The FDA just announced plans to release a draft guidance on prescription drug-use-related software later this year. What should the pharma industry expect?
The past three years have seen a significant increase in the acceptance and adoption of digital health tools. Much of the focus over this time has been on virtual care using telemedicine and remote monitoring, but individuals are increasingly managing their own health, with a recent Morning Consult survey reporting that 40% of adults now use mobile health apps and 35% use wearables.
A wave of innovation is coming from pharmaceutical companies who plan to take advantage of this momentum by seeking to improve the therapy experience with digital companion apps that accompany their drugs. These tools are intended to enable pharma companies to engage with and support patients, improve adherence, monitor treatment progress, collect real-world data, encourage lifestyle change, and potentially improve treatment outcomes.
Numerous companion apps are under development, and many are already on the market. Examples include software to track and manage chemotherapy symptoms, a coaching and educational support tool for multiple sclerosis patients, and a dosing calculator with medication reminders and injection training for patients with psoriatic arthritis.
Most companion apps are unregulated mobile medical applications that are not marketed with a specific drug and can be downloaded for free on the app store. However, there is a growing trend towards companion apps that are branded with a specific drug, as well as companion apps that may have a direct or indirect additive therapeutic effect to a drug, and even some that are expected to generate standalone revenue on their own due to their additive value. Some of these products will act more like digital therapeutics than mobile health apps.
A Growing Framework Around Companion Apps
A framework is already established for the regulation of mobile medical applications, as well as related products such as clinical decision support tools. There is increasing experience with regulated apps, such as digital therapeutics, digital diagnostic and prognostic aids, and active monitoring solutions. However, there is still considerable uncertainty at the intersection of software and drugs.
Fortunately, the FDA has been working on this. The Agency was way ahead of the game when they posted a proposed framework for regulation of Prescription Drug-Use-Related Software (PDURS) to the Federal Register way back in 2018. The goal at the time was “to promote the development of digital technologies that can…help guide the safe and effective use of medicines, to help patients improve their health” and “to modernize our approach to overseeing software products that are designed to be used in conjunction with prescription drugs.”
Public comments were received in 2019 from a variety of stakeholders including industry groups PhRMA and BIO; pharma companies Otsuka, Teva, Takeda, and Novartis; digital health companies Proteus and Omada; and others such as the American Pharmacists Association. FDA mostly went silent on this topic for the next several years.
PDURS was referenced again in the Agency’s January 2023 PDUFA VII Commitment Letter, following reauthorization of the Prescription Drug User Fee Act (PDUFA), which authorizes FDA to collect user fees from drug manufacturers. The Commitment Letter includes many performance goals, including a relatively obscure one buried at the end of the plan that proposes to release draft guidance on PDURS:
“By the end of FY 2023, FDA will publish draft, revised or final guidance on regulatory considerations for Prescription Drug Use-Related Software that includes information about software that is disseminated by a drug applicant for use with a prescription drug or biologic product that may be described in labeling, including prescribing information. This guidance will cover software that is distributed with a drug or integrated as part of a drug- or biologic-led combination product, as well as software that is distributed by an applicant independent of an approved product.”
Based on this, we should expect draft guidance on PDURS to be released this summer, almost five years after posting of the original framework. The release of the draft guidance will be followed by another public comment period, and the final guidance will subsequently be issued.
How Does FDA Propose to Regulate Branded Companion Apps?
Under the proposed framework, FDA anticipates that most PDURS apps will not require regulatory approval and only the output of these apps will need to be reviewed as promotional drug labeling. It does not alter and is independent from the regulatory framework for medical device software.
The framework defines PDURS as “software disseminated by or on behalf of a drug sponsor that accompanies one or more of the sponsor’s prescription drugs.” The scope therefore would include branded companion apps that are released by a pharma company itself or released by a third-party software developer on behalf of the pharma company. As currently written, the PDURS framework would not apply to third-party software developers who independently release software for use with specific prescription drugs or classes of prescription drugs. The framework would also apply to software other than companion apps for use with prescription drugs, and software for use with drug-device combination products (e.g., autoinjectors and digital pills), but the focus of this article is on companion apps.
Notably, the proposed framework only considers the output of software rather than the software itself. The software itself may be unregulated, such as non-device clinical decision support (CDS) software or non-device Medical Device Data Systems (MDDS), categorized as general wellness, or fall under enforcement discretion, as per existing FDA guidance. The software itself could also be regulated as software as a medical device (SaMD), with intended uses similar to digital therapeutics, digital diagnostic aids, decision support tools, or patient monitoring software. The PDURS framework for the software output is therefore independent of the regulatory pathway that the software would follow.
Under the proposed 2018 framework, the software output from PDURS would be regulated as drug labeling. The framework essentially describes three categories that are relevant to companion apps:
1. Unbranded Apps: Software output that does not accompany a specific drug would not be considered PDURS and would not have any drug labeling requirements. Unbranded companion apps would generally fall within this category. There are many examples of these kinds of products, such as disease self-management apps that help patients who are on certain types of medications and regulated apps with basal calculators to support patients with insulin dosing that are manufactured by third-party software developers.
2. Branded Promotional Apps: Companion apps would be considered PDURS if they are branded with a prescription drug or if they are disseminated by or on behalf of a drug sponsor of a prescription drug. PDURS that does not have an additive clinical effect or potential for harm would be considered promotional labeling.The sponsor would simply need to submit screenshots and other representations of what the user would experience as promotional drug labeling FDA form 2253 to FDA’s Office of Prescription Drug Promotion (OPDP) prior to dissemination along copies of the required drug labeling. In this scenario, the review of the software is risk based and is generally minimal. No approval is required prior to dissemination.
Several potential examples are provided in the proposed framework, such as apps with symptom tracking, medication reminders, dose calculators, and information that is conveyed to the patient from the drug labeling, as well as provider-facing software outputs related to dosing support that follows the drug labeling. None of these functions are purely promotional in nature but would still be reviewed as promotional labeling.
3. Branded Apps with Additive Clinical Effect or Potential for Harm: When a PDURS app has an additive clinical effect or potential for harm, the sponsor must submit the software output as FDA-required labeling. This also pertains to when the software provides a function or information that is essential to the intended uses of a drug-led or drug-device combination. In these scenarios, the software output must be 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. This would likely add considerable rigor, including submission of clinical evidence of the additive clinical effect.
Several potential examples are provided, such as branded apps that allow patients to record and track use of the drug and share it with their provider, apps that allow the provider to suggest dosing changes based on active or passive patient inputs, software with integrated patient display of patient inputs, and provider-facing risk calculators based on patient inputs. These products may or may not meet the definition of a medical device. The app used to communicate with the ingestible Abilify MyCite digital pill is another example provided that would be considered FDA-required labeling.
Interestingly, the proposed framework positions the categorization of PDURS as a choice by the sponsor. PDURS would be considered FDA-required labeling when: “a sponsor demonstrates through substantial evidence (from one or more adequate and well-controlled investigations, as necessary) that the use of software with a drug results in a clinically meaningful improvement compared to using the drug alone, and the sponsor chooses to submit such evidence as part of a drug application, information about the prescription drug-use-related software output would be included in FDA-required labeling (e.g., prescribing information, medication guide, or instructions for use). In this scenario, evidence might consist of a demonstration of improvement in a clinical outcome or a validated surrogate endpoint that predicts a chance in a clinical outcome.”
However, there are also scenarios where it would not be a choice – such as when the software “increases the potential for harm to health relative to the information reflected in the FDA-required labeling,” even when the software is not a medical device. If there is potential for harm, FDA suggests that sponsors seek a pre-dissemination review to determine if the software would be considered promotional or FDA-required labeling.
FDA has quietly already begun to implement some of the above steps. Sponsors can currently submit screenshots to OPDP of branded companion apps as promotional labeling. A pre-dissemination review of branded companion apps can also be obtained by submitting materials to OPDP for voluntary advisory comments.
What Should Pharma Expect from the Coming 2023 Draft Guidance?
There are many aspects of the proposed PDURS framework that are ambiguous, and many of these aspects were identified in the 2019 public comments. Pharma has also advanced considerably with digital health since 2019, with many new companion apps on the market and some being developed that will likely be considered FDA-required labeling or even drug-software combinations. Another important point is that FDA announced the demise of the Digital Health Pre-Certification program in 2022, and this had previously been assumed to be integral to FDA’s view on PDURS. The Agency’s interpretation of Clinical Decision Support software has also changed considerably, and as a result many of the examples provided in the 2018 framework may now be considered to have higher risk.
Overall, the updated framework in the coming draft guidance will likely maintain a similar structure as the 2018 framework, with separate categories for software with no drug labeling requirements, software with promotional labeling requirements, and software with FDA-required labeling requirements. However, there are many changes and additions that are expected:
- Further clarity around what software outputs would be considered promotional. Would all branded patient-facing software need to be submitted, including all aspects on all platforms and even minor updates to software outputs?
- The term dissemination should be clearly defined in the context of PDURS. Software branded with the name of a prescription drug would obviously be considered PDURS, but it is not clear if implying use with a specific drug or simply mentioning a drug name would trigger labeling requirements.
- Currently, it appears to be the sponsor’s choice as to whether PDURS with clinical evidence of an additive effect would require promotional or FDA-required labeling. This conflicts with subsequent statements, which suggest that pre-dissemination review is required if there is potential for harm. Logically, most scenarios with evidence of an additive effect would have at least some potential for harm.
- Certain digital products would have an indirect additive clinical effect (such as adherence apps) whereas others would have a direct additive effect (such as digital therapeutics). The Draft Guidance should add examples of these scenarios when considering performance requirements for FDA-required labeling.
- The type of drug application needed for FDA-required labeling should be clarified depending on the scenario (risk, existing marketed drug, new drug, etc.). Further, FDA should clarify how this application would be different than a hypothetical drug-device combination product, where the device is software-only.
- FDA should clarify what information and what clinical benefit information from the software output would be included on the FDA-required labeling, and what kinds of claims would be allowed.
- Clinical performance requirements for the software output of FDA-required labeling should be clarified. The current framework suggests that all such software would need to be clinically validated in a randomized control trial, which would be burdensome and commercially risky for the drug, especially for lower-risk software such as those with indirect additive clinical effects.
- FDA proposes a risk-based approach to regulation of PDURS, but in its current embodiment, the framework has a binary risk categorization – either promotional or FDA-required labeling. Additional levels of risk, perhaps based on the IMDRF risk categorization framework, could be helpful, particularly when considering clinical performance requirements for FDA-required labeling.
We should expect draft guidance on PDURS to be released this summer or early fall. The release of the draft guidance will be followed by a 60-day public comment period, and the final guidance will subsequently be issued. In the meantime, sponsors are encouraged to engage with OPDP when considering drug labeling for a companion app, and with FDA’s Center for Devices and Radiological Health (CDRH) on regulatory pathway considerations of the software itself.
Marty is an innovator at the cross-section of product development and regulatory affairs in the medical device and digital medicine sectors. In recent years, he led the effort to obtain the first ever breakthrough…
Kory is a Regulatory Affairs Associate Director with extensive experience in Software as a Medical Device and Software Development Life Cycle. Kory has 20+ years of experience in business and technology operations and 9…