US Designation Process and Critical Issues for the Combination Product

In the United States, the Office of Combination Products assigns the review responsibility for a CP based on its intended use, its primary mode of action,70 and the FDA Intercenter Agreements.11 These Intercenter Agreements provide guidance and identify products subject to regulation as devices and those subject to regulation as drugs, using a process that has been presented in many publications.51215 Assignment of the lead center for premarket review and regulation is determined based on the primary mode of action of the CP.10 For some products, the designation process is simple, whereas for others, the decision is not as clear. A comparison of the impact of the designation is critical to understanding some of the issues resulting from the designation decision and its outcome. For many companies, obtaining a designation of primary review by the Center for Devices and Radiological Health (CDRH) as a medical device is favorable because fewer clinical trials are required for a PMA than an NDA. Although this is generally true, CDRH would require additional trials if for certain reasons establishing an effective dose was an issue with the CP. Thus, well-designed clinical trials are essential for a successful PMA, which may include only one or two clinical trials.The designation of two CPs that each has the same drug component are compared based on their primary mode of action. The first is a DES with a radioactive pharmaceutical as the drug component that is used for the prevention of restenosis, and the second product is a drug-coated occlusion coil (DCOC) used to heal aneurysms following embolization. For each of these products, it is important to determine the role of the device. For the DES, the drug and device components are "married" owing to the elution profile of the drug from the stent and the therapeutic properties of the stent itself (e.g., prevention of restenosis). For the DCOC comparator, the drug and device components are not "married," because the drug's physicochemical properties allow it to freely bind to the surface of platinum metal, thus any platinum alloy coil could be used as the device component.

From the drug point of view, the role of the device in both cases is simply to facilitate the delivery of the drug to the therapeutic site. The DES' primary role is attributed to the stent, because it is a permanent scaffold that maintains the opening of the coronary artery. The secondary role of the DES comes from the drug, as it acts to prevent restenosis induced by the angioplasty and stent. Changes (e.g., polymer coating, drug) to the stent will directly influence the degree of prevention of restenosis, because the outcome is influenced by inflammatory reactions. The term new chemical entity (NCE) will be used to refer to an investigational new drug. If an NCE is added to the stent to create the DES, the question that needs to be addressed is whether the experience with the stent outweigh the new safety issues raised by the NCE. These are the toxicity issues that arise from systemic exposure of the NCE and not the local toxicity issues associated with any DES. For the DCOC, the primary role is also attributed to the device, because the occlusion coil immediately induces embolization after implantation and acts as a permanent implant to maintain the plug. The secondary role is that of a drug, which facilitates the healing process of the aneu-rysm once the clot (embolization) has been formed. There are no critical device issues to review if a coating is not used to bind the drug to the platinum metal and if the physical properties of the coil (e.g., thrombogenicity) and delivery system are maintained. Another important question to consider for NCEs with a new therapeutic action or claim is whether the drug component has become more critical to the premarket approval process. Section VII.A.2 of the Intercenter Agreement77 between the Center for Drug Evaluation and Research (CDER) and the CDRH states that a "Device incorporating a drug component with the CP having the primary intended purpose of fulfilling a device function" is a CP and market approval authority will be granted to CDRH using device authorities. In addition, it states that intercenter consultation will be required if "a drug has not been legally marketed in the USA as a human drug for the intended effect." Section VIII also needs to be consulted as it outlines the general criteria that CDRH and CDER will apply to reach a verdict regarding the designation. Device Criteria VIII.A.5 states that "A device containing a drug substance as a component with the primary purpose of the combination being to fulfill a device function is a CP and will be regulated as a device by CDRH." Both criteria VII.A.2 and VIII.A.5 support the decision to have CDRH regulate the DES and DCOC as devices. This holds true as long as the primary mode of action is associated with the device component of the CP. For the DES, this determination is positive, because CDRH is experienced with the premarket review of the bare device and has engineering expertise in this area, the stent directly influences the clinical outcome, and any changes to the stent or its delivery may affect restenosis. Although as the device component is a Class III medical device regulated under the PMA regulations, the advantages of a premarket notification (510(k)) application are not available. A major issue that may be encountered during the review of the CP is CDRH's limited experience with drug review; thus, the efficiency of the CP review team will be critical. Although CDER is not experienced with review of the bare device and does not have clinical experience with these types of products, their expertise lies in drug review, which will be an asset to the review team. For a product with an NCE, it will be important to obtain active participation from CDER reviewers for the chemistry, manufacturing and controls, and nonclinical safety issues. The DCOC's case is different, because the product's primary mode of action can arguably be a drug or device. Thus, it is important to look at the advantages and disadvantages of the designation verdict. CDRH is experienced with review of bare occlusion coil devices and has engineering expertise in this area. The properties of the occlusion coil are important for inducing embolization through thrombogenicity. On the other hand, CDRH has minor clinical expertise with occlusion coils, because many of these products are approved without clinical trial data through a premarket notification application. Occlusion coils are Class III medical devices that are regulated through premarket notification (510(k)).* The addition of a drug to this Class III medical device makes the DCOC a product that is regulated through the PMA regulatory pathway. A major issue that will be encountered during the review process is CDRH's inexperience with drug review; thus, the efficiency of the CP review team will be critical for a successful and timely filing, particularly with an NCE. In turn, CDER is not experienced with the review of this medical device and has no clinical expertise in the embolization of cerebral aneurysms. The DCOC's drug component has a major role, because it enhances the clinical performance properties of the medical device. As previously stated, the addition of a drug to this Class III medical device makes the DCOC a product that is regulated through the PMA regulatory pathway, removing the benefits of a 510(k) submission. The regulation of the product as a drug under the NDA pathway could be advantageous to the company, because ruptured aneurysms are considered a rare disease. The NDA pathway would allow designation of the drug component under the Orphan Drug Act. Thus, in cases in which the DCOC makes substantial drug claims, arguments should be made to designate the product with primary responsibility given to CDER.

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