The new FDA guidance document (released September 2023) titled Regulatory Considerations for Prescription Drug Use Related Software describes how the FDA intends to apply its drug labeling authorities to software outputs that are disseminated by or on behalf of a drug sponsor for use with a prescription drug or a prescription drug-led, drug-device combination product.

This guidance is relevant for pharmaceutical companies interested in producing digital applications to support their products and patients, as it gives an insight into how the FDA is thinking about specific use cases within digital therapeutics.

In this article we give a high level summary of the key points from the guidance, including definitions, the key questions addressed, the implications for labeling and a practical example.

What is prescription drug use-related software?

Prescription drug use-related software (PDURS) is software that is:

1. Disseminated by or on behalf of a drug sponsor; and 

2. Produces an end-user output that supplements, explains, or is otherwise textually related to one or more of the sponsor’s drug products. 

A “software function”, as described in the guidance, is any distinct purpose of the software, and “end-user output” is any material or content that the PDUR software presents to the end user - normally a patient, caregiver, or health care practitioner.

The FDA considers end-user output a type of prescription drug labeling, and therefore some labeling regulations apply.

What is prescription drug labeling?

Prescription drug labeling includes a variety of communications by sponsors about their drugs, but the FDA generally recognizes two categories of prescription drug labeling:

1. FDA-required labeling - this includes the labeling reviewed and approved by FDA as part of a new drug application, an abbreviated new drug application, or a biologics license application, as well as supplemental applications.

2. Promotional labeling - any other labeling that is not FDA-required labeling. Promotional labeling can include printed, audio, or visual matter descriptive of a drug that is disseminated by or on behalf of a drug’s manufacturer, packer, or distributor.

The 3 key things addressed in the PDURS FDA guidance

1. How the FDA intends to apply its drug labeling authorities to end-user output of PDURS

2. How the FDA-required labeling, in particular the Prescribing Information (PI), should describe PDURS that:

– Is determined to be essential for the safe and effective use of the drug product; or
– Relies on data directly transferred from the device constituent part of a combination product

3. When and how sponsors should submit end-user output to the FDA

How the FDA intends to apply its drug labeling authorities to end-user output of PDURS

Any material or content presented to a patient, caregiver, or health care practitioner is end-user output and constitutes drug labeling. The FDA intends to analyze several factors to determine whether the end-user output should be treated as FDA-required labeling or promotional labeling and how, or if, the corresponding software function should be described in the PI. 

These factors include:

1. Whether the PDURS 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 PDURS is used; and

3. Whether the PDURS relies on data directly transferred from the device constituent part of a combination product

How to describe PDURS functions and end-user output in the PI

The FDA splits software functions into device-connect functions and non device-connected functions. Those functions that rely on user-inputted data would not be considered device-connected software functions. 

Software functions not considered to be device-connected (an example given is an app with a patient diary where patients record taking their medication and severity of symptoms) should not be described in the PI unless there is an additional factor (e.g., the function is necessary for safe and effective use of the drug) that warrants including this information in the PI.

If a sponsor provided evidence from adequate and well-controlled studies that demonstrate that use of the PDURS results in a meaningful improvement in a clinical outcome (e.g., compared to drug use without the PDURS), it might be appropriate to include such information in the Clinical Studies section of the PI.

How the clinical claims associated with end-user output impact labeling

When the drug sponsor submits evidence demonstrating that the use of PDURS leads to a clinically meaningful benefit (in terms of efficacy or safety outcomes) it is considered to be FDA-required labeling, and post-approval changes to such output (e.g., end-user output from a mobile app) should be reviewed and approved by the FDA.

When the drug sponsor does not submit evidence of a clinically meaningful benefit associated with the use of the PDURS, the end-user output from PDURS with no device-connected software functions generally would be considered promotional labeling and would not be described in the PI, unless the PDURS is considered essential to the safe and effective use of a product.

Additional considerations relating to the review of end-user output

End-user output and updates to end-user output from PDURS that constitutes promotional labeling must be submitted to the FDA by the applicant at the time of initial dissemination using Form FDA 2253 (Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human Use). Software updates that do not alter the end-user output, such as security patches, would not need to be submitted using Form FDA 2253.

A practical example from the guidance

B is a mobile app intended to prompt patients to answer specific questions pertaining to their use of a prescription drug and provides a web-application for health care practitioners to review the patient’s self-reported data stored on a cloud-based application. More specifically, the B mobile app facilitates a patient’s ability to document in a standardized manner the incidence or severity of symptoms of their condition over time while taking their prescription drug and then transfers the self-reported information to a cloud-based application for their health care practitioner to review on a web-application.

B can be characterized using the following terminology:

Software functions: The four distinct software functions include (1) the capture of self reported patient entry of information into the mobile app, (2) the display of symptom incidence and severity data via the mobile app display screen, (3) the transfer of self reported data to a cloud-based application, and (4) the display of data on the health care practitioner web-application.

All four software functions are not considered device-connected software functions because they do not rely on data directly transferred from the device constituent part of a sponsor’s combination product.

End-user output: The two end-user outputs are the mobile app’s display of symptom incidence and severity and the web-application’s display of self-reported information.

Conclusion

The new FDA draft guidance on the regulatory considerations for PDURS is a great step forward for the pharmaceutical industry and its technology development partners to understand how the FDA views companion digital health solutions paired with drugs.

As this guidance is draft and intended for comment, we'll be keeping an eye out for any updates and to see what the final guidance looks like once it's published.

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