Combination products: FDA experts address UDI, harmonization, OPQ reorganization

Fort Worth, TX — Officials from the US Food and Drug Administration (FDA) fielded wide-ranging questions on the development and marketing of combination products — from UDI requirements to harmonization of product classifications — at the 2023 Combination Products Summit held by the AFDO/RAPS Healthcare Products Collaborative.

The following is an excerpt from the “fireside chat” moderated by Susan Neadle, principal consultant and president of Combination Products Consulting, and several FDA experts from the Office of Combination Products (OCP), the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER). The discussion has been edited for length and clarity.

UDI requirements

Neadle: Can you comment on the unique device identifier (UDI) requirements for combination products? Specifically, what parts of a co-packaged product need to be serialized? Is it the drug and the device?

Andrew Yeatts (combination product policy analyst, CDRH): In a co-packaged device, the device constituent would be subject to the UDI requirements. How you meet those requirements depends on the center that leads it. If it’s a device-led combination product, then the UDI is placed on the outer package. If it’s a drug-led combination product and subject to the Standardized Numerical Identification or the serialized National Drug Code (sNDC), you would follow those requirements on how to package. You then could either place the new UDI on the outer combination product package, or the device constituent part. We generally recommend placing it on the device constituent part so there’s not multiple identifiers on the outer package.

Neadle: Do you need a separate UDI for the device part of a co-packaged product when the device part is also marketed separately?

Yeatts: That goes to whether you become the labeler of the device constituent. If you are kitting it and don’t become the labeler, you can keep the same UDI from the device. If you’re changing that label, you become the labeler under the regulations, and then use your own UDI for that device.

Harmonization

Neadle: What efforts is FDA engaging in to align and harmonize product classifications across countries and regulators? As an example, the challenges when the product is regulated as a drug in the US, a device in Canada and a cosmetic or personal care item in Latin America.

John “Barr” Weiner (associate director for policy, OCP): We’re trying to work on alignment in broader terms about approaches to regulation. But in terms of how to classify in the first place, there are definitely hard differences of opinion. There are definitely situations where companies come into the Office of Combination Products for a Request for Designation (RFD) or a pre-RFD, and say “Hey, we’re a device in Europe so we should be a device in the USA.” And it doesn’t work that way. We have to complete our analysis. But I think it’s a fair point; we can try to get more alignment on some of these issues.

Neadle: We have an effort through the ASTM New Practice for Current Good Manufacturing Practices for Combined Use Systems [medicinal product-device] working group. This does have international regulators participating in it, along with industry. The idea is that even though they have different classifications in these different jurisdictions, from a scientific and technological perspective, there should be some considerations that are consistent across jurisdictions.

510(k) data

Neadle: Is clinical data necessary for 510(k) devices?

Kristina Lauritsen (combination product regulatory advisor at CDER): We ask for verification and validation information [to support] whatever the claims are for the intended use, and the design of a product. So clinical data is not needed for that. We just wouldn’t ask for it; that would be burdensome and unnecessary. If the data that we can collect from bench testing or other information covers all of the claims that you’re making and how the product is designed, then we would not ask for clinical data.

Early development considerations

Neadle: The guidance document, “Early Development Considerations for Innovative Combination Products” [2006] has a lot of variables. What is the expectation of the FDA? Is this something that we need to add to the existing design control elements?

James Bertram (director, OCP): I don’t think we would see that guidance as a requirement. It speaks to early considerations and arguably there’s a lot of more contemporary guidances on OCP’s website that would better speak to how to best frame and prepare your submission. I would use those more contemporary guidance documents to help inform you on how best to engage early, particularly if you have a novel product. And as I think you probably know, early engagement with us is beneficial.

Cell and gene therapies

Neadle: How is the FDA interpreting the use of general purpose use devices such as cannulas or infusion pumps in emerging cell or gene therapies, when they were likely not evaluated with cell or gene therapy specifically? Is this within a general use indication or is it considered a new indication?

Bertram: I’m going to speak in generalities here. A general use indication for these items is broad, for delivery of therapeutics, fluids, etc. I don’t think we would necessarily say that this is inconsistent with that label. I can guarantee you that [the Center for Biologics Evaluation and Research (CBER)], likely with CDRH at the table, will ask for information ensuring the compatibility between the biologic and the device. If for some reason there are risks, it could be decided that the device needs to have that particular biologic on its label and vice versa. I would highly recommend early questions on that in your engagement with CBER. But I would not find that inconsistent with the label. I don’t want to speak for CDRH, but I would warn you that if you do come in looking to update that label for general use to include specific delivery of cell or gene therapies, I think there would be a serious question whether 510(k) is appropriate for that, and that would present different questions for safety and effectiveness.

OPQ reorganization

Neadle: How do you expect the upcoming Office of Pharmaceutical Quality (OPQ) reorganization to affect combination products, if at all? (RELATED: FDA announces OPQ reorganization to alleviate ‘long-standing pain points’, Regulatory Focus 13 November 2023).

Ashley Boam (director, Office of Policy, CDER): I’m happy to say I don’t think it’ll impact it negatively and I think it actually may have a positive effect. One of the things that we are doing is to have better mixing together of our assessment folks to look at the different application types. Right now, we have a lot of separate groups looking at individual categories, and there will be a lot more overlap between these groups. We will have groups looking at both New Drug Applications and Abbreviated New Drug Applications; groups that are looking at both pre-market and post-market items. My hope is that there’ll be a lot more learning from the assessment process, which will become even more conducive to our work on combination products as we continue to educate folks and build those relationships.

FDA 21 CFR 820 and ISO 13485

Neadle: Regarding the harmonization between FDA 21 CFR 820 and ISO 13485, can you give us a little bit of insight into what pieces of ISO 13485 clause 7 would be adopted? And secondarily, do you know the medium in which we’ll be given that guidance?

Yeatts: We issued a proposed rule and you should expect a final rule. I’m not sure of the exact timing, but we are doing our best to push that out. It’s been a high priority. After the rule issues, we’ll look at what other guidance may be needed to implement it.

Combination products: FDA experts address UDI, harmonization, OPQ reorganization

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