Drug delivery
That’s because the different components are typically managed by different regulatory agencies (or, in the FDA’s case, different FDA centres). What’s more, as well as looking at the drug and the device in isolation, regulators need to pay attention to the way the two parts interact. It isn’t always clear how these products should be assessed, nor what standards the manufacturers should be striving to meet. In June 2024, the FDA brought some long-awaited transparency into the discussion, with its draft guidance on Essential Drug Delivery Outputs (EDDOs) for devices intended to deliver drugs and biological products. The guidance, says the FDA, will apply to devices such as syringes, injectors, infusion products, nasal sprays, inhalers, nebulisers, and vaginal systems. It doesn’t address all the information that manufacturers need to consider when applying for regulatory approval. For instance, it doesn’t look at factors like drug-device compatibility, biocompatibility, or (in the case of smart devices) cybersecurity. However, it does cover all the characteristics that allow the device to function as intended. As the FDA phrases it: “EDDOs are the design outputs necessary to ensure delivery of the intended drug dose to the intended delivery site.” That might apply to a wide range of design features – anything that’s involved in preparing the drug and delivering it safely and effectively. For instance, ‘dose accuracy’ would be an EDDO for an autoinjector, whereas ‘packaging integrity’ would not. According to the FDA, other EDDOs for the syringe might include extended needle length, activation force, audible/visual feedback, and cap removal force. Importantly, all these aspects are dependent on the device design itself, rather than being controlled by the user. Under the guidance, manufacturers will be tasked with identifying what their EDDOs are and identifying an appropriate control strategy during the development process. They must also evaluate any changes to their product that are made during clinical development or post-market to make sure the EDDOs aren’t adversely affected.
Challenges and concerns
So, is this the burst of clarity the industry was hoping for? Bonnie Odom and Megan Robertson, attorneys at Epstein Becker & Green, see more work to do before the agency should consider issuing its final guidance. Their firm heads up the Combination Products Coalition (CPC) – a group of drug, device and biologics manufacturers who engage in various advocacy-related efforts to improve the regulatory environment for combination products in the US. They note that, while the industry has been anxiously awaiting guidance on this topic, the draft guidance is not without its areas of confusion. Despite being so foundational to the FDA’s new approach, EDDOs are not an established concept within the industry. As
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
the FDA wrote in the draft guidance: “Prior to this guidance, the term essential performance requirements (EPR) was generally used in communication between FDA and applicants for the EDDOs described herein. FDA is now using the term EDDO as we believe it is more descriptive.” As Odom and Robertson explain, the term EPR first appeared around 2017, when the industry reported receiving requests from FDA reviewers related to EPRs.
“These new requests were challenging to manage as there was no formal guidance from FDA defining the term EPRs or providing details around related expectations,” they say. “This created an ongoing lack of clarity and predictability around the application and interpretation of EPRs during the review process, in some cases, leading to delays. Accordingly, getting formal guidance on EPRs has been a top priority for industry for a number of years.”
Although ‘EPR’ and ‘EDDO’ are intended to mean the same thing, Odom and Robertson suggest the approach outlined in the draft guidance may not allow for the same level of flexibility that industry has had in managing EPRs. While there was never a uniform, industry-wide approach to EPRs – meaning a straightforward comparison isn’t possible – some features of the new guidance may pose headaches where there weren’t any before.
“There seems to be alignment among many in the industry that the draft guidance includes certain recommendations around EDDOs that are new, or more stringent, than what industry would have expected,” they say. For instance, manufacturers might be tasked with providing additional details when submitting clinical applications. And they may have to perform tasks that weren’t previously expected. As an example, the guidance states that design verification of EDDOs ‘generally includes preconditioning’. That’s a way of simulating the kind of stressors the product will be exposed to throughout its life cycle, and it can be a useful way
27
The FDA’s draft
guidance on drug-device combination products introduces EDDOs but raises industry concerns over unclear standards.
Dorota Szymczyk/
www.shutterstock.com
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