Stakeholders concerned with FDA’s definition of labeling in PDURS guidance

Stakeholders want the US Food and Drug Administration (FDA) to narrow its scope of what it considers labeling in a draft guidance for prescription drug-use-related software (PDURS) frameworks, with many commenters wanting the agency to employ a risk-based approach that considers safety and effectiveness, rather than a broader definition of PDURS and end-user output.

The goal of the draft guidance is to better define how FDA views PDURS, which consists of software that comes from a drug sponsor and creates an outcome related to that sponsor’s product. The draft guidance contains the agency’s proposed thinking on how it would treat PDURS software functions and end-user output as required labeling or promotional labeling. It also elaborates on situations concerning the prescribing information where a drug sponsor either does or does not submits evidence that software is tied to a clinically meaningful benefit, and what software information would need to be included in the prescribing information for a drug product as well as specific considerations for how the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH) would review respective end-user output submitted to the respective centers. (RELATED: FDA releases guidance on labeling of drug use-related software outputs, Regulatory Focus 21 September 2023)

When FDA initially proposed a new framework for PDURS, industry comments emphasized the need for cross-center alignment with respect to review standards and regulatory initiatives across CDER, CBER and CDRH, and the agency published the current draft guidance based in part on this feedback. (RELATED: Industry Seeks Cross-Center Alignment in FDA Proposal on Prescription Drug Software, Regulatory Focus 2 April 2019)

Stakeholders continue to support FDA’s efforts for a risk-based regulatory approach in prescription drug-use-related software but have reiterated their desire for better alignment to regulatory initiatives present in agency centers. However, the bulk of concerns mainly centered around what stakeholders say a broad interpretation of labeling by FDA, including what and how it defines terms such as PDURS, intended use, output, labeling and promotional labeling. Several stakeholders called for the definition of PDURS be redefined, and scope of what the agency is considering as labeling of PDURS end-user output be narrowed.

PDURS and labeling

The Academy of Managed Care Pharmacy (AMCP) said they support FDA using drug labeling authority for PDURS, arguing that the oversight will give patients and providers “the necessary information to make an informed decision about the benefits and risks of the prescription drug product will improve safety and effectiveness.”

However, the Biotechnology Innovation Organization (BIO) noted the definition of PDURS as stated by FDA should be clarified, and the agency should “and narrow the scope of PDURS output considered to be labeling.” BIO argued FDA should reconsider its stance on describing all PDURS output not included in FDA-required labeling as promotional labeling, which “appears intended to be coextensive with the definition of ‘labeling,’ because FDA states that both ‘accompany’ a prescription drug. However, BIO said they were concerned this definition of promotional labeling would be an overbroad conception of the term and “could discourage innovation in the digital health space.”

Instead, the agency should take a risk-based approach to software output, they explained. “We believe that only software output that includes safety or effectiveness claims or dosing and administration information for a drug could be regarded as labeling and thus PDURS output,” BIO said. The Combination Products Coalition shared similar comments on the need for redefining the definition of PDURS and narrowing the scope of what is considered labeling for PDURS end-user output.

Commenting on the “expansive definition of end-user output of PDURS,” Eli Lilly & Company said that the draft guidance’s definition “is neither risk-based nor evidence-driven, because it imposes regulatory burdens on sponsors even when the PDURS output is not likely to have a meaningful impact on the safety or efficacy of a drug product.”

In their comment, Teva Pharmaceuticals said it “has practical concerns with the regulatory landscape proposed in the draft guidance,” including regulatory requirements for software products that are “dissimilar or overburdensome,” cross-labeling requirements and challenges with implementation.

The Pharmaceutical Research and Manufacturers of America (PhRMA) concurred with BIO and other stakeholders in their comment, noting that expanding the scope to consider PDURS output as promotional labeling “runs counter to congressional intent, as reflected in the Cures Act, to exempt certain digital health-related medical products from FDA regulation.”

For PDURS functions and output with respect to FDA-required drug labeling, PhRMA said a more flexible standard is needed than the one proposed by the agency. “PhRMA is concerned about the unnecessarily high bar FDA has proposed for inclusion of PDURS in FDA-required labeling,” they said. “We encourage FDA to adopt a more flexible approach that enables sponsors to more openly reference software in drug labeling, to ensure that prescribers can access accurate, reliable, and timely information on digital health innovations.”

In a lengthy comment drafted by the Medical Information Working Group, medical product manufacturers expressed their concern that not only is the agency’s definition of labeling in the draft guidance overly broad, it contradicts existing FDA regulations for labeling and “raises significant issues under the First Amendment.”

“In particular, we are concerned that such a broad definition of labeling to include anything merely ‘textually related’ to a drug could be interpreted to mean that any written, printed, or graphic matter that mentions or effectively identifies a specific product, even if it includes non-promotional content, is labeling,” the Medical Information Working Group wrote. “Similarly, a policy by which FDA would consider non-PDURS functions of multi-function software products to be promotional labeling would also implicate First Amendment concerns and chill manufacturer communications to the detriment of patient health.

More guidance on appropriate data, consider emerging technology

AMCP also noted in their comment that the agency should consider standardized guidance on what data is acceptable for FDA-required labeling of end-user output, and potentially include alternative approaches to adequate and well-controlled studies such as the use of real-world evidence. “Considering a broad range of data that supports inclusion of prescription drug use-related software information in FDA-approved labeling would encourage greater innovation in digital applications,” they said.

Responding to a line in the draft guidance’s definition of PDURS software output, BIO requested FDA clarify what constitutes a “dissemination” of software by a drug sponsor, since software built by third parties can sometimes, but not always, include information on a drug product, and a drug sponsor may regularly interact with that third party to ensure the software output contains the correct information.

BIO also expressed concern that there is a lack of acknowledgement for emerging technologies like chatbots within the draft guidance. “These software platforms are commonly used by the general public to receive information on a variety of topics and are not created on behalf of an individual sponsor, nor are they created in collaboration with a sponsor,” they explained.

Patients could potentially receive information from chatbots that is out of date or unintentionally creates misinformation through poorly worded summaries despite not falling within the definition of being “disseminated by or on behalf of a drug sponsor,” BIO noted. “We recommend that FDA consider issuing guidance on chatbot and other artificial intelligence services unaffiliated with sponsors, prior to finalizing the Prescription Drug Use-Related Software guidance,” they said.

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Stakeholders concerned with FDA’s definition of labeling in PDURS guidance

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