboratories”).  It does not extend to tests for which FDA has historically not exercised enforcement discretion (e.g., direct-to-consumer tests, tests for use in a public health emergency).  FDA proposes a five-stage transition period for all affected laboratories currently who are not subject to one of the areas of continued enforcement discretion (as discussed later in this post):

• Stage 1 (one year after issuance of the final rule): Begin filing medical device reports (MDR) under 21 C.F.R. Part 803 and notices of correction and removal under 21 C.F.R. Part 806.
• Stage 2 (two years after issuance of the final rule): Register with FDA as a device establishment and list LDTs performed, pursuant to 21 C.F.R. Part 807. Labs must also begin complying with device labeling requirements (21 C.F.R. Part 801) and investigational device exemption requirements (21 C.F.R. Part 812).
• Stage 3 (three years after issuance of the final rule): Comply with the Quality System Regulation (QSR) (21 C.F.R. Part 820).
• Stage 4 (three and a half years after issuance of the final rule): Laboratories offering high‑risk LDTs (i.e., Class III) would be required to submit an application for premarket approval (PMA) to FDA.
• Stage 5 (four years after issuance of the final rule): Laboratories offering low and moderate‑risk LDTs (i.e., Class I or II) would be required to submit a 510(k) premarket notification, unless eligible for exemption.

A few observations are in order:

First, FDA’s timeline is, to put it mildly, wildly ambitious.  The Proposed Rule states that Stage 4 and Stage 5 would not begin before October 1, 2027, and April 1, 2028, respectively, in order to enable laboratories to participate in negotiations preceding user fee reauthorization in 2027 (taking effect in FY2028, which begins on October 1, 2027).  However, meeting this timeline would require FDA to issue a final rule within approximately six months of the PR’s publication date—in other words, by April 2024.  Issuing any final regulation that quickly would be a challenge; given the number of affected stakeholders, the number of questions posed in the PR (see further discussion below in Call for Comment), and the far-reaching effects of the PR, it would be nearly impossible.  Thus, in our view, it is highly unlikely that Stages 4 and 5 would come close to these “not before” dates.

Second, much remains to be done—by both FDA and affected laboratories—before these stages can be implemented.  The PR acknowledges that a proposed rule was issued that, if finalized, will make changes to the QSR.  FDA claims that three years should be plenty of time for labs to come into compliance with the QSR, but the Agency would only aim to have the new QSR rule in effect “before the proposed beginning of stage 3.”  This timing undermines the Agency’s rationale that three years is enough time to come into compliance.  In order for labs to implement a compliant system, they need to know what they are working towards.  Without a final rule, labs cannot be certain that any quality system it puts in place will meet the requirements of the new QSR rule, if finalized.

Third, it’s unclear which tests FDA intends to fall into Stages 4 and 5.  On its face, it seems simple – Class III in Stage 4 and Class I and II into Stage 5.  But, by statute all devices not previously classified are automatically placed into Class III.  LDTs are some of the most novel tests, meaning that a large proportion of them are not classified and would not have a predicate device, even if they are arguably a Class II test, for example.  The PR says that tests going through the De Novo process would fit within Stage 4, but who will ultimately determine whether a test is appropriate for De Novo classification or a PMA and, therefore, either fall into Stages 4 or 5?  Will the responsibility be on the lab?  What will happen if FDA disagrees?

Fourth, The PR does not mention what will happen to the premarket submissions from Stages 4 and 5 that are not cleared/approved.  With regard to both stages, the PR says, that “FDA generally would not intend to enforce against IVDs offered as LDTs after a [510(k), De Novo, or] PMA has been submitted . . . until FDA completes its review of the application.”  This suggests that if the submission is unsuccessful, FDA could take enforcement action, which could include requiring the lab to cease offering the test, among other things.

Remaining Enforcement Discretion

The PR indicates that FDA plans to continue to exercise enforcement discretion, as appropriate for certain kinds of tests.  FDA notes that it would consider issuing enforcement discretion policies for labs developing LDTs during the early phase of any future public health emergencies.  Specifically, FDA states that it plans to issue a draft guidance with an enforcement policy for IVDs for emerging outbreaks offered prior to FDA review to address the immediate public health need.  Ironically, perhaps, FDA cites problems with LDTs for COVID as part of the rationale for FDA regulation of LDTs, so the logic doesn’t quite hold together.

In addition, FDA proposes to continue to exercise enforcement discretion (i.e., to not enforce the new framework) with respect to certain categories of LDTs:

• “1976-Type LDTs,” which FDA describes as “us[ing] manual techniques (without automation) performed by laboratory personnel with specialized expertise; use of components legally marketed for clinical use; and design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.” As an example, the PR cites immunohistochemistry tests that involve no automation (e.g., preparation or interpretation) and would not include lateral flow tests as they do not, typically, rely on lab personnel expertise;
• Human Leukocyte Antigen (HLA) tests used in CLIA high complexity laboratories;
• LDTs intended for forensic use (over which, we note, FDA already lacks jurisdiction); and
• LDTs intended exclusively for use in public health surveillance where a result is not reported directly to a patient or provider (where, again, FDA lacks jurisdiction).

Call for Comment

Despite the significant potential impact of the PR for a wide array of stakeholders, and the many questions it raises, comments must be submitted no later than December 4, 2023—just 60 days after the PR’s issuance.  The PR itself solicits feedback from the public on a number of complex issues, making the short comment period even more puzzling.  Specifically, FDA asks for comment on:

• “Whether specific enforcement discretion policies would be appropriate for IVDs offered as LDTs for other public health scenarios.” FDA asks that comments provide “a description of those scenarios, an explanation of why enforcement discretion policies with respect to those scenarios would be appropriate, [including how public health interests are served by such a policy], and any relevant evidence to support such policies.”
• “What, if any, unintended consequences may result from the proposed phaseout policy to certain patient populations (for example, Medicare beneficiaries, rural populations, etc.) and what steps could be taken to mitigate those consequences.”
• Whether there is “a public health rationale to have a longer phaseout period for IVDs offered as LDTs by laboratories with annual receipts below a certain threshold (e.g., $150,000).”
• Whether academic medical centers should be treated differently than other laboratories offering LDTs.
• How to leverage “programs such as the New York State Department of Health Clinical Laboratory Evaluation Program (NYSDOH CLEP) or those within the Veterans Health Administration (VHA).”

The PR cites CDC’s report that “70 percent of medical decisions are based on laboratory test results.”  Given the potentially massive impact of the proposed changes on a wide range of stakeholders, and indeed on the healthcare system, we strongly encourage interested parties to submit comments, which can be done using the provided link.

The fate of the PR is far from certain.  Given the number of open questions, we hope that the Agency would consider publishing an amended proposed rule prior to issuing a final rule once it has a firmer stance on these and other important questions.  For context, a quick review of a number of notable CDRH rules in the last ten years shows that most rules take approximately three to four years to be issued as final from the time that they are proposed.  There was one outlier, the hearing aid rule, which went from proposed to final in just under a year.  As readers of our blog will recall, however, the Agency missed its statutory deadline to issue that proposed rule (see prior post here).  During the media call, in response to the question about the timing of publishing the final rule, CDRH Director Jeff Shuren commented, “That is ultimately up to the administration.”

Even if FDA completes rulemaking, a final rule will likely face judicial challenge.  Future blog posts will analyze FDA’s legal authority as well as FDA’s claimed public health need for LDT regulation.