FDA Takes Steps to Ensure Safety of Cinnamon Products Sold in the US

  • On March 6, 2024, the U.S. Food and Drug Administration (FDA) sent a letter to all cinnamon manufacturers, processors, distributors, and facility operators in the US, reminding them of the requirement to implement controls to prevent contamination from potential chemical hazards in food, including ground cinnamon products. The Agency also recommended the voluntary recall of certain ground cinnamon products sold by a number of brands at six different retail chains that were found to contain levels of lead.
  • This letter follows the recent incidents associated with certain cinnamon apple sauce pouches that resulted in lead poisoning in young children. As we have previously blogged, FDA’s investigation into the contaminated apple sauce pouches traced the contamination back to a manufacturer and cinnamon supplier in Ecuador.
  • FDA notified the distributors and manufacturers of products found to contain elevated levels of lead and recommended that the manufacturers voluntarily recall these products because prolonged exposure to them may be unsafe. The products were identified during an FDA-initiated sampling and testing effort to assess cinnamon sold across numerous retail stores. No illnesses or adverse events have been reported to date related to the ground cinnamon products listed in this news release, but the FDA is concerned that, because of the elevated lead levels in these products, continued and prolonged use of the products may be unsafe.
  • Since the issuance of the letter, recipient companies El Chilar and Raja Foods, as well as Stonewall Kitchen and Colonna, have issued voluntary recalls for some of their cinnamon products.
  • FDA continues to work with the Center for Disease Control and Prevention (CDC), as well as state and local partners, to investigate elevated lead and chromium levels in individuals with reported exposure to apple cinnamon fruit puree pouches.

Navigating Hemp THC Beverages

Nonalcoholic beverages infused with delta-9 tetrahydrocannabinol (THC) derived from hemp (aka intoxicating hemp beverages) are becoming increasingly popular for consumers looking for an alternative to alcohol.

With major alcohol retailers like Total Wine entering the cannabis space, alcohol beverage producers may be looking for opportunities to leverage their existing experience in manufacturing, marketing and distributing alcohol beverages towards the emerging intoxicating hemp beverage market. While intoxicating hemp beverages are arguably legal pursuant to the Agriculture Improvement Act of 2018 (2018 Farm Bill), risks remain under federal and state food and drug laws. Accordingly, beverage producers looking to enter this emerging market should become familiar with the ambiguities involved.

Federal Treatment of Intoxicating Hemp Beverages

The 2018 Farm Bill removed hemp, defined as cannabis (Cannabis sativa L.) and derivatives of cannabis with extremely low concentrations of delta-9 THC (specifically, no more than 0.3 percent THC on a dry weight basis), from the definition of “marijuana” in the Controlled Substances Act. The federal government defines hemp as “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.” Accordingly, products that meet the definition of “hemp” may be marketed and sold in the United States and are no longer classified under federal law as illegal drugs.

How Is Hemp Regulated?

Under the 2018 Farm Bill, the US Department of Agriculture (USDA) has been assigned to regulate hemp production.

However, any hemp-derived foods, including beverages, are subject to regulation by the US Food & Drug Administration (FDA) under the Food, Drug, and Cosmetics Act (FDCA). While the FDA has largely avoided enforcement actions against such products, focusing most of its efforts on products making unsubstantiated medical and therapeutic claims, it has clearly concluded that it is a prohibited act under federal law to introduce any food in the market to which THC or cannabidiol (CBD) has been added. Therefore, the risk of federal enforcement remains until the agency changes its stance towards THC as a beverage additive.

State Regulation

While the federal government has been inactive in this space, the legal status of intoxicating hemp beverage products varies significantly by state. On the one hand, several states, including Minnesota, have expressly legalized the inclusion of hemp-derived cannabinoids in beverage products, with clear regulations regarding testing, labeling, advertising and more. On the other hand, some states have legalized hemp beverage products but lack a robust regulatory framework – leading to a mostly unregulated, laissez-faire market.

Further, many states fall into a grey area when it comes to the legality of such products. Some of these states have legalized hemp along the lines of the 2018 Farm Bill but have not officially opined on whether it can be added to beverage products, while others do not mention hemp products at all. A subset of states has expressly legalized hemp in beverages, as long as it complies with federal guidance, which currently does not affirmatively allow hemp to be used as a beverage additive.

One of the most extreme measures taken by state officials to ban hemp from beverage products is currently underway in South Carolina. The state’s Department of Health and Environmental Control (DHEC) recently issued a letter to the hemp industry warning that certain hemp products are not approved to be added to beverage products, including delta-9 THC.

In its letter, the DHEC also ruled that labels and packaging may not contain references to “THC,” “CBD” or “delta-9” products, or isolates, as this implies the product is no longer a food item but is a drug and is unlawful.

This new guidance is far from outlawing cannabinoids in beverages, but it affects a growing industry that has already been promoting intoxicating hemp beverages in the state. Indeed, some beverage manufacturers in South Carolina have been forced to halt production, citing confusion over the new labeling and packaging requirements. This demonstrates how the legal landscape around intoxicating hemp beverages can change rapidly.

Finally, it is important to note that even states that expressly allow and regulate THC-infused beverage products fall into a grey area when we consider the current state of federal regulations. Until Congress acts or the FDA changes its stance towards THC as a beverage additive, we will continue seeing a patchwork of different approaches.

 
For more on THC, visit the NLR Biotech, Food, Drug section.

FDA Lists Regulations Under Development and Updates Priority Guidance Topics for Foods Program

  • The U.S. Food and Drug Administration’s (FDA’s) Foods Program has posted a new website listing regulations it plans to publish by October 2024 and long-term regulations it is prioritizing for publication at a later date. Additionally, FDA has updated the list of guidance topics it is considering and expects to publish by the end of 2024.
  • Regulations are officially announced in the Unified Agenda of Regulatory and Deregulatory Actions published each spring and fall. Some of the regulations FDA has listed on its website include use of the “healthy” nutrient content claim, the use of ultrafiltered milk in cheese and cheese related products, and front-of-package nutrition labeling, among others.
  • The following five topics have been added to the list of guidance documents the FDA expects to publish by the end of December 2024:
    • Notifying FDA of a Permanent Discontinuance in the Manufacture or an Interruption of the Manufacture of an Infant Formula; Draft Guidance for Industry;
    • Action Levels for Lead in Food Intended for Babies and Young Children: Guidance for Industry;
    • The Food Traceability Rule: Questions and Answers; Draft Guidance for Industry;
    • Hazard Analysis and Risk-Based Preventive Controls for Human Food; Chapter 12: Preventive Controls for Chemical Hazards: Draft Guidance for Industry; and
    • Voluntary Sodium Reduction Goals: Target Mean and Upper Bound Concentrations for Sodium in Commercially Processed, Packaged, and Prepared Foods (Edition 2): Draft Guidance for Industry
  • Public comments on the list of guidance topics can be submitted to www.regulations.gov using Docket ID FDA-2022-D-2088.

FDA Announces Draft Supplemental Guidance on Menu Labeling

  • Today FDA announced an update to its Menu Labeling Supplemental Guidance which addresses implementation of menu nutrition labeling requirements. The menu labeling rules only apply to standard menu items offered by “covered establishments,” which are defined as restaurants and similar retail food establishments with 20 or more locations doing business under the same name and offering for sale substantially the same menu items, as well as restaurants and similar retail establishments that register to voluntarily subject themselves to the menu labeling requirements. (21 CFR 101.11).
  • The menu labeling regulations require disclosure of calories on menu and menu boards, and require that other nutrition information (e.g., fat, sugar, protein) be available in written form on the premises and provided to the customer upon request. Notably, the menu labeling regulations do not require disclosure of “added sugars” as is now required on packaged foods.
  • The draft update includes two new Q&As which (1) clarify that nutrition information can be provided on third party platforms (TPPs) through which food is ordered and delivered and (2) that added sugars may voluntarily be declared.
  • Although FDA accepts comments on any guidance at any time, comments on the draft new Q&As are due by February 12, 2024, to ensure they are considered before FDA begins work on final versions.

MoCRA Enforcement Pushed Six Months

Key Takeaways

  • What Happened: FDA announced delayed enforcement for MoCRA facility registration and product listing information.
  • Who’s Impacted: Cosmetic product manufacturers
  • What Should You Do: Keep up to date with the ongoing updates and prepare to register your facilities and list your products by July 1, 2024.

As described in our previous alert, Congress enacted the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) in December 2022. MoCRA amended the Federal Food, Drug, and Cosmetic Act (FFDCA) to add several new provisions, including requiring manufacturers and processors of cosmetic products to register their facilities with the Food and Drug Administration (FDA) and submit product lists to FDA. FFDCA § 607. Prior to the November 8, 2023 announcement, every person who owns or operates a facility that engages in manufacturing or processing a cosmetic product for distribution in the U.S. was required to register with FDA starting on December 29, 2023. FFDCA § 607(a)(1)(A). Additionally, the responsible person for each cosmetic product sold in the U.S. was required to submit a cosmetic product listing to the FDA starting on December 29, 2023. FFDCA § 607(c)(2). The FDA’s announcement pushed back the enforcement of these requirements for six months to ensure that the industry had time to comply. The new deadline for both facility registration and product listing information is July 1, 2024.

The accompanying guidance document indicates that FDA still intends to be ready to accept registration and listing information by the statutory deadline of December 29, 2023. Companies will be able to submit their information then.

The delay was precipitated by industry comments to FDA indicating that companies needed more time to gather the required information for facility registration and product listing. The commenters cited concern about the timeframe required to obtain facility registration numbers for cosmetic product listings, to access the electronic submissions database (which at the time of this alert, is not live), and to enter and submit accurate registration and listing information.

Cosmetic product manufacturers should ensure they are on track to meet the new July 1, 2024 deadline, and also note that the December 29, 2023 deadline remains in effect for other MoCRA requirements, including the requirement that FDA propose regulations for standardized testing methods for the detection and identification of asbestos in talc-containing cosmetic products, and the requirement that responsible persons ensure adequate safety substantiation.

Sharing Scientific Information with HCPs on Unapproved Uses of Medical Products: Dos and Don’ts Under FDA’s New Draft Guidance

In October 2023, the FDA released draft guidance entitled “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products: Questions and Answers Guidance for Industry” (“2023 Draft Guidance”).[1] The 2023 Draft Guidance supersedes previous draft guidance from 2014 entitled “Distributing Scientific and Medical Publications on Unapproved New Uses–Recommended Practices” (“2014 Draft Guidance”), which was a revision of a 2009 final guidance entitled “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.”

All three of these FDA guidance documents provide recommendations for industry regarding the sharing of scientific information with Health Care Providers (“HCPs”)[2] on unapproved uses of approved or cleared drugs and medical devices, termed “SIUU communications” by the 2023 Draft Guidance. HCPs are permitted to prescribe medical products for unapproved uses when the unapproved use is determined to be medically appropriate for a given patient. However, manufacturers may not promote their products for an unapproved use. For this reason, FDA’s position (which is articulated to some extent across all of the above-mentioned guidance documents, but most clearly and emphatically in the 2023 Draft Guidance) is that firm[3] communications to HCPs regarding unapproved uses of approved or cleared products should include all of the information necessary for HCPs to evaluate the strengths, weaknesses, validity, and utility of the information about the unapproved use in order to make determinations regarding medical appropriateness.

In the 2023 Draft Guidance, FDA seeks to balance the interests of HCPs in learning, and manufacturers in sharing, truthful and non-misleading information about unapproved uses of approved medical products, with the intent to inform clinical practice decisions against the government’s interest in protecting patients from medical product uses that have not met applicable safety and effectiveness standards required under FDA’s premarket approval framework.

While the 2023 Draft Guidance reiterates many of the recommendations from the 2014 Draft Guidance, the 2023 Draft Guidance leverages a new “Q&A” format to provide firms with more detailed and specific recommendations, including hypothetical scenarios, around SIUU communications. Below, we restate the four Q&A questions included in the 2023 Draft Guidance and then highlight key aspects of the responses provided by FDA through brief commentary and recommended Dos and Don’ts.

Q1. What should firms consider when determining whether a source publication is appropriate to serve as the basis for an SIUU communication?

According to the 2023 Draft Guidance, any study or analysis described in a source publication that serves as the basis for an SIUU communication should be scientifically sound,[4] and should provide information that is relevant to HCPs engaged in making clinical practice decisions for the care of an individual patient; in other words, these sources should be clinically relevant.[5] While the 2014 Draft Guidance suggested that scientific or medical journal article reprints intended for distribution to HCPs should describe studies that are considered “scientifically sound” by appropriate experts, the 2023 Draft Guidance builds out this standard and provides greater insight into what types of source material would meet (and not meet) the standard.

Do:

  • Choose scientifically sound studies that provide clinically relevant information to support your SIUU communications
    • For human and animal drugs, randomized, double-blind, concurrently controlled superiority trials are most likely to provide both scientifically sound and clinically relevant information (though other well-designed and well-conducted studies may also be appropriate)
    • For medical devices,[6] look to well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, reports of significant human experience with a marketed device as sources of scientifically sound and clinically relevant information
  • Consider studies with real-world data and associated real-world evidence, which may meet the scientifically sound and clinically relevant threshold depending on the nature of the data and underlying analyses

Don’t:

  • Rely on studies without an adequate control group, isolated case reports, or studies that lack sufficient detail to permit scientific evaluation as the sole basis for an SIUU communication
  • Rely on studies with “unreliable” data, even if you include disclaimers noting the limitations (e.g., studies that fail to control for confounding factors or fail to clearly define study endpoints)
  • Rely on articles focused on non-clinical studies as the sole basis for an SIUU communication
  • Rely on scientific data generated in early stages of medical product development as the sole basis for an SIUU communication, as such data can produce results that are inconsistent with later studies
  • Distort studies in SIUU communications or base SIUU communications on publications that distort studies or include fraudulent data
  • Continue to share an SIUU communication that is based on a study or analysis that is no longer clinically relevant (ex: subsequent research has established the findings from the study are not reliable)

Q2. What information should firms include as part of SIUU communications?

Like the 2014 Draft Guidance, the 2023 Draft Guidance emphasizes the importance of providing certain disclosures with SIUU communications to ensure such communications are not misleading and provide all the information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information. The recommended disclosures in the 2023 Draft Guidance are similar to those recommended in the 2014 Draft Guidance, but are more detailed and extensive.

Do:

  • Provide a disclosure statement with any SIUU communication, which should include:
    • A statement that the use described in the communication is unapproved and the safety and effectiveness of the medical product for the unapproved use(s) has not been established
    • Disclosure of the FDA approved use of the medical product, including any limitations and contraindication(s) specified by the product’s FDA-required labeling[7]
    • Disclosure of any limitations, restrictions, cautions, warnings, or contradictions described in the FDA-required labeling about the unapproved use(s)
    • Disclosure of any serious, life-threatening, or fatal risks posed by the medical product that are relevant to the unapproved use(s) (that are either in the FDA-required labeling or known by the firm and relevant to the unapproved use)
    • Disclosure of any financial relationships between the firm and any authors, editors, or other contributors to the publications in the SIUU communication
    • A copy of the most current FDA-required labeling (or a mechanism for obtaining the labeling)
    • The publication date of any referenced or included publication(s) (if not specified in the publication or citation)
  • For an SIUU communication based on a source publication that is primarily focused on a particular scientific study or studies, for each such study where the following information is not included in the publication, provide a description of:
    • All material aspects of study design, methodology, and results
    • All material limitations related to the study design, methodology, and results
    • Any conclusions from other relevant studies, when applicable, that are contrary to or cast doubt on the results shared, including citations for any such studies

Don’t:

  • Omit any risk evaluation and mitigation strategy (REMS) applicable to the medical product (firms should disclose any REMS and should describe the goal(s) of the REMS)

Q3. What presentational considerations should firms take into account for SIUU communications?

The 2023 Draft Guidance offers a number of presentation-focused recommendations to ensure that SIUU communications are conveyed in a manner that enhances and does not interfere with HCP understanding of the underlying scientific information, and to avoid such SIUU communications being confused with promotional communications about approved uses.

Do:

  • Clearly and prominently present all recommended disclosures, considering type size, font style, layout, contrast, graphic design, headlines, spacing, volume, articulation, pace, and any other techniques to achieve emphasis or notice
  • For SIUU communications with both audio and visual components, present disclosures in both the audio and in text at the same time using the same/substantially similar language
  • Keep SIUU communications (including those relayed via email) separate and distinct from promotional communications about approved uses of medical products
  • Use dedicated vehicles, channels, and venues for sharing SIUU communications that are separate from the vehicles, channels, and venues used for promotional communications about approved uses of medical products. For example –
    • Present SIUU communications on a separate web page from the web page that hosts promotional communications about approved uses
    • At conferences and similar venues, ensure that SIUU communications are clearly identified and distinct from promotional communications about approved uses (e.g., by dividing booth space to allow a dedicated space for SIUU communications)
  • Use plain language in the content developed for SIUU communications to facilitate comprehension (i.e., clear and concise language that does not include technical jargon and clearly explains any scientific or technical terms)

Don’t:

  • Use persuasive marketing techniques, such as the use of celebrity endorsements, premium offers, and gifts. According to FDA, a firm’s choice to use persuasive marketing techniques suggests an effort to convince the HCP to prescribe or use the product for the unapproved use based on elements other than the scientific content of the communication
  • Include direct links from web pages that host promotional communications about approved uses to webpages that host SIUU communications
  • Utilize platforms with character limits that do not enable the firm to include the recommended disclosures for sharing SIUU communications (however, such platforms could be used to direct an HCP to an SIUU communication, subject to certain restrictions)

Q4. What additional recommendations apply to specific types of SIUU communications?

The 2023 Draft Guidance offers additional recommendations related to certain specific types of SIUU communications including journal reprints and clinical reference resources (such as clinical practice guidelines and reference texts). Of note, the 2023 Draft Guidance provides recommendations for a category of SIUU communications that is not specifically addressed in the 2014 Draft Guidance – “firm-generated presentations of scientific information from an accompanying published reprint.”

Discussion of such firm-generated presentations in the 2023 Draft Guidance represents a departure from the 2014 Draft Guidance, which stated that reprints (as well as clinical reference resources) regarding unapproved uses (of cleared or approved medical products) should not be “marked, highlighted, summarized, or characterized” by medical product manufacturers to emphasize or promote an unapproved use. The 2023 Draft Guidance provides new flexibility in this regard, expressly acknowledging that firms may develop their own presentations of scientific information from an accompanying reprint provided such presentation is truthful, non-misleading, factual, unbiased, and provides all the information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the presented information. The 2023 Draft Guidance includes a number of recommendations for firms to follow to prepare and distribute firm-generated presentations of information from an accompanying reprint.

Do:

  • Include the full reprint with the firm-generated presentation
  • Include the disclosures outlined above in Q2, and clearly disclose what portions of the communication are firm-generated
  • Follow the presentational considerations outlined in Q3

Don’t:

  • Imply that the study, analysis, or underlying data or information from the reprint(s) represents larger or more-general experience with the medical product than it actually does
  • Present information, such as excerpts, quotes, etc., from the reprint(s) out of context, without the information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information
  • Include representations or suggestions about the safety or effectiveness of the medical product for the unapproved use(s) that are not consistent with the reprint
  • Present any conclusions or representations about safety or effectiveness for the unapproved use without expressly attributing such statements to the reprint, and without immediately following such statements with a disclosure of any financial relationships between the firm and any authors, editors, or other contributors to the publications in the SIUU communication
  • Use statistical analyses or techniques to indicate clinical significance or validity of a finding not supported by the data or information in the reprint
  • Use tables or graphs or other presentational elements to distort or misrepresent the relationships, trends, differences, or changes among the outcomes evaluated in the reprint

Conclusion

While the 2023 Draft Guidance veers from the 2014 Draft Guidance in some respects, many of the same principles have been pulled through into the current guidance. As such, a medical product manufacturer who has already implemented the recommendations from the 2014 Draft Guidance should not face too heavy of a lift to adjust its activities to align with the 2023 Draft Guidance. While the landscape has not shifted drastically overall, firms should still closely review the additional detail and clarifications provided by the 2023 Draft Guidance to mitigate potential risk in navigating the often murky regulatory waters of engaging in off-label and pre-approval communications.

ENDNOTES

[1] Comments on the 2023 Draft Guidance are due by December 26, 2023.

[2] The 2023 Draft Guidance only applies to HCPs engaged in making clinical practice decisions for the care of an individual patient. Per the 2023 Draft Guidance, HCPs include physicians, veterinarians, dentists, physician assistants, nurse practitioners, pharmacists, or registered nurses who are licensed or otherwise authorized by law to prescribe, order, administer, or use medical products in a professional capacity. The 2014 Draft Guidance applied to “health care professionals,” but the term was not specifically defined.

[3] As defined by the 2023 Draft Guidance, firms are the “persons legally responsible for the labeling of medical products, and includes applicants, sponsors, requestors, manufacturers, packers, and distributors of medical products, and licensees of such persons, and any persons communicating on behalf of these entities.”

[4] To be “scientifically sound,” at a minimum, studies should meet generally accepted design and other methodological standards for the particular type of study performed, taking into account established scientific principles and existing scientific knowledge.

[5] Additionally, statistical robustness is generally necessary, though not sufficient, to determine if a study or analysis is appropriate for an SIUU communication. While statistical robustness factors into the rigor of the design and methodology of a study, it does not assure that the study relates to outcomes of clinical relevance to HCPs.

[6] Notably, while the 2014 Draft Guidance stated that journal articles discussing significant non-clinical research could fall within FDA’s enforcement discretion policy under the guidance, the 2023 Draft Guidance clarifies that, generally, sharing articles focused on non-clinical studies alone would not be consistent with FDA’s enforcement discretion policy as a non-clinical study alone is unlikely to provide information that is clinically relevant.

[7] “FDA-required labeling” includes, but is not necessarily limited to, the labeling reviewed and approved by FDA as part of the medical product premarket review process. For a prescription human drug (including biological products), this consists of the FDA-approved prescribing information that meets the requirements of 21 CFR 201.100. For a device, it includes the labeling approved during the review of a premarket approval application or De Novo classification.

Software as a Medical Device: Challenges Facing the Industry

SaMD Blog Series: Introduction

Editor’s Note: We are excited to announce that this article is the first of a series addressing Software as a Medical Device and the issues that plague digital health companies, investors, clinicians and other organizations that utilize software and medical devices. We will be addressing various considerations including technology, data, intellectual property, licensing, and contracting.

The intersection of software, technology and health care and the proliferation of software as a medical device in the health care arena has become common place and has spurred significant innovations. The term Software as a Medical Device (SaMD) is defined by the International Medical Device Regulators Forum as “software intended to be used for one or more medical purposes that perform these purposes without being part of a hardware medical device.” In other words, SaMD need not be part of a physical device to achieve its intended purpose. For instance, SaMD could be an application on a mobile phone and not be connected to a physical medical device.

With the proliferation of SaMD also comes the need for those building and using it to firmly grasp legal and regulatory considerations to ensure successful use and commercialization. Over the next several weeks, we will be addressing some of more common issues faced by digital health companies, investors, innovators, and clinicians when developing, utilizing, or commercializing SaMD. The Food and Drug Administration (FDA) has already cleared a significant amount of SaMD, including more than 500 algorithms employing artificial intelligence (AI). Some notable examples include FDA-cleared SaMD such as wearable technology for remote patient monitoring; doctor prescribed video game treatment for children with ADHD; fully immersive virtual reality tools for both physical therapy and mental wellness; and end to end software that generates 3D printed models to better plan surgery and reduce operation time. With this rapid innovation comes a host of legal and regulatory considerations which will be discussed over the course of this SaMD Blog Series.

General Intellectual Property (IP) Considerations for SaMD

This edition will discuss the sophisticated IP strategies that can be used to protect innovations for the three categories of software for biomedical applications: SaMD, software in a medical device, and software used in the manufacture or maintenance of a medical device, including clinical trial collaboration and sponsored research agreements, filing patent applications, and pursuing other forms of protection, such as trade secrets.

Licensing and Contracting with Third Parties for SaMD

This edition will unpack engaging with third parties practically and comprehensively, whether in the context of (i) developing new SaMD or (ii) refining or testing existing SaMD. Data and IP can be effectively either owned or licensed, provided such licenses protect the future interests of the licensee. Such ownership and licensing are particularly important in the AI and machine learning space, which is one area of focus for this edition.

FDA Considerations for SaMD

This edition will explore how FDA is regulating SaMD, which will include a discussion of what constitutes a regulated device, legislative actions to spur innovation, and how FDA is approaching regulation of specific categories of SaMD such as clinical decision support software, general wellness applications, and other mobile medical devices. It will also examine the different regulatory pathways for SaMD and FDA’s current focus on Cybersecurity issues for software.

Health Care Regulatory and Reimbursement Considerations for SAMD

This edition will discuss the intersection of remote monitoring services and SaMD, prescription digital therapeutics and how they intersect with SaMD, licensure and distributor considerations associated with commercializing SaMD, and the growing trend to seek out device specific codes for SaMD.

Our hope is that this series will be a starting point for digital health companies, investors, innovators, and clinicians as each approaches development and use of SaMD as part of their business and clinical offerings.

© 2023 Foley & Lardner LLP

For more information on Healthcare, click here to visit the National Law Review.

 

FDA’s Digital Health High Notes from 2022

There has been a lot of discussion lately of the Food and Drug Omnibus Reform Act of 2022 (FDORA), which was enacted on December 29, 2022 as part of the larger Consolidated Appropriations Act for 2023 (you can find our blog post on it here). As important as these kinds of future reforms are to medical product developers, we should also take a moment to review last year’s actions and policy updates on digital health from the Food and Drug Administration (FDA) and to reflect on the transformations that have been taking place at the agency as a result of the rapid pace of innovation in the field. The year 2022 marked the conclusion of the five-year Software Precertification Pilot Program and the release of the final Clinical Decision Support Software guidance, among other things, although FDA’s digital health policies generally remained consistent. In this post, we summarize the agency’s key actions in the digital health space in 2022.

Expanding into Extended Reality

Over the past few years, FDA has started a number of initiatives to explore the use of virtual, mixed, and augmented reality (the agency typically uses the term “extended reality” to cover all types of immersive digital systems) as therapeutic devices for use by patients in clinical environments and at home. The agency granted marketing authorization to two virtual reality devices for patient use, EaseVRx for chronic pain (de novo classification) and Luminopia One for treatment of lazy eye in children, in 2021 and the CureSight system, also for lazy eye in children, in 2022. It is also conducting multiple internal research projects on medical extended reality within the Center for Devices and Radiological Health (CDRH).

In conjunction with its internal research, FDA is engaging health care professionals and the industry to learn about possible benefits, as well as the risks and limitations, of medical extended reality systems to guide future decisions about the therapeutic and clinical uses of such devices. A meeting of FDA’s Patient Engagement Advisory Committee in July 2022 provided an opportunity for the agency to hear from experts and researchers in the field of extended reality and its uses, as well as companies developing medical extended reality devices and patients who have experienced such devices. The materials from the meeting are available here.

FDA also published a list of medical extended reality devices that have received marketing authorization on its website devoted to the Digital Health Center of Excellence (DHCoE), which is part of CDRH.

Application of extended reality technology and the metaverse to medicine is an exciting area of development, and we expect FDA to continue to be active in the space and to develop formal policies and guidance on extended reality devices in the near future.

Precertification Pilot Ends with Uncertain Future

FDA’s Software Precertification Pilot Program, launched in 2017 to explore innovative methods and approaches to regulating software as a medical device (SaMD), officially ended in September 2022 (see our previous posts on the Precertification program here and here). Although FDA was able to glean some key insights from the pilot, including a better understanding of SaMD manufacturer practices throughout the product life cycle, including design, development, and management of SaMD products, the agency ultimately admitted that it had encountered significant challenges in implementing the pilot program. Such challenges included:

  • limited statutory authorities, which hindered FDA’s ability to gather consistent and harmonized information on manufacturer practices and SaMD performance;
  • focusing only on SaMD for De Novo classification, which limited the number of eligible devices and created issues for testing pilot-specific special controls; and
  • the small number of participants (only nine SaMD manufacturer were accepted to the pilot program).

You can read FDA’s final report from the pilot program here.

FDA may use its observations from the pilot program when developing new guidance or other policies pertaining to SaMD, but any new rules or guidances must be consistent with the agency’s current statutory authorities. It is very likely that we have seen the end of any FDA software precertification program, unless or until Congress decides to grant the agency specific authority to implement a new or different regulatory regime for SaMD.

Leadership Changes at the Digital Health Center of Excellence

The past year marked a number of watershed changes at the DHCoE, including the departure of Bakul Patel, longstanding CDRH official in many capacities and the first director of the DHCoE, and the naming of a new acting director, Brendan O’Leary. Subsequently, in January 2023, the agency named Troy Tazbaz, former senior vice president at Oracle, as the new director of DHCoE. It will be interesting to see how Mr. Tazbaz, a newcomer to the agency, will direct the DHCoE in further developing the regulatory framework for digital health devices and in building strategic partnerships with industry stakeholders.

Digital Health Guidances

FDA introduced a number of new and revised guidance documents relating to digital health technologies in 2022. The following is a list with brief descriptions of each such agency guidance:

  • Clinical Decision Support Software (final guidance) – After a long wait (the previous draft version was published in September 2019), FDA issued a final guidance covering clinical decision support (CDS) software devices on September 28, 2022. You can find our analysis of this critical guidance in this previous post. In addition, FDA created some helpful resources to determine the regulations that may apply to a company’s CDS software or other types of SaMD: a CDS software flowchart, and a Digital Health Policy Navigator.
  • Policy for Device Software Functions and Mobile Medical Applications (revised final guidance) – FDA issued an updated version of this guidance in September 2022 to implement changes consisted with the CDS final guidance.
  • Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions (draft guidance) – In recent years, FDA has repeatedly emphasized the importance of addressing cybersecurity in medical devices and has made great efforts in keeping its policies and guidance documents aligned with current cybersecurity recommendations. This guidance describes methods for incorporating cybersecurity into the design and development process for connected medical devices (including SaMD) and for maintaining cybersecurity as part of device quality systems throughout the product lifecycle. Once finalized, this guidance will supersede final guidance Content of Premarket Submissions for Management of Cybersecurity in Medical Devices, issued in October 2014. It is also worth noting that FDORA grants the agency new authorities to require cybersecurity plans as part of premarket submissions for so-called “cyber devices,” which will need to be considered and incorporated into any upcoming final guidance on this topic.
  • Computer-Assisted Detection Devices Applied to Radiology Images and Radiology Device Data – Premarket Notification [510(k)] Submissions (final guidance) & Clinical Performance Assessment: Considerations for Computer-Assisted Detection Devices Applied to Radiology Images and Radiology Device Data in Premarket Notification (510(k)) Submissions (final guidance) – This pair of final guidances describes FDA’s expectations for information included in premarket notification submissions for CADe devices, and specifically for the design of clinical studies to support marketing authorization of such devices. Many companies have developed, or are interested in developing, software with CADe functionality to detect lesions or abnormalities in radiology images for the purpose of assisting human readers, and with the rapid risk of artificial intelligence/machine learning-based software, some manufacturers may seek to develop CADe software that replaces human readers altogether. These guidances are especially useful for companies developing CADe software and preparing for clinical testing and submission to FDA.
  • Electronic Submission Template for Medical Device 510(k) Submissions (final guidance) – Although this guidance does not specifically apply to digital health technologies, it represents an important development for all medical device companies, including digital health device manufacturers. FDA released this guidance in conjunction with the announcement that CDRH will accept electronic submissions of device premarket notifications from all applicants using the electronic submission template and resource (eSTAR) tool. The guidance describes the structure of the template (and helpfully cross-references other guidance documents that relate to each section of the template). FDA has designated October 1, 2023 as the date of full transition to electronic submission for premarket notifications, meaning that FDA will no longer accept eCopies of premarket notification submissions for filing and review as of that date.

As the preceding list highlights, digital health is an active and rapidly advancing field both in the private sector and at FDA. We will continue to monitor and report on notable developments in terms of regulatory policies affecting developers and investors in the broader field.

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FDA Finalizes Cannabis Guidance Focusing on Clinical Research and Quality Considerations

On January 23, 2023, the U.S. Food and Drug Administration (FDA) issued its final guidance, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research” (the Final Guidance). The agency outlines current recommendations for drug sponsors developing cannabis and cannabis-derived compounds for use in human drug clinical research. Cannabis and cannabis-derived compounds include botanical raw materials, extracts, and highly purified substances of botanical origin.[i] FDA published the draft version of the guidance in July 2020 and received 60 public comments. Below, we outline key points from the Final Guidance.

Background

  • The Agriculture Improvement Act of 2018 (Public Law 115-334), known as the 2018 Farm Bill, removed “hemp” from the definition of “marihuana” under the Controlled Substances Act (CSA). Now, hemp is not considered a controlled substance. “Hemp” is defined in the 2018 Farm Bill as including cannabis and derivatives or extracts of cannabis with no more than 0.3% by dry weight of the compound delta-9 tetrahydrocannabinol (THC). The Drug Enforcement Administration (DEA) still regulates as Schedule I controlled substances those botanical raw materials, extracts, and derivatives that contain cannabis or cannabis-derived compounds with delta-9 THC content above 0.3% by dry weight.
  • Cannabis and cannabis-derived compounds – even those meeting the 2018 Farm Bill’s definition of “hemp” – are typically subject to the same FDA clinical research regulatory requirements and standards as human drug products containing other substances.

Cannabis Sources and Quality Considerations

  • Sponsors may use cannabis (including hemp) in human drug clinical research if FDA deems the cannabis to be of “adequate quality.” The agency will review quality issues in the context of an investigational new drug (IND) application.
  • Historically, the National Institute on Drug Abuse (NIDA) Drug Supply Program (DSP) was the only domestic, federally legal source of cannabis for clinical research. That is no longer the case. Human drug sponsors may now source cannabis regulated as a Schedule I controlled substance from other DEA-authorized growers.
  • Human drug sponsors should consider the recommendations in FDA’s final guidance, “Botanical Drug Development” (Dec. 2016). Importantly, the agency does not recommend relying on published literature as a substitute for data from a full toxicology program to support drug product development for phase 3 clinical research (and beyond). Dedicated toxicology studies are specifically recommended for 7-COOH-CBD, the major human metabolite of cannabidiol.

CSA Controlled Status

  • When a drug sponsor submits an IND to FDA as part of cannabis-related human drug clinical research, the sponsor should determine the potential controlled substance status of any botanical raw materials, drug substances, and drug products by taking into consideration the delta-9 THC content. The agency encourages sponsors to calculate the delta-9 THC content in the proposed investigational product early in the drug development process and to consult with the DEA.
  • Generally, the delta-9 THC percentage in botanical raw materials is calculated as the amount of delta-9 THC (and THCA) naturally present in a material sample relative to the sample’s dry weight prior to extraction or other manufacturing steps. For intermediates or finished products containing cannabis or a cannabis-derived compound, sponsors should calculate the total delta-9 THC percentage using the composition of the formulation with the amount of water removed (including water contained by excipients). These calculations should not be used for other purposes (e.g., Chemistry Manufacturing and Controls (CMC)).
  • FDA may have concerns with drug abuse liability. As part of the agency’s review of a new drug application (NDA), FDA may conduct an abuse potential assessment. Such an assessment could impact drug product labeling as well as DEA scheduling or rescheduling.

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FOOTNOTES

[i] Fully synthetic versions of substances occurring in cannabis (e.g., dronabinol) fall outside the Final Guidance’s scope.

FDA Finalizes FSVP Guidance for Importers of Human and Animal Food

On January 10, the FDA issued a final guidance for the Foreign Supplier Verification Programs (FSVP) for Importers of Food for Humans and Animals. As our readers know, under the Food Safety Modernization Act (FSMA), FSVP requires that importers verify that the food which they import provides the same level of public health protection as the preventive controls or produce safety regulations (as appropriate) in the U.S. and to ensure that supplier’s food is not adulterated and is not misbranded with respect to allergen labeling.

The guidance is intended to assist importers in developing and implementing FSVP records, and following FSVP requirements for each food they import. The guidance includes recommendations on the requirements to analyze the hazards in food; how to evaluate a potential foreign supplier’s performance and the risk posed by the food; ways to determine and conduct appropriate foreign supplier verification activities; and how importers of dietary supplements or very small importers can meet modified FSVP requirements.

The guidance finalizes a 2018 draft guidance, and addresses comments received regarding what food the FSVP regulation applies to, what information must be included in the FSVP, and who must develop and perform the FSVP activities.

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