On September 19, 2023, the U.S. Food and Drug Administration (“FDA” or “the Agency”) published a draft guidance, Regulatory Considerations for Prescription Drug Use-Related Software (the “Guidance”) which adds a piece to the ever-expanding puzzle that is FDA’s regulatory scheme for digital health products. The Guidance clarifies how FDA plans to apply its drug labeling regulations to software products that “supplement, explain, or otherwise textually relate to” the use of a prescription drug. As most of FDA’s recent regulatory activity with respect to medical software regulation has been in the device space, this Guidance represents a concerted focus by the Agency to unify its approach to digital health across all regulated categories (e.g., drugs, biologics, and devices).
1. Key Terms
In order to keep up with the rapidly evolving digital health landscape, FDA continues to establish new terms, which define specific features of digital health products that are pivotal in determining the need for regulatory oversight. With respect to the regulation of drug-related software products, these terms include the following:
- End-User Output: Any material (content) that the prescription drug use-related software presents to the end user (a patient, caregiver, or health care practitioner). For example, a function that assists patients in tracking their own drug ingestion, allows healthcare practitioners to monitor patients taking a drug, or provides information on how to use a drug.
- Prescription Drug Use-Related Software: Software that (i) is disseminated by or on behalf of a drug sponsor and (ii) produces an End-User Output that supplements, explains, or is otherwise textually related to one or more of the sponsor’s drug products (either a prescription drug or a drug-led, drug-device combination product).
- Software Function: Any distinct purpose of the Prescription Drug Use-Related Software.
- Device-Connected Prescription Drug Use-Related Software Functions (“Device-Connected Software Functions”): Software Functions that rely on data directly transferred from the device constituent part of a sponsor’s combination product. A “combination product” is a product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic), and a “constituent part” is the drug, device, or biological product that is part of a combination product.
2. Application of FDA Drug Labeling Rules
The Guidance clarifies that FDA considers End-User Output a type of prescription drug labeling, meaning that information contained in an End-User Output is subject to FDA’s drug labeling regulations.
A. Two Categories of Drug Labeling
When applying the drug labeling rules in this context, FDA delineates between (1) “FDA-required labeling” and (2) “promotional labeling”. FDA considers FDA-required labeling to be any labeling reviewed and approved by FDA as part of a new drug application (“NDA”), abbreviated new drug application (“ANDA”), biologics license application (“BLA”), or supplemental application. On the other hand, FDA considers “promotional labeling” to be any labeling other than FDA-required labeling (i.e., information that is not strictly required for FDA approval).
FDA intends to analyze several factors to determine whether a specific End-User Output should be treated as FDA-required labeling, as opposed to promotional labeling. These factors are: (1) whether the software provides a function that is essential to the safe and effective use of the product; (2) whether evidence is provided to support a clinical benefit when the software is used; and (3) whether the software relies on data directly transferred from the device constituent part of a combination product. With respect to the third factor, output for software that does not rely on data directly transferred from a device constituent part, including mobile apps, is not, on its own, considered FDA-required labeling, unless one of the other factors is present (e.g., the output relates to a Software Function that is necessary for the safe and effective use of the drug).
B. Drug Labeling Requirements
FDA requires that all labeling, whether FDA-required or promotional, be truthful and non-misleading, convey balanced information about the drug’s efficacy and risks, and reveal material facts about the drug. However, the purpose of FDA’s delineation between FDA-required labeling and promotional labeling is to determine the manner in which the information must be conveyed to both the end user and to FDA itself.
- Presentation to End Users
End-User Outputs that qualify as FDA-required labeling must be included in the drug’s PI in order to allow healthcare practitioners to make informed decisions about the benefits and risks of prescribing the drug. A drug’s PI is intended to reflect FDA’s findings regarding the safety and efficacy of the drug under the labeled conditions of use, including essential scientific information needed to inform safe and effective use; and, thus, it is necessary to include information that qualifies as FDA-required labeling (i.e., evidence showing that the software adds a clinical benefit when used with the drug). On the other hand, End-User Outputs that constitute promotional labeling should not be included in a drug’s PI because the PI should be “informative and accurate, and neither promotional in tone nor false and misleading.”
- Presentation for FDA Review
Depending on a Software Function’s classification as either FDA-required labeling or promotional labeling, FDA will review the End-User Output in one of two ways. If the End-User Output constitutes FDA-required labeling, the drug sponsor must submit the output content for FDA review as part of the drug’s NDA, ANDA, BLA or supplemental application prior to marketing approval. On the other hand, if the End-User Output constitutes promotional labeling, the sponsor must submit the output content for FDA review after marketingapproval, at the time of the output’s initial dissemination, by submitting an FDA Form 2253 (Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human Use).
Additionally, sponsors of combination products will need to determine the appropriate department within FDA to review and/or approve drug use-related software associated with the combination product – the Center for Device and Radiological Health (“CDRH”), the Center for Drug Evaluation and Research (“CDER”), the Center for Biologics Evaluation and Research (“CBER”), or a combination thereof. FDA makes clear that the Guidance is intended to align with, not override, the digital health framework being developed for device-related software by CDRH. Accordingly, if the Software Function of a combination product is subject to premarket review by CDRH (i.e., is a Device-Connected Software Function), CDRH will consult CDER and/or CBER, as necessary, during the review process, and the sponsor is not expected to submit a separate notice to CDER and/or CDER. However, if a Software Function does not qualify as a Device-Connected Software Function (i.e., the function does not rely on data directly transferred from the device constituent part) or if a change to the software affects the clinical benefit and/or risk of using the drug component of a combination product, an FDA Form 2253 should be submitted to CDER. Because of the existence of a rather grey area in terms of department involvement, the Guidance encourages sponsors of combination products to “engage with the appropriate CDER or CBER review division if they are considering developing new or significantly modified device-connected software that requires a new or modified device constituent part or component of a combination product.”
3. Industry Takeaway
As a result of FDA’s recognition that “the use of digital health technologies with prescription drugs has the potential to offer new opportunities for patient care,” the Agency has, for the first time since docketing the issue for public comment in 2018, officially expanded its regulatory scheme for medical software to apply to drug-related Software Functions, as opposed to strictly device-related Software Functions. This expansion represents a significant step in the formation of FDA’s regulatory scheme for digital health products, which is consistently evolving to keep up with the rapid pace of innovation.
As part of the development process for Prescription Drug Use-Related Software products – for example, an app that collects patient data from an orally ingested sensor device taken with a certain drug or an app that allows patients to track symptoms in a standardized manner over time – sponsors should analyze the three factors to determine whether the software output qualifies as “FDA-required labeling” or “promotional labeling.” If the output qualifies as FDA-required labeling, sponsors should take care to include all relevant risk/benefit information, including adequate and well-controlled studies, in the drug’s FDA marketing application or supplement. If the output qualifies as promotional labeling, sponsors should ensure that the information is not presented in a false or misleading manner, and should be prepared to submit an FDA Form 2253 at the time the software capability is disseminated. Appendix A to the Guidance provides concrete examples that can facilitate this determination process.
Additionally, during the development process, sponsors of combination products should identify whether the product is primarily regulated as a drug or a device in order to determine whether End-User Outputs should be submitted to CDRH, CDER, or both, for regulatory review. Appendix B to the Guidance provides concrete examples that may help sponsors find clarity on this relatively hazy issue.
Overall, drug sponsors should be aware that software products offered in tandem with a drug product are subject to FDA’s drug labeling rules, just as any other written or recorded claims about the drug product would be, and should incorporate pre- and post-market review of associated software products into compliance and/or risk mitigation programs for an associated drug.
 The Guidance does not apply to software developers (e.g., companies or individuals) who are unaffiliated with the drug sponsor even if the developer’s intention is for the software to be used with one or more drugs or combination products.
 Section IV of the Guidance provides additional detail, including examples, to clarify how and where on the PI a sponsor should include evidence that a certain End-User Output provides a “meaningful improvement in clinical outcome” as compared to using the drug without the Software Function, as well as the necessary evidentiary standard (i.e., one or more adequate and well-controlled study).
 See id.
 See 83 Fed. Reg. 58574.
 These factors are: (1) whether the software provides a function that is essential to the safe and effective use of the product; (2) whether evidence is provided to support a clinical benefit when the software is used; and (3) whether the software relies on data directly transferred from the device constituent part of a combination product.