Stakeholders warn of potential burdens in FDA’s drug delivery guidance

Industry stakeholders have asked the US Food and Drug Administration (FDA) to revise a new draft guidance on essential drug delivery outputs (EDDOs) to clarify key terminology and avoid costly and burdensome new regulatory requirements. Some also asked FDA to change the title of the guidance to better reflect all of the products that fall under it.

The draft guidance was released in June, with public comments open through September 30. FDA defines EDDOs as “the device drug-delivery design outputs necessary to ensure the drug delivery function.” These include syringes, injectors, infusion products, nasal sprays, inhalers, nebulizers, and vaginal delivery systems. (RELATED: FDA drafts guidance on essential outputs for drug delivery devices, Regulatory Focus 1 July 2024)

The guidance directs sponsors to submit information about EDDOs in investigational product and marketing applications for combination products that rely on a delivery device, and outlines processes that should be followed. “Drug delivery includes successful product preparation and the initiation, progression, and completion of dose delivery,” the guidance document explained.

In comments to FDA, stakeholder groups requested a change to the title of the guidance document and clarification of terminology definitions. The Advanced Medical Technology Association (AdvaMed) recommended changing the title to Application of Essential Drug Delivery Design Outputs for Combination Products and Medical Devices. The group said the change would clarify that the guidance applies to all medical devices and device constituents or potential future therapies, such as cell and gene treatments.

The International Society for Pharmaceuticals and Engineering (ISPE) asked for a similar change, noting that the title should “reflect the various product types and therapies.”.

Several stakeholders requested that FDA clarify whether the guidance also applies to submissions of standalone products used for drug delivery. Regeneron proposed the text be revised to clarify that it applies to EDDOs for medical devices reviewed by the Center for Devices and Radiological Health (CDRH) and the device parts of drug and biologic combination products submitted to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

Confusing new terms

FDA notes that the use of the term EDDO linked to the design outputs of a device is new and will take some getting used to for the industry.

“Prior to this guidance, the term essential performance requirements (EPR) was generally used in communication between FDA and applicants for the EDDOs described herein,” the agency explained in the draft guidance. “FDA is now using the term EDDO as we believe it is more descriptive.”

The ISPE wrote that more information is needed on how EDDOs differ from design input requirements. Similarly, the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) commented that some of the examples of design outputs are traditionally considered to be design input requirements.

“Overall, the guidance does not provide enough definition of terminologies,” IPAC-RS wrote. “The terminology surrounding Design Inputs, EDDOs, Essential Performance Requirements, and Primary Functions should be clearly defined to ensure there are no discrepancies in application, and to provide clarity versus existing FDA requirements and definitions.”
The Combination Products Coalition (CPC) noted that EPR requests have not traditionally been accompanied by formal FDA guidance, which has led to companies addressing them differently.

“For example, while some companies reference EPRs as outputs within their quality management systems (“QMS”), other companies reference EPRs as inputs,” CPC wrote. “There are also some companies that have not specifically labeled EPRs as inputs or outputs within their QMS, instead referring to them as regulatory requirements that factor into design controls.”

The new approach could force major changes to existing design control and QMS processes, CPC warned.

Concerns about new burdens

Concerns about new burdens on industry sponsors was a theme in stakeholders’ comments about the EDDO draft guidance.

“As it is currently written, the draft Guidance has the potential to significantly increase the level of evidence required for clinical and marketing applications for drug delivery products, including requests for copies of device development artifacts,” the IPAC-RS wrote.

The Association for Accessible Medicines (AAM) said it is “particularly concerned” with the requirement for sequential preconditioning testing for emergency-use injectors as a patient safety precaution.

“Sequential preconditioning is burdensome, time-consuming and expensive,” AAM wrote. “For example, performing mechanical stress testing or normal shipping before a batch can be placed on stability is costly and can delay the availability of stability data and consequently the availability of a product to patients,” AAM wrote.

“We urge FDA to revise the draft guidance to clarify that sequential preconditioning generally will not be required and to precisely (and narrowly) identify in which exceptional cases the agency expects sequential preconditioning,” AAM added.

The Pharmaceutical Research and Manufacturers of America (PhRMA) asked FDA to clarify the preconditioning recommendations for verification testing to specify they only apply to EDDOs and ensure they are in sync with international standards.

“Sponsors would typically apply and follow applicable standards such as ISO 10993-1 for biocompatibility testing, and PhRMA requests that the Agency confirm that FDA is not imposing any new, additional requirements in those areas that may not even be required under, or aligned with, existing standards,” PhRMA wrote.

CPC also advised that after the FDA reviews written comments on the draft guidance, it should host or participate in public forums to clarify the proposed requirements. Echoing other stakeholders, CPC also suggested the agency provide an implementation period of one year or more after final guidance is issued to allow time for the industry to transition.

Stakeholders warn of potential burdens in FDA’s drug delivery guidance

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