by Anna Longwell, Esq.

Combination Product Clinical Trials

A. What is a combination product?

The Food, Drug and Cosmetic Act has no definition of a combination product. However, it does have a requirement that FDA write regulations addressing the methods for obtaining US marketing permission for combination products, and FDA has done that. In these regs, at 21 CFR part 3, FDA defines a combination product. There are three general categories: first, a product composed of two or more of the three regulated categories; second, two or more of the three categories packaged as a single product; and third, any two or more of the regulated categories packaged separately that may ONLY be employed together to achieve the intended use, indication or effect. For a device drug/combination, option 3 would mean that the device label says, “for use with drug x for intended use y,” and the drug label says, “for use with device a for intended use y”.

According to these regulations, a combination product can be made up of a device that is intended to be used only with a specific drug like an insulin pen, if it uses insulin formulated specifically for the pen.

A device/drug combination is an investigational combination product if the investigational device is to be used only with a specific unapproved drug, or only with a specific approved drug that would require re-labeling to include the use of the device. However, if only one of the two are investigational, (e.g., device with all marketing requirements, to be used with investigational drug, or vice versa), the regulations are silent. Presumably this is still a combination product, but it may not be an investigational combination product, simply either an investigational device or an investigational drug.

The key words here are only a specific drug. These regulations do not say how to classify an investigational device that can be used to deliver a number of drug products, especially if some drug products already are approved/labeled for the route of delivery provided by the device. (example: an investigational catheter set investigated for the intended use, iv infusion of any number of parenteral fluids). Presumably, these products are simply investigational devices, because their critical properties would not be drug specific.

The regulation at 21 CFR 3 only address market approval or clearance. It does not address questions of GMP, import/export, investigational device exemptions, investigational new drug applications, etc for combination products. Also, FDA has not offered much guidance in this area, with the exception of the preamble (cited below), and the 1991 Intercenter Agreements, (which FDA has not always followed).

We know that FDA has taken fairly individual approaches to regulating combination products, depending on what they thought was the most critical aspect of the new combination product. Several of these are described in the preamble to the ill-fated tobacco regulation. (See p 44403, 61 FR, vol. 168 (1996)). FDA interprets the law at 21 USC 353(g)(2)-which says, “Nothing in this subsection (the one addressing combination products) shall prevent the Secretary from using any Agency resources…necessary to ensure adequate review of…safety, effectiveness or substantial equivalence…” to mean they have the authority to make it up as they go along, and this is what they are doing.

A good response to any “gray” regulatory area is to develop a rational approach that is consistent with the regulations, document it, and apply it consistently.

B. Investigational devices and investigational combination products: which GMP?

Clinical trials of drug delivery devices, with a new drug (or new drug administration route, or new formulation) in the US would usually be conducted under the Investigational New Drug requirements. Drugs studied under IND require drug GMP (21 CFR parts 210-211) for finished product. The only exception to drug GMP is the expiration date requirement, from which investigational drugs are excepted.

The regulation as written does not clearly apply to the manufacture of device components of an investigational combination product provided as two separate parts, drug and device. It is not clear what the finished drug product would be in this case. Also, FDA expectations for investigational combination products provided together have not extended the finished drug GMP regulation to these device components (contrast expectations for API components).

Until more explicit FDA interpretations are available which preclude this approach, the investigational device components made for an investigational combination product are regulated by the Investigational Device Exemption (I.D.E.) requirements. These requirements are detailed at 21 CFR 812, and exempt makers of investigational devices from most of the device GMP (21 CFR 820), with the exception of the design control segment at 21 CFR 820.30.

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