OCP chief reassures stakeholders on EDDO guidance

PROVIDENCE, RI – The head of the US Food and Drug Administration’s (FDA) Office of Combination Products (OCP) said the agency has heard industry's concerns about its draft guidance on essential drug delivery outputs (EDDOs). While there is no deadline to issue a final version, he said the agency is taking the feedback to heart as they work on the final guidance.

During a fireside chat with FDA officials at the AFDO/RAPS Healthcare Products Collaborative Combination Products Summit, Ryan McGowan, senior director for devices and digital therapeutics at AstraZeneca and a co-moderator, asked regulators about its EDDO draft guidance, which has been a big concern for the industry. (RELATED: Stakeholders warn of potential burdens in FDA’s drug delivery guidance, Regulatory News, 4 October 2024)

"It's industry's understanding that there are several key topics in the EDDO draft guidance that FDA is revisiting and that the guidance generally should not be considered applicable until FDA completes its revisions to the guidance, addressing comments received from industry," said McGowan. "However, FDA boilerplate device-related feedback as part of type C meetings currently references the draft EDDO guidance document.

"Could the FDA clarify the status of the provisions of the guidance and how industry should be thinking about the applicability of the current EDDO draft guidance?" he asked.

OCP Deputy Director Patricia Love noted that, although the guidance was in draft form, it was being referenced during certain investigational new drug (IND) reviews where the review team believed it might be useful. She also noted that certain parts of the guidance remain relevant to the review process while the agency works on revising it.

"If there's a question about whether something should or should not be considered for a particular product, I would recommend submitting a request to the IND review division to get information and guidance on what, on a product-specific basis, is important," she added.

Jason Lipman, senior director for global regulatory affairs for devices and combination products at Sanofi, and another co-moderator, inquired about when FDA plans to share the updated EDDO guidance and what timeline it is working with to finalize it. In response, OCP Director James Bertram assured attendees that the agency has heard their concerns about the guidance and is actively working on addressing those concerns.

"There isn't a date that's driving our effort," said Bertram. "We appreciate this opportunity [for feedback]. We're working through our processes, and we want to make sure we do a thorough job. It's an evolving dynamic review."

Asking more broadly about EDDOs, Lipman asked what FDA's sample size expectations are in drug-led combination products and the application of statistical methods when testing device parameters. He also presented a situation where an upstream control strategy for an EDDO exists, but an additional confirmatory batch release test is used for the final assembled product. He asked what the agency's expectations for choosing between qualitative and quantitative specifications and test methods were.

Responding to the first question, Ashley Boam, director of the Office of Policy for Pharmaceutical Quality at the Center for Drug Evaluation and Research (CDER), stated that the agency wants a statistically justified rationale, specifically a significant sample size for the testing being performed, based on the risk associated with the device. On the second issue, she said it would depend on the EDDO and the specifications.

Control strategies

Lipman asked how a sponsor should present a control strategy in a marketing application. More specifically, he asked where in the electronic Common Technical Document (eCTD) the sponsor should present the strategy, what FDA considers an appropriate rationale, and what level of information do they want to see.

Love noted that the eCTD technical guidance details what information goes in which sections, and for unclear issues, sponsors are instructed to submit it in similar sections that they would use for a drug application.

"So wherever you might have placed control strategy data for the drug constituent part you create another section in that same area for the device constituent," said Love.

Shruti Mistry, an assistant director at the Center for Devices and Radiological Health (CDRH), said the rationale depends on the control strategy and what is being proposed.

"If there are component-level controls, it would be helpful for justification on why this doesn't need to be controlled at the final finish stage, or why the final finished combination product is not needed to control that," she added.

More broadly, McGowan asked FDA to elaborate on its expectations regarding the types of rationales or data needed in a pre-IND meeting to get feedback and commitment on an upstream control strategy. Kathryn Drzewiecki, digital health policy team lead at CDRH, said that it will depend on what the sponsor is looking for.

"The amount of information that we need is going to be tied to how specific the question is that you are asking," said Drzewiecki. "If you're asking us generally, what kind of information would be needed to support an upstream control strategy for particular parameter... Then walk us through what you're proposing and, generally, why you think you could support that approach.

"If you're looking for higher-level information, you don't need to provide as much," she added. "If your device design is closer to lockdown, if you're looking for more general guidance, that can be earlier or where you might still be working through the device development process."

McGowan brought up FDA's Form 356H, which is used to apply for marketing a new or abbreviated new drug or biologic. He asked what device constituents and components should be listed in the form.

Margaret Kober, chief of project management staff in the Office of Regulatory Operations at CDER, told attendees that Form 356H doesn't require sponsors to list device components. However, she also noted they must identify their product as a combination product under field 24, based on the type of product they believe it is. Furthermore, she reminded sponsors that they need to list all the drug, device, and biologic component establishments in field 28.

"When you're looking at the device establishments, think about everything, the testing, kitting, packaging, all the different types of activities, and also you can list your master file sites if you are relying on a master file," added Love. "There's a guidance on information for manufacturing establishments that might also help sort through those details."

Lipman praised OCP for prioritizing its device changes in post-approval submissions guidance but noted that there were instances where products were being converted from changes being effected in 30 days supplement (CBE-30) status to prior approval supplement (PAS). He asked FDA if they had analyzed the occurrences to help it mitigate the conversion risks as it updates its guidance.

Bertram said the agency wants to mitigate the risks for such conversions and provide more clarity based on experience. "We would be looking to use the experiences we have and make sure we're getting the contemporary view," he said.

McGowan asked whether FDA is open to alternatives to requiring five samples of human factor protocols in submissions and marketing applications, especially for non-unique devices such as needle safety syringes or devices where samples have already been provided. He noted that the requirement may be logistically challenging in certain instances to implement, especially when other useful options, such as videos, are available.

Love noted that CDER has a guidance on the contents of a complete submission, which states that if providing the number of samples is infeasible, the agency may accept alternatives; however, sponsors should reach out to regulators to discuss the issue. She noted that the waivers were product-specific and regulators would individually look at the issues in question.

Lipman said there have been situations where FDA has asked for a response to a request for information (RFI) with "no apparent reason for urgency." Even if granted an extension, he noted such requests can be unduly burdensome and impact the quality of the responses. He asked if there are ways that industry can advocate for more reasonable timelines for RFIs.

Kober noted that while it may seem like there is no apparent reason for urgency in some instances, there are situations when it is critical FDA receives a response to complete a review within a specific timeframe. She gave examples of when that may happen and noted that the best way to avoid such situations is to provide as much of a complete application as possible.

"There are going to be situations where we need the information, and there's a reason we need the information, even though you can't see it in the background," said Kober. "Also, there are internal timeframes that folks have to meet."

Love echoed the sentiments, saying that reviewers may be working on multiple products simultaneously, which affects their workflow.

"While we understand that it may not be apparent why there is an urgency, sometimes it just does relate to everything else that's going on surrounding your particular product," she added. "But as was mentioned, you can ask for an extension.”

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OCP chief reassures stakeholders on EDDO guidance

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