In June 2011, the Food and Drug Administration (FDA) published two companion draft guidance documents to assist industry and FDA staff in distinguishing medical devices from drugs. There has been a pressing need for guidance as the number of “drug-like” devices has been increasing, for example, in the form of gels, liquids, semi-liquids, and powders. The pathway to market is often less burdensome for certain lower risk devices than for drugs, so a device classification determination could mean the difference between bringing a product to market and forgoing the opportunity. Due to the perception of desirability of a device classification, increasing innovation in the gray area between drugs and devices has the potential to generate controversy between FDA and disappointed sponsors. But the draft guidance, if implemented, has the potential to intensify the problem by upsetting established precedents and shifting even more products to a drug classification.

Drug vs. Device Classification Issues: First Draft Guidance Document

An Intercenter Agreement (IA) between the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) heretofore carved up the responsibilities of these Centers to regulate a number of gray-area products. The IA categories are too granular to keep pace with the emergence of gray-area devices, thus the potential for FDA to regulate as drugs those products that sponsors would like to position as devices has been growing.

The new draft guidance, “Classification of Products as Drugs and Devices & Additional Product Classification Issues” (available at www.fda.gov/RegulatoryInformation/Guidances/ucm258946.htm) states that IAs should be “considered in the light of statutory definitions and current scientific understanding,” and will be regarded as “helpful, nonbinding guidance” for the time being. Under the draft guidance, the CDRH/CDER IA would continue in effect, but with the understanding that it should not be relied upon, by itself, as the Agency’s current, complete jurisdictional statement.

The new draft guidance takes a broad view of the “drug” definition, stating that all devices also meet the “drug” definition, even though they may be regulated as devices under the statute. When there is uncertainty as to whether a product meets the device definition, the draft guidance states that FDA will continue its historical preference for classifying the product as a drug. Indeed, if any therapeutic effect of a product, even one of relatively minor therapeutic importance, is drug-like in nature (i.e. based on “chemical action,” see discussion below), the draft guidance proposes that such effect should be treated as a “primary intended purpose,” thus rendering the product a drug, and not a device. Industry comments to the docket assert that this interpretation of the term “primary intended purpose” is at odds both with legislative intent and FDA’s historical approach — constituting a major departure from precedent and heralding a new policy that should be addressed by formal rulemaking and not merely by the issuance of guidance. In part, this has led to comments asking that FDA withdraw all or part of the draft guidance.

When it is unclear, or in dispute, that a product is a device versus a drug, a sponsor may file a request for designation (RFD) with the Office of Combination Products (OCP), and receive a formal determination within 60 days. The draft guidance discusses the effect of precedent under two scenarios. For those products that do not fall within the scope of an existing classification issued by regulation, but are the same as another product that has already been classified, current scientific understanding will be key in making the determination. (“Sameness” will be judged on chemical or physical structure, intended use, and the mode of action by which the product achieves its intended use.) For these products, if scientific factors could lead to a change in classification, and the submitter recommends it, the product will be classified according to the recommendation of the submitter – as a final determination. Procedurally, under the Federal Food, Drug, and Cosmetic Act, this will occur because FDA will take no action within the mandated 60-day determination period. Once the determination is final, the Agency may not modify it unless the sponsor agrees in writing, or if scientific evidence exists that the determination is not consistent with the interests of public health.

When, as a result of an RFD determination for a product not covered by regulation, a product is classified differently from a “same” existing product, a temporary inconsistency will result. Under these circumstances, FDA will initiate a public administrative process to resolve the classification discrepancy. When deemed appropriate, entire groups of products may be reclassified and jurisdiction transferred among Agency components. The Agency is considering its marketing approval options regarding the classification and transfer of these products. Among them are to

1. exercise enforcement discretion for products subject to an existing classification,
2. determine, for example, that an approved NDA also meets applicable requirements for an approved PMA, and vice versa, or
3. withdraw existing approvals and require new ones according to the requirements of the new classification.

For those products that are described by an existing regulation for the use proposed in the RFD, the picture is different from those where no regulation applies. This could occur in the case where a product meeting the device definition is already covered by an over-the-counter (OTC) drug monograph, or conversely, where there is evidence that a product falling under a device classification for the intended use described in the RFD is now thought to achieve its primary purposes via chemical action within or on the body. In these cases, FDA plans to continue to apply the current classification. The Agency, therefore, would not allow its statutory 60-day determination period to expire before acting. Only after making a determination consistent with existing regulation would the Agency assess the appropriateness of a classification change, and if deemed appropriate, would initiate notice and comment rulemaking.

“Chemical Action” in Distinguishing a Drug from a Device: Second Draft Guidance Document

Both the “drug” and “device” definitions describe products that are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease (although devices also encompass those articles intended for the diagnosis of “other conditions”). Both definitions also include products intended to affect the structure or any function of the body. What distinguishes a device from a drug is exclusionary in nature.

A device “does not achieve its primary intended purposes through chemical action within or on the body” and “is not dependent upon being metabolized for the achievement of its primary intended purposes.” The draft guidance “Interpretation of the Term ‘Chemical Action’ in the Definition of Device under Section 201(h) of the Federal Food, Drug, and Cosmetic Act” (available at www.fda.gov/RegulatoryInformation/Guidances/ucm259059.htm) attempts to flesh out the definition of “chemical action.” The draft guidance defines the term, and provides examples of the four categories of situations that meet the definition of “chemical action.” Importantly, chemical action of a product within or on the body will not, by itself, defeat its classification as a device. The entire statutory definition for the term “device” must be applied. The device classification is defeated only if the primary intended purposes of the product are achieved through that chemical action within or on the body.

The draft guidance interprets “chemical action” to mean, “Through either chemical reaction or intermolecular forces or both, the product: mediates a bodily response at the cellular or molecular level, or combines with or modifies an entity so as to alter that entity’s interaction with the body of man or other animals.” (“Entity” includes chemicals and microbial life.) A “chemical reaction” has occurred if covalent or ionic bonds have formed or been broken. Intermolecular forces are “electrostatic interactions or forces resulting from the interaction of localized, short-range electrical fields among atoms and/or molecules.” So, “chemical action,” to defeat a device classification, must involve the product either breaking or forming covalent or ionic bonds, or, through intermolecular forces, either (1) mediating a cellular or molecular bodily response, or (2) combining with or modifying an entity so as to alter that entity’s interaction with the body. In addition, to be a drug and not a device, that chemical action must be the way the product achieves its primary intended purposes within or on the body.

The draft guidance sets forth four categories of chemical action:

1. a chemical reaction whereby a bodily response at the cellular or molecular level is mediated by the product,
2. a chemical reaction in which the product combines with or modifies an entity, thus altering that entity’s interaction with the body,
3. intermolecular forces whereby a bodily response at the cellular or molecular level is mediated by the product, and
4. intermolecular forces through which the product combines with or modifies an entity, thus altering that entity’s interaction with the body.

In the first category, two examples are given. The first includes aspirin inactivating the COX-1 or COX-2 enzyme through formation of covalent bonds, thus suppressing inflammation, and the second includes reactions through reversible covalent bonding that catalyze bodily enzymatic reactions. In the second category, a product may bond chemically to a harmful chemical agent, changing it to another chemical agent that is harmless, thereby neutralizing or detoxifying it. In the third category, intermolecular forces could be at least partially responsible for mediating a bodily response by contributing to the stereochemistry of a binding interaction. Additionally, intermolecular forces could influence molecular diffusion in liquids — such as Epsom salts, which influence diffusion of water into the intestine to facilitate evacuation. The fourth and last category includes such chemical actions as precipitation and crystallization of a solute from a solution and the dissolution of a solute by a solvent. These reactions involve electrostatic interactions. An example is the dissolution of encrustations by saline nasal preparations. Additionally, surfactant actions fall into this last category. The draft guidance gives in-depth explanations of the nature of the chemical actions involved in these examples.

Summary

The controversial June 2011 companion draft guidance documents explain how FDA intends to distinguish devices from drugs. The guidances, if implemented, may subject more products to the more burdensome drug approval process. Sponsors of existing products — and products under development — that are in the “gray area” between drugs and devices should therefore stay tuned for further developments if and when FDA issues its final version of the guidances. FDA accepts comments on its draft or final guidances at any time.

John Moore is counsel in the Washington, D.C. office of Hunton & Williams LLP (hunton.com) in the firm’s Food and Drug Practice. He can be reached at moorej@hunton.com.
Adele Gilpin is an associate in the firm’s Food and Drug Practice. She can be reached at agilpin@hunton.com.