US Pharm. 2009;34(6)(Generic Drug Review suppl):31-38.
In recent years, the prescribing and dispensing of generic drugs has gained much interest, especially as many industrialized countries try to minimize rapidly rising health costs. Using high-quality, less expensive generic drugs can help reduce expenses while providing an equivalent level of treatment as the brand-name drug. The FDA’s designation of therapeutic equivalence indicates that the generic formulation is bioequivalent to the brand formulation and can be expected to have “equivalent clinical effect and no difference in their potential for adverse effects.”1 This article will review the different bioequivalence testing procedures required by the FDA for generic drug approval.
FDA Generic Classification
The FDA classifies products as therapeutically equivalent according to the general criteria listed in TABLE 1.1 Note that the FDA’s designation of therapeutic equivalence does not consider product packaging, scoring, configuration, shape, or pharmaceutical additives such as color, preservative, or flavorings.1 Additionally, the FDA’s narrow therapeutic index drugs (e.g., lithium, phenytoin, digoxin, warfarin) do not have any special requirements.
Statistics: Generic Drugs
The use of generic drugs is increasing worldwide every year. Between now and 2012, brand-name drugs with $139 billion in annual sales in the world’s top eight markets will face generic competition.2 According to IMS Health, generics generated $78 billion in revenue in the top eight markets for the year ending September 2008, an increase of 3.6% over the prior year. This was primarily due to the patent expirations of several popular drugs. In the United States, generic drugs accounted for nearly 64% percent of all prescriptions filled, with sales of $33 billion in 2008. The FDA approved or tentatively approved a record 682 generic-drug products in fiscal year 2007, a 30% increase over the previous year.2
The generic is not an exact duplicate of the brand-name drug. When properly regulated and tested, generic drugs have the same therapeutic effect as the brand name and can be considered to be safe and effective. The quality of a generic drug is evaluated by undergoing bioequivalency testing. Currently, this is the primary method for determining drug quality in the U.S., United Kingdom, and many other countries. Additionally, a high degree of bioequivalence actually guarantees the therapeutic equivalence of the original and the generic drugs.
Interpatient and Intrapatient Pharmacokinetic Variability
Patients have different pharmacokinetic profiles and this must be addressed during drug planning and therapy.3 Much clinical and scientific work is attempting to understand and overcome interpatient variability.4 Interpatient variability is often seen by observing the concentration versus time profile of a drug following administration of a fixed dose to several patients.4
On the other hand, intrapatient variability refers to the differences in pharmacokinetics that happen within the same patient from dose to dose during the course of drug therapy.4 Unfortunately, not much attention is paid to this variable. However, intrapatient variability still is a major factor in bioequivalence testing studies.4
Bioequivalence and Bioavailability
Bioequivalence is defined as two pharmaceutical products that are pharmaceutically equivalent; their bioavailabilities after administration are in the same molar dose and are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same.5,6 Another term, pharmaceutical equivalence, is defined as the same amount of the same active substance(s), in the same dosage form, for the same route of administration, and meeting the same or comparable standards.
All generic formulations must be tested for bioequivalence or pharmacological equivalence to the brand formulation, which is usually performed at the registration stage. Most of the drugs undergo bioequivalence testing at various clinical centers with the necessary equipment available. Bioequivalence is considered the principal requirement for registering a generic drug and it determines the identity of pharmaceutically equivalent drugs. The main tests proving the bioequivalence of drugs include the evaluation of bioaccessibility and pharmacokinetic features in human volunteers and animals, and comparative clinical tests and the evaluation of dissolution of the drug. Selection of the testing method depends on the form of the drug, its physical and chemical characteristics, indications to the drug use, and the drug’s pharmacological characteristics, as well as other factors.
Results of testing can prove that a bioequivalent generic drug responds the same in laboratory conditions as does the original drug. The drugs are regarded as equivalent to the brand-name drug when they display the same pharmacokinetic characteristics of the active substance, which includes the: 1) extent and the speed of absorption into the blood (i.e., maximum concentration [Cmax] reached in the blood); 2) pattern of distribution in tissues and extracellular spaces; and 3) type and speed of elimination.7
In Vivo Bioequivalence Testing
High levels of bioequivalence can be considered to also prove therapeutic equivalence of the drug. Under current FDA standards, bioequivalence is concluded in cases where the brand and test product differ in terms of their rate and extent of absorption by -20% to +25% or less. Even so, once a drug has been proven to be bioequivalent in vitro, the drug is tested in vivo for therapeutic equivalence on healthy volunteers. This test outlines a statistical method for assessing data and provides a decision rule for concluding bioequivalence.6 Intrapatient variability appears as a key factor in designing and assessing bioequivalence studies. Tsang et al have shown a failed bioequivalence determination from a small study assessing verapamil absorption from the same lot of sustained-release tablets, administered on two occasions in a crossover study.8 In practical terms, large numbers of subjects are often required to produce confidence interval (CI) limits within the current guidelines. It has been argued that the current standards present an unfair obstacle to companies developing formulations of these drugs; however, the FDA is currently considering a draft guidance to address this concern.9
The standard bioequivalence (PK) study is conducted using a two-treatment crossover study design including a limited number of subjects. Approximately 24 to 36 adults are randomly separated into test and reference drug groups. Single oral doses of the test and reference drugs are administered, and blood or plasma levels of the drug are measured over time. The rate and extent of drug absorption are statistically measured. In drugs with long half-lives, a parallel study design is best used. In addition, alternative study methods must be used in drug products where absorption is not considered, such as topical skin products, inhalers, and nasal sprays.1 With these products, in vitro study or an equivalence study might be used to determine clinical or pharmacodynamic endpoints.1
According to the FDA, two products are considered to be bioequivalent if the 90% clearance (CI) of the relative mean Cmax, AUC(0-t), and AUC(0-∞) of the generic drug to the brand-name drug is within 80% to 125% in the fasting state.1 Although there are a few exceptions, generally a bioequivalent comparison of test-to-reference formulations also requires administration after an appropriate meal at a specified time before taking the drug, a so-called “fed” or “food-effect” study. A food-effect study requires the same statistical evaluation as the fasting study previously described.1
The data resulting from these bioequivalence studies are statistically evaluated using the two one-sided test procedure.1 This test is designed to establish equivalence with the hypothesis that there may be some bioinequivalence.10 The first of the two one-sided tests determines if a generic drug, when substituted with a brand-name drug, exhibits significantly less bioavailability. The second one-sided test looks at the reverse: whether a brand drug, when substituted by a generic, show significantly less bioavailability.1 The results are statistically significant if there is a difference of less than 20% for each of the tests. If there is a difference of greater than 20% for the two tests, then there is a failure of bioequivalence between the two drugs. This translates to an 80% difference in the bioavailability of the products. All of the data is expressed as a ratio of average values of the AUC and Cmax. Therefore, as mentioned earlier, the limits of acceptable bioavailability for a pharmaceutical equivalent are 80% and 125% of the innovator product.1 Although the FDA contends that this process of approval is adequate, there are others who do not agree.
Switchability of Generic Drugs
Metrics of the rate and extent of drug absorption bioequivalence studies attempt to gain insight on formulation “switchability,” or the ability to substitute one formulation for another without concern of the potential for reduced effectiveness or increased probability of adverse effects.11 A key assumption is that switchability may be inferred from plasma concentration versus time data and metrics reflecting the rate and extent of drug absorption. The area under the plasma concentration versus time curve (AUC) is usually used as the metric describing the extent of drug absorption, while the maximal concentration observed following drug administration (Cmax) is the metric recommended by the FDA to evaluate the rate of drug absorption.
FDA Generic Formulation Ratings
After testing has been completed and a drug has been found not to be equivalent to the original drug, it is labeled as being biologically nonequivalent, which means that equal doses of similar drugs produced in the same forms by different manufacturers resulted in the drug being pharmacokinetic nonequivalent. This can happen due to many different factors that can alter the dissolution, liberation, absorption, distribution, and elimination of the drug. Drugs with similar chemical content can have very different effects on the body. The term therapeutic nonequivalence is used to refer to drugs that have a different effect on the body from the original, and it is applied only to those drugs that correspond entirely to the State Pharmacopoeia and other standards.
The FDA provides a code to indicate the level of bio equivalency demonstrated for therapeutic equivalents; these drugs are rated as either A or B. A-rated drugs are bioequivalent to the brand-name drug either because of results submitted from human studies (AB) or are considered to unlikely have bioequivalence/bioavailability problems (AA) such as oral solutions or drugs that readily dissolve in water. Only A-rated drugs are interchanageable with the corresponding brand-name drugs. Other formulations such as AO (injectable oil solutions), AN (solutions and powders for aerosolization), AP (injectable aqueous solutions and, in certain instances, IV nonaqueous solutions), and AT (topical products) refer to non oral drug products. On the other hand, B-rated drugs have not been demonstrated to be bioequivalent by an in vivo bioequivalency test.1,12
Biopharmaceutics Classification System
By knowing the Biopharmaceutics Classification System (BCS) category of an immediate-release (IR), orally administered drug, the FDA will grant a waiver of the expensive and time-consuming bioequivalence studies. A biowaiver is an exemption granted by the FDA from conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and the dissolution profile of the dose form meets the requirements for an IR dose form. Biowaivers are based on the BCS class of the active ingredient. Currently, BCS class I and some class III compounds are eligible for biowaivers.13 Bioavailability and bioequivalence play a central role in pharmaceutical product development, and bioequivalence studies are presently being conducted for new drug applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in abbreviated new drug applications (ANDAs) of generic products, and in applications for scale-up and postapproval changes. The BCS has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate-release dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain bioequivalence studies by accurate in-vitro dissolution tests.13
Currently, the FDA is amending its regulations on the submission of bioequivalence data to require an ANDA applicant to submit data from all bioequivalence (BE) studies the applicant conducts on a drug product formulation submitted for approval. In the past, ANDA applicants have submitted BE studies demonstrating that a generic product meets bioequivalence criteria in order for the FDA to approve the ANDA, but they have not typically submitted additional BE studies conducted on the same drug product formulation, such as studies that do not show that the product meets these criteria. The FDA is amending the regulation because this data from additional BE studies may be important in determining whether the proposed formulation is bioequivalent to the reference listed drug (RLD) and are relevant to the evaluation of ANDAs in general.14
Dissolution testing methods must keep up with the new challenges posed by poorly soluble and lipophilic drugs. Bioequivalence and bioavailability studies must meet stricter European Medicines Agency (EMEA) and FDA guidelines. Successful novel dosage forms and accurate pharmacokinetics-pharmacodynamics (PK-PD) modeling must be achieved early in the development cycle. The in vitro specifications for generic drugs should be established based on a dissolution profile that should be based on acceptable clinical, bioavailability, and/or bioequivalence batches. Once determined, the dissolution specifications are published in the U.S. Pharmacopoeia (USP) as compendial standards, which become the official specifications for all subsequent drugs with the same active ingredients.15 Establishing bioequivalence for interchangeable controlled-release products usually requires more extensive data, including clinical trial data.
In June 2007, the Office of Generic Drugs (OGD) developed a question-based review (QbR) for its Chemistry, Manufacturing, and Controls (CMC) evaluation of ANDAs. QbR is an assessment system focused on critical pharmaceutical quality attributes, which will concretely and practically assess a sponsor’s implementation of the FDA’s Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century and Quality by Design initiatives. OGD intended the QbR implementation process to have goals that were SMART (Specific, Measurable, Acceptable, Realistic, and Timely). As QbR represents a significant change for ANDA sponsors, much effort was focused on education, communication, and measuring the response to this outreach.16
On October 4, 2007, the FDA launched the Generic Initiative for Value and Efficiency (GIVE). The initiative will use existing resources to help the FDA modernize and streamline the generic-drug approval process. GIVE aims to increase the number and variety of generic drug products available. Having more generic-drug options means more cost-savings to consumers, as generic drugs cost about 30% to 80% less than brand-name drugs.17
Today, generic drugs can be tested efficiently for bioequivalency, so that the medicine reaching the patient should provide the same therapeutic result as the original. Without bioequivalency testing, however, it is unacceptable to substitute one drug with a supposedly equivalent one based only on the similarity of ingredients. The USP standards should be more accurate about the requirements for additives, as these additives can influence the efficacy of a drug. It should also address issues in the production process, such as pressing or granulation in pill production, or differences in drug production equipment and packing materials, as these could also lead to therapeutic differences in the final product.
Testing drugs for biological equivalence is the only way to determine that they are safe and effective. When biological equivalence testing is used properly, generic drugs offer a safe and inexpensive alternative to brand-name drugs and can help bring necessary treatment to all. Although regulations pertaining to bioequivalence have been in place for more than 20 years in the U.S., controversies continue to be of concern. Consensus on various issues is influential to the development of new FDA guidances regarding bioequivalence.18 A better understanding of the scientific basis for establishing bioequivalence and the FDA generic drug approval process is the main concern many people have regarding generic substitution. Many studies of clinical equivalence do not set boundaries for equivalence. Claims of “difference” or “similarity” are often made not by thoughtful examination of the data but by tests of statistical significance that are often misapplied or accompanied by inadequate sample sizes. These methodological flaws can lead to false claims, inconsistencies, and harm to patients.19
1. Approved Drug Products with Therapeutic Equivalence Evaluations. 29th ed. FDA Center for Drug Evaluation and Research; 2009. www.fda.gov/cder/orange/
obannual.pdf. Accessed December 26, 2008.
2. IMS Health reports annual global generics prescription sales growth of 3.6 percent, to $78 billion. December 10, 2008. www.imshealth.com/portal/site/
152ca2RCRD&vgnextfmt=default. Accessed December 28, 2008.
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8. Tsang YC, Pop R, Gordon P, et al. High variability in drug pharmacokinetics complicates determination of bioequivalence: experience with verapamil. Pharm Res. 1996;13:846-850.
9. Food and Drug Administration, HHS. Draft guidance for industry on average, population, and individual approaches to establishing bioequivalence; availability. Fed Regist. 1999;64(173):48842-48843. www.fda.gov/ohrms/dockets/98fr/cd9955.pdf. Accessed December 28, 2008.
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14. Food and Drug Administration, HHS. Requirements for submission of bioequivalence data; final rule. Final rule. Fed Regist. 2009;74(11):2849-2862.
15. Guidance for Industry. Dissolution testing for immediate release solid oral dosage forms. Center for Drug Evaluation and Research. August 1997. www.fda.gov/cder/Guidance/
1713bp1.pdf. Accessed December 31, 2008.
16. Question-based review for CMC evaluations of ANDAs. FDA. www.fda.gov/cder/ogd/QbR.htm. Accessed December 26, 2008.
17. Generic Initiative for Value and Efficiency (GIVE). FDA. www.fda.gov/oc/initiatives/
advance/generics.html. Accessed December 31, 2008.
18. Welage LS, Kirking DM, Ascione FJ, Gaither CA. Understanding the scientific issues embedded in the generic drug approval process. J Am Pharm Assoc. 2001;41:856-867.
19. Greene WL, Concato J, Feinstein AR. Claims of equivalence in medical research: are they supported by the evidence? Ann Intern Med. 2000;132:715-722.
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