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The FDA unifies Premarket Review for Combination Products

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In January 2022, the Food and Drug Administration (FDA) published an interesting guide, called Principles of Premarket Pathways for Combination Products, which establishes the unification of premarket review of combination products.

For the FDA, a combination product is a product comprised of two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product with one another). The drugs, devices, and biological products included in combination products are referred to as constituent parts of the combination product. These may include:

– A product comprised of two or more regulated components, i.e., drug/device, that are physically, chemically, or otherwise combined or mixed and produced as a single entity (such as a prefilled syringe or drug-eluting stent);

– Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products (a co-packaged combination product, such as a surgical or first-aid kit containing bandages and an antiseptic drug);

– A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved, individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose), a cross-labeled combination product, as might be the case for a light-emitting device and a light-activated drug indicated for use together for treatment of a dermatologic condition; or

– Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect (also a cross-labeled combination product).

The FDA clarifies that they will conduct the premarket review of any combination product under a single application, whenever appropriate and that a sponsor may choose to submit separate applications for the different constituent parts of a combination product unless FDA determines that a single application is necessary. The FDA’s current thinking is that a single application would generally be appropriate for a combination product, to streamline regulatory interactions with the Agency and to avoid unnecessary duplication that may occur with multiple applications. However, separate applications would generally be permissible for the constituent parts of a cross-labeled combination product. In limited situations, FDA may determine that a single application is not appropriate and thus that an application for each constituent part is warranted.

In determining what is needed to demonstrate the safety and effectiveness of the combination product, the FDA takes into account the questions and considerations, reflected in the statutory and regulatory provisions associated with each constituent part in its review of the combination product as a whole and its constituent parts. This includes how the constituent parts may interact and interrelate. For example, a drug may be coated on a device to mitigate undesired local physiological responses associated with the implantation procedures or the use of the product. Examples of this may include an anti-inflammatory drug on a cardiac lead to reduce inflammation at the implantation site or an anti-coagulant bound to the inner-lumen of a catheter to prevent clot formation within the catheter thereby maintaining catheter patency.

Finally, the guide also addresses pathway availability, as combination products may be device-led or drug-led.

Undoubtedly, this regulation reflects a big technological evolution in the field of drugs and devices with such novel and diverse technologies in the field of health to which other regulatory agencies around the world need to prepare and adapt.

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