REGULATORY CLASSIFICATION OF DELIVERY SYSTEMS

IV. REGULATORY CLASSIFICATION OF DELIVERY SYSTEMS

The regulatory requirements for each legally defined class of medical pro- ducts vary, and so it is important to know how a potential new ophthalmic delivery system will be classified. Each FDA Center, in addition to statutory requirements, differs in its rules and procedures for submission and review of applications.

A. Drug Versus Device

A drug is legally defined as:

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1. Articles recognized in the official United States Pharmacopoeia (USP), official Homeopathic Pharmacopoeia of the United States or the National Formulary (NF) and their supplements.

2. Articles intended for use in the diagnosis, cure, mitigation, treat- ment, or prevention of disease in man or other animals.

3. Articles other than foods intended to affect the structure or any function of the body of man or other animals.

4. Articles intended for use as a component of any article specified in the above three clauses.

A device is defined as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory which is:

1. Recognized in the official USP or NF or any supplements

2. Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease in man or other animals

3. Intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal intended purpose through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its princi- pal intended purposes

While there are some similarities in the two definitions, there are also important differences. The definition of a device lists specific types of articles that are covered, and these are the articles that one would typically associate with the literal definition of a device. A device is also an accessory of one of these articles. For example, contact lens care products, which have compo- sitions containing chemicals such as disinfectants, lubricant polymers, etc., are regulated as devices since they are considered necessary for the safe use of another device, a contact lens.

Another ophthalmic example is seen with the regulatory history of the Lacrisert, 1 a sterile rod-shaped solid consisting entirely of a cellulosic poly- mer intended for use in the eye to slowly erode and dissolve in the tear film to provide lubrication for painful dry eye conditions. The FDA initially approved it as a device and then changed its mind and reclassified it as a drug (4). In doing so, the FDA explained that the term article in the defini- tion of a drug is a broad category in contrast with the specific types of articles listed in the device definition, and the Lacrisert is not one of those specific device articles. The FDA also stated that a drug is a chemical or a combination of chemicals in liquid, paste, powder, or other drug dosage

672 Roehrs and Krueger form that is ingested, injected, or instilled into body orifices or rubbed or

poured onto the body in order to achieve its intended medical purpose. Also, note that the legal definition of a drug does not require it to achieve its principal intended purpose through chemical action or by being meta- bolized.

B. New Drug

A new drug is legally defined as one that is not generally recognized among experts qualified by scientific training and experience as safe and effective for use under the conditions prescribed, recommended, or suggested in its label- ing (FD&C Act Section 201(p)). New drugs require INDs for conducting clinical investigations and NDAs for marketing approval. The terms drug and new drug are inclusive of the drug substance and the drug product.

It is important to understand that a new drug is not just a newly discovered chemical or biological compound. This can best be illustrated by several examples of when a drug can become a new drug for regulatory purposes:

1. The drug is a new derivative of a known molecule such as a prodrug of epinephrine.

2. A previously approved drug has been discovered to have a new therapeutic use such as a nonsteroidal anti-inflammatory agent used to inhibit miosis during cataract surgery.

3. A component of a drug is new for drug use such as an EVA polymer film to control the release of pilocarpine in the eye or

a gel-forming polymer to extend the duration of IOP-lowering of timolol maleate.

4. Two or more approved drugs are combined for use such as a fixed combination of tobramycin and dexamethasone.

5. A change is made in the route of administration such as a topical ocular dosage form of acetazolamide for IOP reduction.

6. A change is made in the dosage or strength of an approved drug.

7. A change is made in the intended patient population such as the use of a drug, approved to lower IOP in glaucoma patients, to be used in normotensive patients prior to laser surgery to prevent IOP spikes.

8. The addition or deletion of an inactive component changes the risk-to-benefit ratio for an approved drug.

9. Radiation sterilization is used for a drug product (21 CFR 200.30).

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C. Combination Drug and Device It is possible to have as a new ophthalmic delivery system a combination of

a drug and a device. For example, the system could contain the drug in aerosolized form, which is associated with a novel apparatus (device) to instill the drug directly onto the surface of the eye in a manner that avoids the blink response. The FDA product review jurisdiction would be deter- mined by Intercenter agreements and usually assigned based on the primary mode of action of the product.

In this chapter, we will discuss the requirements for ophthalmic deliv- ery systems in which a drug is incorporated in a carrier for its pharmaco- logical effect on the human eye and is reviewed as a new drug product by the FDA’s Drug Center (CDER).