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.
As described in the December 2009 Psychopharmacology article, the U.S. Food and Drug Administration (FDA) is permitted to approve generic versions of brand-name medications without necessarily requiring that research be conducted to prove them safe and effective, provided that generic drugs (a) contain the same active ingredients; (b) are identical in strength, dosage form, and route of administration; (c) are bioequivalent; (d) have the same clinical use indications; (e) meet the same batch requirements for identity, strength, purity, and quality; and (f) are manufactured according to good manufacturing practice regulations. Because the concepts of bioavailability and bioequivalence are essential to understanding the development of generic drugs (Welage, Kirking, Ascione, & Gaither, 2001), I will describe how these are defined and evaluated in the United States.
Evaluating 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.
Various methods are used to evaluate bioavailability and determine bioequivalence for the purposes of generic drug approval, including pharmacokinetic (PK) studies (Howland, 2006a), pharmacodynamic studies (Howland, 2006b), comparative clinical trials, and in vitro (animal) studies. The kind of study chosen is based on the site of action of the drug and the ability of the study design to compare the amount of drug delivered to that site by the two products, although PK studies are most commonly conducted.
Most generic drugs are approved based on a standard bioequivalence PK study, which is conducted in a small number of healthy adult volunteers (typically 24 to 36 individuals of the same gender). Single dosages of the test and reference drug products are administered, and blood or plasma levels of the drug are repeatedly measured over a specified period of time (usually less than 12 hours, although longer periods may be required for delayed-release or extended-release drug formulations). The PK parameters characterizing the rate and extent of drug absorption are then determined. The PK parameter used to characterize the rate of absorption is the maximum or peak drug concentration (referred to as Cmax). The PK parameter used to characterize the extent of drug absorption is the resulting area under the plasma concentration-time curve (referred to as AUC).
The statistical methodology for analyzing bioequivalence compares Cmax and AUC for generic product (test) versus brand-name product (reference). A difference between test and reference drugs of greater than 20% for Cmax or for AUC is considered significant by the FDA. If the Cmax, AUC, or both differ by more than 20%, then the two drugs would not be considered bioequivalent. By convention, all Cmax and AUC data are log-transformed (a statistical method). These data are then analyzed as a ratio of the average values for test/reference. In other words, the Cmax(test)/Cmax(reference) ratio and the AUC(test)/AUC(reference) ratio are analyzed separately. The lower limit of the ratios for both parameters must be 80% (i.e., within the 20% allowed difference). Because the data are log-transformed, the upper limit of these ratios must be 125% (the reciprocal of the lower 80% limit, which is one divided by 80%).
The statistical testing is carried out using a 90% confidence interval for each PK parameter. The confidence interval is a statistical way to characterize how much variability (compared with the average value) there is of the data. The mean of the study data lies at the center of the confidence interval. The 90% confidence interval for the mean ratios of both PK parameters (Cmax and AUC) must fall entirely within the 80% to 125% boundary for the two drugs to be considered bioequivalent. A misconception is that the 80% to 125% boundary means there could be a variation between the test drug and reference drug of up to 45% (Blier, 2007). If the average ratio is close to the 80% or 125% limit, the variability of the data would have to be small enough such that the 90% confidence interval still falls within the 80% to 125% boundary (Birkett, 2003). If not, the test drug and reference drug would not be considered bioequivalent.
The bioequivalence methodology and criteria described above simultaneously control for differences in the average response between test drug and reference drug, as well as the precision (variability) with which the average response in the population is estimated. This system of assessing bioequivalence of generic products is intended to assure they do not deviate substantially from the brand-name product.
Multiple generic versions (from different manufacturers) of a brand-name product are sometimes developed. The bioequivalence of each generic version is separately evaluated compared with the same brand-name product, but generic products generally are not compared to each other directly. The FDA Office of Generic Drugs has conducted two surveys to quantify the differences between generic and brand-name products. The first survey included 224 bioequivalence studies of generic drugs submitted to the FDA and subsequently approved during 1985 and 1986. The second survey included 127 bioequivalence studies of generic drugs submitted and approved in 1997. The observed average differences between reference and generic products from both surveys ranged from 3% to 4% (FDA, 2009b).
Bioequivalence studies are also often used to develop and gain approval for pharmaceutical alternative drugs (in lieu of clinical safety and efficacy studies), especially when the goal is simply to demonstrate the pharmaceutical alternative drug delivers a bioequivalent amount of the active ingredient. However, additional safety and efficacy studies may be required before the approval of a pharmaceutical alternative drug, if the drug is not necessarily expected to have the same clinical effect or safety profile when administered to patients under the conditions specified in the labeling.
Only therapeutically equivalent drugs (generic drugs) can be substituted (e.g., by a pharmacist) for a brand-name drug. Pharmaceutical alternative drugs cannot be substituted in the same way; switching to a pharmaceutical alternative requires a change in prescription. If there are “generic” versions of a pharmaceutical alternative drug, then these can be substituted for the prescribed product. For example, a prescription written for “Wellbutrin” can be filled by dispensing a substitution generic “bupropion hydrochloride” product but not a “sustained release” (SR) or “extended release” (XL) formulation of bupropion hydrochloride. An SR generic or an XL generic can be substituted only if the original prescription was written for an SR drug or an XL drug, respectively.
The Orange Book and Drugs@FDA
How do physicians, pharmacists, or nurses know whether a brand-name product has an FDA-approved therapeutic equivalent (a generic)? On the FDA website, the publication Approved Drug Products with Therapeutic Equivalence Evaluations (FDA, 2009a) (commonly known as the Orange Book) lists all approved drug products. The Orange Book database can be searched by active ingredient or propriety name (brand name). The lists within the database describe the active ingredient, the dosage form and route of administration, the strength, the propriety name, and the company manufacturing or marketing each drug product. A therapeutic equivalence rating is indicated for any and all generic drugs—if they exist—along with the reference drug (typically the “brand name”) that was used for the bioequivalence assessment. If a generic version of a drug product is not FDA approved, it will not be found on the list. An FDA-approved pharmaceutical alternative drug having the same active ingredient will be found on the same list, but it will not have a therapeutic equivalence rating.
Also on the FDA website, the database Drugs@FDA ( http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm) lists all FDA-approved products. This database can be searched by active ingredient or by brand name. If a medication is available only in a brand name, however, searching for the product by active ingredient will not yield any results. If the clinician does not remember a medication by its brand name but knows what its active ingredient is, the clinician can search for the brand name in the Orange Book database. For any particular drug product (including brand-name and all FDA-approved generic versions), Drugs@FDA provides separate links to obtain information about the drug’s label, as well as the drug’s approval history and regulatory reviews. If the drug has therapeutic equivalents, another link to this information is provided. This kind of information is not available in the Orange Book database. Because the Orange Book and Drugs@FDA contain different kinds of information about FDA-approved drug products, familiarity with both databases is important.
The evaluation of bioequivalence is critical for understanding how generic drugs, and sometimes pharmaceutical alternative drugs, are approved by the FDA in the absence of safety and efficacy studies. Nurses should understand this process, especially when counseling patients about any concerns or questions patients or their families might have about the approval of generic products. The distinction between pharmaceutical equivalent and pharmaceutical alternative drug products, described in the December 2009 article, can lead to considerable confusion with respect to generic medications, and this will be the topic of the next month’s Psychopharmacology section article.
- Birkett, D.J. (2003). Generics—Equal or not?Australian Prescriber, 26(4). Retrieved from http://www.australianprescriber.com/magazine/26/4/85/7/
- Blier, P. (2007). Generic medications: Another variable in the treatment of illnesses. Journal of Psychopharmacology, 21, 459–460. doi:10.1177/0269881107081126 [CrossRef]
- Howland, R.H. (2006a). Personalized drug therapy with pharmacogenetics—Part 1: Pharmacokinetics. Journal of Psychosocial Nursing and Mental Health Services, 44(1), 13–16.
- Howland, R.H. (2006b). Personalized drug therapy with pharmacogenetics—Part 2: Pharmacodynamics. Journal of Psychosocial Nursing and Mental Health Services, 44(2), 13–16.
- U.S. Food and Drug Administration. (2009a). Approved drug products with therapeutic equivalence evaluations (Orange book) (29th ed.). Retrieved from http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
- U.S. Food and Drug Administration. (2009b). Orange book preface. Retrieved from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.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.