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FDA publishes draft guidance on prescription drug use-related software
2023 PRINDBRF 0517
• Practitioner Insights Commentaries
• October 6, 2023
(October 6, 2023) - Ropes & Gray attorneys Kellie Combs, Joshua Oyster, Sarah Blankstein and Jessica Band discuss the Food and Drug Administration's new draft guidance on regulating medication sponsors' software relating to prescription drugs or biological drug products.
On September 18, 2023, the U.S. Food and Drug Administration ("FDA") issued a draft guidance for industry entitled Regulatory Considerations for Prescription Drug Use-Related Software1 (the "PDURS Draft Guidance"). The new draft guidance outlines how the Agency intends to regulate the end-user output of prescription drug use-related software ("PDURS") — that is, broadly speaking, software disseminated by or on behalf of a drug sponsor that relates to one or more of the sponsor's prescription drugs or biological drug products.
The PDURS Draft Guidance follows upon FDA's November 2018 proposed framework for PDURS ("Proposed Framework"), which we discussed in a previous Alert.2 FDA's release of the PDURS Draft Guidance fulfills a performance goal from FDA's January 2023 PDUFA VII Commitment Letter associated with the most recent reauthorization of the Prescription Drug User Fee Act ("PDUFA").
While the PDURS Draft Guidance is largely consistent with the Proposed Framework, there are some key differences. Of particular note, under the PDURS Draft Guidance, in some cases the end-user output from PDURS would itself be considered FDA-required labeling subject to FDA's labeling regulations, including potentially the need for FDA approval of a supplemental new drug application or the submission of a CBE-30 supplement prior to implementing changes to the PDURS.
The PDURS Draft Guidance also provides more detailed recommendations on when PDURS should be described in the drug's Prescribing Information ("PI"), as well as revised recommendations to reduce duplicative submissions and reviews by FDA. It does not discuss considerations under FDA's Guidance for Industry: Medical Product Communications That Are Consistent With the FDA-Required Labeling ("CFL Guidance") nor recommend seeking advisory comments for particular types of PDURS, both of which were a significant focus in the Proposed Framework.
This Alert summarizes key principles from the guidance, highlighting some departures from the Proposed Framework, as well as implications for drug sponsors and software developers.
Key principles from the PDURS draft guidance
Scope. The draft guidance applies to PDURS, defined as "software that (1) is 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." The end-user output refers to "any material (content) that the prescription drug use-related software presents to the end user (a patient, caregiver, or health care practitioner)," and may include, for example, screen displays and sounds created by the software, which would be regulated by FDA as prescription drug labeling.
Like the Proposed Framework, the PDURS Draft Guidance advances an overbroad interpretation of the definition of "labeling," citing Kordel v. United States3 for the proposition that software output that "supplements, explains, or is otherwise textually related to one or more of the sponsor's drug products" constitutes labeling subject to FDA's regulatory oversight.
This is an oversimplification of the Kordel analysis of when material qualifies as labeling, which considered, among other things, whether the material constitutes an "essential supplement" to the label on the package and whether the material and drug were part of an "integrated distribution program." While there are a number of problems with FDA's interpretation of Kordel, it is particularly troubling that FDA has asserted authority over output that is "textually related" to the sponsor's drug, something that it did not do explicitly in the Proposed Framework.
By asserting authority over PDURS output that is merely "textually related" to a drug, FDA would bring within its oversight potentially any software distributed by or on behalf of a drug sponsor that merely mentions the name of the sponsor's drug and arguably even software that does not mention the sponsor's product by name but, for example, summarizes its approved indication in some way.
Aside from exceeding FDA's authority and raising significant First Amendment concerns, this interpretation of labeling may ultimately discourage pharmaceutical manufacturers from developing innovative digital health tools that benefit the public and inform the safe and effective use of their products.
General Regulatory Framework. Consistent with the Proposed Framework, the PDURS Draft Guidance asserts that PDURS end-user output is a type of prescription drug labeling regulated by FDA. The guidance distinguishes between end-user output that would be classified as FDA-required labeling, which generally requires approval prior to dissemination, and output that would be characterized as "promotional labeling."
FDA-required labeling includes the labeling reviewed and approved by FDA as part of a drug application. Promotional labeling generally refers to any labeling other than FDA-required labeling and can include printed, audio, or visual matter. Promotional labeling does not require pre-approval but must generally be submitted to FDA no later than the time of initial dissemination of promotional materials under FDA Form 2253.
As described in the PDURS Draft Guidance, FDA will 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.
The factors considered by FDA 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 clinically meaningful benefit when the PDURS is used; and (3) whether the PDURS relies on data directly transferred from the device constituent part of a drug-device combination product.
(1) PDURS provides a function that is essential to safe and effective use of the drug: Under the PDURS Draft Guidance, FDA would treat the end-user output of the PDURS as FDA-required labeling and include information on the PDURS in the PI if the software provides a function essential to the safe and effective use of the drug. Because the end-user output would be FDA-required labeling rather than promotional labeling, it would be submitted to and approved by FDA as part of the NDA or BLA process, rather than being submitted as promotional labeling using Form 2253. Any post-approval changes to the PDURS output could potentially trigger the need for FDA approval of a supplemental new drug application or the submission of a CBE-30 supplement prior to implementing the changes and would, at a minimum, require inclusion in the NDA annual report.
(2) Evidence is provided to support a clinically meaningful benefit when the PDURS is used: As described in the PDURS Draft Guidance, sponsors may propose including information in the PI specifying that use of the PDURS with the product results in a meaningful improvement in a clinical outcome as compared to use of the product without the PDURS. In such a case, where the benefit has been demonstrated by one or more adequate and well-controlled studies, FDA generally intends to recommend that this information be included in the CLINICAL STUDIES section of the PI. FDA would treat the end-user output of the PDURS as FDA-required labeling. Given the potentially burdensome and restrictive implications of a PDURS output being regulated as FDA-required labeling, we expect that many sponsors will choose not to propose including such information in the PI or may reject FDA's recommendation to do so. This is particularly so given sponsors' ability to describe data assessing the benefits of the PDURS software promotionally even if not included in the PI under FDA's CFL Guidance.
(3) PDURS relies on data directly transferred from the device constituent part of a drug-device combination product: These software functions are referred to in the PDURS Draft Guidance as "device-connected software functions." An example of a device-connected software function would be a mobile app that collects data from an oral tablet with an embedded sensor device system ingested by the patient and displays data on tablet ingestion. Under the PDURS Draft Guidance, the PI should typically describe device-connected software functions and the end-user output (e.g., in the HOW SUPPLIED/STORAGE AND HANDLING section). Unless the sponsor provides evidence to support a clinical benefit when the PDURS is used, the end-user output would be considered promotional labeling and should be submitted to FDA on Form 2253 at the time of initial dissemination. Although the PDURS Draft Guidance does not speak to this, because the PDURS would be described in the PI, post-approval changes to the PDURS output could potentially require changes to the approved labeling and therefore trigger the need for FDA approval of a supplemental new drug application or the submission of a CBE-30 supplement prior to implementing the changes.
Beyond these labeling considerations, the PDURS Draft Guidance also provides that, for device-connected PDURS, FDA will assess whether the combination product used with the software can accurately and reliably provide the data, perform analyses, and display the end-user output. Sponsors will be expected to provide information to support how the combination product used with the software will not lead to medication errors.
(1) PDURS does not include device-connected software functions, is not considered essential to safe and effective use of the drug, and evidence is not provided to support a clinical benefit from the PDURS: The PDURS would not be described in the PI, and FDA will treat the end-user output as promotional labeling.
PDURS Regulated by FDA as Medical Devices. Like the Proposed Framework, the PDURS Draft Guidance contemplates that in some cases PDURS may also be regulated by FDA as a medical device. For PDURS that are medical devices requiring a marketing submission to CDRH, FDA states that sponsors would not need to submit the PDURS end-user output on Form 2253.
Instead, any considerations raised during CDRH's premarket review related to representations about the drug within the PDURS would be addressed within CDRH's review, and CDRH would consult with CDER or CBER. However, any subsequent revisions made to end-user output considered promotional labeling that do not require a new CDRH marketing submission would need to be submitted on Form 2253 at the time of initial dissemination.
Software with Multiple Functions. Consistent with FDA's approach in the medical device context, the PDURS Draft Guidance contemplates that software may have multiple functions, some of which are device-connected and some which are not, and some that are medical device software and some that are not. In theory at least, this also means software may have some functions which are PDURS software functions and some which are not.
Unfortunately, the PDURS Draft Guidance does not clearly articulate FDA's approach to software with multiple functions in the PDURS context, and it is unclear whether FDA intends to regulate the end-user output of all functions within software that includes some non-PDURS functions as labeling. In the scenario where some PDURS functions are medical device functions, but some are not, the PDURS Draft Guidance provides that — at least in the case of a change to the non-device PDURS functionality — the end-user output would need to be submitted to FDA on Form 2253.
While the manufacturer should also assess the impact of the new non-device software function on the safety and effectiveness of the device functions, and this analysis might lead to submission of an additional premarket submission for the device function, the new non-device software function would not itself be the subject of CDRH's review.
Implications for drug sponsors
The regulatory framework articulated in the PDURS Draft Guidance will have a significant impact on drug sponsors seeking to develop and use innovative digital health tools as companions to their prescription drugs, particularly if they were not already considering these issues under the Proposed Framework, which was issued for discussion purposes only. FDA's categorization of all PDURS end-user output as labeling adds a new layer of regulatory complexity.
Sponsors will need to assert more stringent oversight over PDURS developers with whom they partner or from whom they license software, as any updates to the end-user output could necessitate a submission to FDA, either on Form 2253 or in accordance with FDA regulations governing FDA-required labeling.
Critically, sponsors will need to analyze software under two separate but overlapping FDA regulatory frameworks, analyzing both whether the software is an FDA-regulated medical device and whether it constitutes PDURS regulated by FDA as prescription drug labeling.
While the PDURS Draft Guidance provides some important clarity on FDA's proposed approach to regulating PDURS output, important questions remain, such as:
•The PDURS Draft Guidance does not clearly address how FDA will regulate software with multiple functions, some of which are PDURS and some of which may not be PDURS, such as software that includes medication tracking functionality but also includes a portal for clinical trial participants to log information for a clinical study.
•The PDURS Draft Guidance does not address disease-awareness functions of software that also includes PDURS software functions, raising the question of whether FDA may assert jurisdiction to regulate a purely disease-focused function as part of the PDURS promotional labeling.
•Although FDA solicited stakeholder feedback on this issue in the Proposed Framework, the PDURS Draft Guidance does not address the appropriate balancing of benefit and risk information when PDURS output includes a benefit claim about the drug.
•Although the PDURS Draft Guidance includes two brief footnotes discussing implications for generic and biosimilar products where the branded product has a PDURS described in the PI, the guidance is minimal, essentially stating that FDA will consider these under its existing regulatory frameworks. FDA also does not address other key considerations related to generic competition, for example, how software regulated by FDA will be subject to regulatory exclusivity.
Comments on the PDURS Draft Guidance are due by December 18, 2023.
Notes
1 https://bit.ly/46AQ7ia
2 https://bit.ly/3ru97Qu
3 355 U.S. 345 (1948).
Kellie Combs is a partner in Ropes & Gray's life sciences regulatory and compliance practice in Washington, D.C. She provides legal and strategic advice to pharmaceutical, biotechnology, medical device, food and cosmetic manufacturers, as well as health care providers and academic institutions, on a broad range of issues. Combs also advises clients on FDA regulatory submissions, regulation of digital health tools, and approval programs, and post-approval compliance. She can be reached at [email protected]. Joshua Oyster, also a D.C.-based partner in the firm's life sciences regulatory and compliance practice, counsels clients on a wide range of FDA regulatory issues to help them bring innovative products to market and ensure regulatory compliance. Oyster advises life sciences and health care companies, as well as private equity firms and investment banks focused on investing in these sectors. He can be reached at [email protected]. Sarah Blankstein is counsel in the firm's life sciences regulatory and compliance practice in Boston. She provides legal and strategic advice to pharmaceutical and medical device companies on a wide array of FDA regulatory matters, with a focus on promotional and post-approval compliance, regulation of digital health tools, product development, and life cycle management. She can be reached at [email protected]. Jessica Band is an associate in the firm's life sciences regulatory and compliance practice in San Francisco. She advises life sciences companies, as well as private equity firms and investment banks, on a wide range of FDA regulatory matters, including product development, life cycle management, promotional compliance, regulation of digital health tools, and post-approval compliance. She can be reached at [email protected]. This article was originally published Sept. 27, 2023, on the firm's website. Republished with permission.
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