Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
To contain medication costs, nearly all states have adopted regulations that encourage or require the substitution of generic drug products for brand-name products. Generic drugs account for approximately two thirds of all prescription medications in the United States (Frank, 2007). But what is a generic drug? In this article, I will describe how generic drugs are defined in the United States.
Regulation of Generic Drugs
Within the U.S. Food and Drug Administration (FDA), the Office of Generic Drugs is responsible for the evaluation and approval of generic drug products (FDA, 2009a). According to the FDA, a generic drug should be the same as a brand-name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use. Before approving a generic drug product, the FDA requires certain tests and procedures to assure the generic drug can be substituted for the brand-name drug (Lionberger, 2008). By law, a generic drug product must contain the identical amounts of the same active ingredient(s) as the brand-name product. Drug products evaluated and classified as therapeutically equivalent by the FDA are intended to be substituted with the full expectation that the substituted generic product will produce the same clinical effect and safety profile as the brand-name product.
The Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act, expedited the availability of generic drugs (Frank, 2007). Prior to 1984, generic-drug makers were obligated to conduct the same efficacy and safety tests required of the original brand-name manufacturer (Welage, Kirking, Ascione, & Gaither, 2001). The Hatch-Waxman Act permitted the FDA to approve generic versions of brand-name drugs without necessarily requiring that research be conducted to prove them safe and effective. Generic-drug manufacturers were required only to establish bioequivalence (see below) to the active ingredients of the original drug and to demonstrate adherence to FDA-approved manufacturing processes.
This regulatory change greatly reduced the time and expense necessary for a manufacturer to develop and market a generic version of a brand-name product. To compensate manufacturers of the original product, the Act permitted companies to apply for up to 5 years of additional patent protection for their product to make up for time lost while their products were going through the FDA’s extensive New Drug Application (NDA) approval process (Howland, 2008).
When patents for brand-name drugs expire, manufacturers can apply to the FDA to market generic versions by submitting an abbreviated NDA (ANDA) (FDA, 2009b). This process does not require the generic drug sponsor to repeat preclinical and clinical research (i.e., Phase I, II, and II studies) on ingredients, dosage forms, and clinical indications previously approved for safety and efficacy (Howland, 2008). In the ANDA, the sponsor must demonstrate that, compared with a brand-name drug, a generic drug (a) contains the same active ingredients (although inactive ingredients may vary); (b) be identical in strength (e.g., milligram amount), dosage form (e.g., tablet, capsule), and route of administration; (c) be bioequivalent; (d) have the same clinical use indications; (e) meet the same batch requirements for identity, strength, purity, and quality; and (f) be manufactured according to the same FDA good manufacturing practice regulations. An approved generic drug may later be further developed for use with a different strength, dosage form, route of administration, or clinical indication, but the requisite preclinical or clinical studies to support these changes would need to be conducted and submitted to the FDA as a regular or supplemental NDA, rather than an ANDA.
Pharmaceutical Equivalence, Therapeutic Equivalence, and Generic Drugs
The most important aspect of generic drug development are the concepts of bioavailability and bioequivalence. Bioavailability refers to the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of drug action. Bioequivalence means there is an equivalent rate and extent of absorption of the same active ingredient from two or more drug products or formulations. According to the concept of bioequivalence, if a drug product contains an active ingredient that is chemically identical and is delivered to the site of action at the same rate and extent as another drug product, then it is considered to be clinically equivalent and can be substituted for that drug product.
Medications are composed of active ingredient(s) and excipients. Excipients are the various inactive ingredients of a medication that serve as carriers of the active ingredient and make up the medication formulation. Excipients could affect the bioavailability or stability of a drug, and they may be associated with adverse effects independent of the active ingredient (e.g., hypersensitivity, allergic reactions). Although the type and amount of an active ingredient of a brand-name medication is known, the overall drug-excipient formulation is usually a trade secret. Hence, the manufacturer of a generic drug must independently develop a formulation and evaluate its bioavailability in direct comparison to a batch of the brand-name product. In addition, an approved generic medication must not resemble the brand-name product.
Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, have the same route of administration, and are identical in strength or concentration. Pharmaceutically equivalent drug products may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients, expiration time, and certain aspects of their labeling.
Drug products are considered pharmaceutical alternatives if they contain the same active ingredient (chemical moiety), but are different salts, esters, or complexes of that moiety. For example, paroxetine hydrochloride tablets (Paxil®) and paroxetine mesylate tablets (Pexeva®) are pharmaceutical alternatives because they contain the same chemical moiety (paroxetine), but the paroxetine is bound in a different chemical complex in each drug. Similarly, bupropion hydrochloride extended-release tablets (Wellbutrin XL®) and bupropion hydrobromide extended-release tablets (Aplenzin®) are pharmaceutical alternative drugs containing the same chemical moiety (bupropion). Differences in the chemical complex may influence the bioavailability of the drug or the release of the chemical moiety from the complex.
Drug products are also considered pharmaceutical alternatives if they are different dosage forms or strengths—each of which might influence bioavailability. For example, venlafaxine hydrochloride extended-release capsules (Effexor XR®) and venlafaxine hydrochloride extended-release tablets (marketed by Osmotica Pharmaceutical) are pharmaceutical alternatives. Different dosage forms and strengths within a product line by a single manufacturer are also pharmaceutical alternatives. For example, bupropion hydrochloride tablets (Wellbutrin®), bupropion hydrochloride sustained-release tablets (Wellbutrin SR®), and bupropion hydrochloride extended-release tablets (Wellbutrin XL) are pharmaceutical alternatives. Extended-release and immediate-release formulations of the same active ingredient are considered pharmaceutical alternatives. Hence, valproic acid capsules (Depakene®) and valproic acid delayed-release capsules (Stavzor®) are pharmaceutical alternative drugs.
Generic drugs are technically referred to as therapeutic equivalents. Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents (as defined above) and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling. For this reason, generic drug labeling information is required to be relatively similar to brand-name drugs (including their therapeutic indications, clinical use, and side effects), even though safety and efficacy clinical trials of the generic drug have not been independently conducted.
The concept of therapeutic equivalence applies only to drug products containing the same active ingredient(s) and does not cover a comparison of different therapeutic agents used for the same condition. Therapeutic equivalence determinations are not evaluated by the FDA for unapproved, off-label indications.
The use of generic medications may be confusing or of concern to patients and families. In their role in patient care, nurses should have a fundamental understanding of how generic drugs are defined. Various methods are used to evaluate bioavailability and to determine bioequivalence for the purposes of generic drug approval. In addition, bioequivalence studies are often used to develop and gain approval for pharmaceutical alternative drugs (in lieu of clinical safety and efficacy studies). Because these concepts are so important, how bioavailability and bioequivalence are evaluated will be the subject of next month’s article.
- Frank, R.G. (2007). The ongoing regulation of generic drugs. New England Journal of Medicine, 357, 1993–1996. doi:10.1056/NEJMp078193 [CrossRef]
- Howland, R.H. (2008). How are drugs approved? Part 3. The stages of drug development. Journal of Psychosocial Nursing and Mental Health Services, 46(3), 17–20. doi:10.3928/02793695-20080501-06 [CrossRef]
- Lionberger, R.A. (2008). FDA critical path initiatives: Opportunities for generic drug development. The AAPS Journal, 10, 103–109. doi:10.1208/s12248-008-9010-2 [CrossRef]
- U.S. Food and Drug Administration. (2009a). About FDA: Office of Generic Drugs. Retrieved from http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm119100.htm
- U.S. Food and Drug Administration. (2009b). How drugs are developed and approved. Retrieved from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm
- Welage, L.S., Kirking, D.M., Ascione, F.J. & Gaither, C.A. (2001). Understanding the scientific issues embedded in the generic drug approval process. Journal of the American Pharmaceutical Association, 41, 856–867.