EU and FDA Policies in Conflict over Product Designation

The FDA’s loss to Genus Medical Technologies forced the agency to regulate barium sulfate products for some uses as devices rather than as drugs, but the agency acknowledged that other product types may follow barium sulfates in the switch from drugs to devices. There are a number of imaging agents that could ultimately be classified as devices by the FDA, but the transition process is likely to prove expensive and cumbersome, and as we previously highlighted in our blog, the process of cross-referencing the good manufacturing practices (GMPs) for drugs and those for devices may prove to be the most expensive and time-consuming undertakings in that transition. It should be noted that the FDA user fees for devices are substantially less than those required for pharmaceutical applications, however.

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The MDCG guidance states that if an analysis of the product leads to the conclusion that the product falls within the definitions of both drugs and devices, the provisions for medicinal products for human use apply. This position is consistent with the FDA’s overall position that a product is a drug until the manufacturer can demonstrate otherwise, but the MDCG guidance makes clear that some products will henceforth be regulated as drugs as in the EU despite that they may be regulated as devices in the U.S. This exposes manufacturers that do business in both areas to two radically different regulatory regimes for a single product.

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MDCG stated that this question of product jurisdiction will be considered on a case-by-case basis, but advised that the decisive factor will be whether the data support the manufacturer’s preferred product designation. Information or data on safety and performance alone will not suffice to cause a product to be a device. Among the characteristics that fulfill, in part or in whole, the definition of a device are articles that are intended to:

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• Diagnose, prevent, monitor, predict, treat or alleviate a disease, injury or disability;
• Replace or modify a part of the anatomy or physiological function;
• Provide information about a specimen from the human body by means of an in vitro examination of the specimen; and
• A product that does not achieve its principal intended action by pharmacological, immunological or metabolic means.

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There are two branches of the definition of a medicinal product, the first of which is that the substance or combination of substances possesses properties for treating or preventing disease. The second branch is that the substance or combination of substances can be administered to restore, correct, or modify a physiological function by exerting a pharmacological, immunological or metabolic action. However, any substance that can be used to aid in making a diagnosis would also qualify as a drug, even if the product fulfills that function by other than pharmacological, immunological or metabolic means. This language highlights some forthcoming tensions between the European and U.S. markets, should the FDA follow through on the regulatory conversion of some imaging drugs into devices.

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The language in the MDCG guidance makes clear that any new entries to market must carefully consider their investments in the affected products as their GMP due diligence may require a dual drug/device GMP framework. It should be noted that the MDCG guidance does not require that the manufacturer follow a dual-track GMP system for marketing solely in the EU, but a manufacturer of an affected product may nonetheless be forced to run a dual-track system if manufacturing at a single site and shipping to both markets.

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Combination Products Still a Complex Regulatory Undertaking

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Another point we believe is worth considering is that the MDCG guidance provides a definition of principal mode of action for combination products, which at first glance seems to roughly parallel the FDA’s primary mode of action (we’ll use PMOA for both for the purposes of this blog). The definition of PMOA in the MDCG guidance is “the means by which the product achieves its principal intended action.”

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This latest guidance from MDCG does not go much further into the question of PMOA, although some clarification is available from other documents regarding drug-device combinations (DDCs). This document states that a DDC product will be deemed:

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• A device if the drug product provides only an ancillary function;
• A drug if the action of the drug is principal and not ancillary to the action of the device;
• A drug if the non-reusable combination is marketed as a single integral product intended exclusively for use in that combination; and
• A device if the device component is co-packaged with the drug, or the drug is available separately, but is labeled for use with the device.

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The FDA’s approach is similarly ambiguous in that it states that the PMOA is “the single mode of action of a combination product that provides the most important therapeutic action of the combination product.” The most important therapeutic action is “the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.” Obviously, there is considerable ambiguity in these definitions, just one of several reasons that combination products present a series of unusual challenges.

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The key consideration for companies that are developing combination products – and products that don’t fall neatly into the category of a drug rather than a device – is to interact with the regulator or the notified body as early in the research and development phase as possible. This advice applies as well to companies that will have to retool their compliance systems for products the FDA will change over from a drug to a device, but either way, we at Enzyme continue to emphasize the importance of planning to ensure a positive outcome for your product.

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