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FDA has been encouraging drug sponsors to use a systematic approach such as quality-by-design principles for pharmaceutical development.
In the United States, drug products are deemed therapeutically equivalent if they meet the regulatory criteria of pharmaceutical equivalence and bioequivalence (1). Designation of therapeutic equivalence dictates interchangeability between a generic drug and its reference-listed drug (pioneer) product. As defined in Approved Drug Products with Therapeutic Equivalence Evaluation (i.e., the Orange Book):
Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity).
Hence, the regulatory concept of therapeutic equivalence only applies to drug products containing the same active ingredient(s) and does not encompass a comparison of different therapeutic agents used for the same clinical indication(s).
According to US regulations, bioequivalence means
the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study (2).
Based on this definition, theoretically several methods can be used to demonstrate bioequivalence. However, the US Food and Drug Administration further recommends that drug sponsors use the following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, to demonstrate bioavailability and bioequivalence:
Therefore, pharmacokinetic studies using blood-level measurement have generally been used to demonstrate bioequivalence. This approach is especially applicable for systemically absorbed drugs found in many orally administered dosage forms and transdermal delivery systems because for such products, drug concentrations in the blood or plasma reflect drug availability at the site of action. The pharmacokinetic approach, however, cannot be applied to locally acting drug products because their blood/plasma concentrations may not reflect drug availability at the site of action. Another limitation in using pharmacokinetic studies lies in the fact that blood/plasma concentrations may be too low to be measured for these products. Consequently, bioequivalence methods recommended by FDA for locally acting drugs are tailored to individual dosage forms and drug products using various approaches (3). For example, to establish bioequivalence of orally inhaled products, FDA has required in vitro tests for comparison of device performance, pharmacodynamic studies for comparison of local delivery between products, and pharmacokinetic studies to ensure that systemic exposure to the drug is minimal. Likewise, depending on individual drugs or drug products, bioequivalence of gastrointestinal (GI) acting products is currently evaluated using one or more of the following methods: in vitro binding assay, in vitro dissolution studies, pharmacokinetic studies, and clinical trials.
Challenges of advanced dosage forms and delivery systems
Advances in pharmaceutical science and technology have led to an increasing growth in pharmaceutical dosage forms, including the availability of various modified-release platforms (e.g., sustained-, delayed-, and pulsatile-release) and complex drug delivery systems (e.g., liposomes, drug-eluting stents, and nanotechnology-derived products). In view of the intricate features of these products, pharmaceutical scientists have encountered significant challenges, ranging from designing and manufacturing such products with high quality to demonstrating and evaluating therapeutic equivalence between generic and innovator drugs.
The following is a recent example relating to the establishment of bioequivalence of liposome drug products. Liposomes are microscopic vesicles comprising one or more bilayers of amphipathic lipid molecules that enclose one or more aqueous compartments. Drug distribution in liposomes depends on the lipophilicity of the incorporated drug. Doxil (doxorubicin HCl liposome injection, Ortho Biotech Products, Bridgewater, NJ) is an example in which doxorubicin, a hydrophilic drug, is encapsulated in the aqueous space of the liposomes. In contrast, amphotericin B is hydrophobic, thus it is intercalated within the lipid bilayers of AmBisome (amphotericin B, Gilead Sciences, Foster City, CA). With the lipophilic surface, AmBisome is easily taken up by the endogenous macrophages residing in the reticuloendothelial system (RES). As a result, AmBisome has a relatively short residence time in the blood. On the contrary, the stealth liposome structure of Doxil protects the liposomes from RES uptake and prolongs circulation time in the bloodstream. With its long residence time in the blood and its small particle size (~100 nm), Doxil possesses an increased permeability through the altered and often compromised vasculature of tumors.
Given the potential of phagocytosis and extravasation processes occurring in vivo, one of the regulatory questions that have arisen is whether blood-level measurement can be used to assess bioequivalence of liposome drug products (4, 5). To address this question, one must understand the disposition of the liposome product under examination. For most conventional liposomes that are prone to RES uptake, it is unlikely that blood levels can be used to determine bioequivalence. Liposomes that are designed to avoid RES uptake may be able to circulate in the bloodstream for a long period of time. However, these liposomes have a greater chance of extravasating through the leaky vascular wall into various tissues. At issue is whether one can demonstrate that the test and reference products have comparable "rate and extent to which the active ingredient or active moiety becomes available at the site of action," a regulatory mandate for establishing bioequivalence (2). It is conceivable that similar questions may be raised for other targeted delivery systems, advanced dosage forms, and combination products.
The trend in the evaluation of therapeutic equivalence
In retrospect, over the decades, the field of biopharmaceutics has evolved from empirical science that investigates the bioavailability and pharmacokinetics of various formulations to more sophisticated mechanism-based approaches that delineate the relationship between drug kinetics and various formulation or administration factors at the molecular level. Similarly, the evolution in science and technology has provided regulatory scientists with opportunities to enhance the equivalence assessment of certain products on a mechanistic basis from time to time. A prominent example is the regulatory application of the Biopharmaceutics Classification System (BCS) that uses biopharmaceutical attributes (i.e., aqueous solubility and intestinal permeability) for predicting bioavailability and bioequivalence (6). The waiver of in vivo bioequivalence studies for a BCS I drug (highly soluble and highly permeable) has been relied on the mechanistic rationing that intrinsic gastric emptying (rather than formulation) is the "rate-limiting" step for in vivo delivery and absorption of the drug if it is formulated in a rapidly dissolving product.
Another example is cholestyramine resins for which in vitro equilibrium binding and in vitro kinetic binding studies have been used to determine bioequivalence by FDA (7). In essence, both in vitro assays use the resin's mechanism of action (i.e., binding of bile acid salts) to assess the binding behavior of different formulations. Undoubtedly, the continued progress in science and technology will facilitate a greater characterization of pharmaceutical attributes as well as better understanding of in vivo drug delivery and absorption processes so that more mechanism-based approaches can be used to establish therapeutic equivalence between products. The following section provides theoretical considerations for bioequivalence assessment, which may shed some light on how we can move forward in this area.
An alternative approach to assessing bioequivalence
Given the assumption of constant clearance, which is generally true within each individual across different formulations of the same drug substance, it has been recognized that bioequivalence should be assessed by focusing on the comparison of absorption pattern rather than distribution, metabolism, or elimination process of the drug. This recommendation is preferred because the absorptive process is more sensitive to a difference between formulations as compared with other biological events occurring subsequent to drug absorption. It follows that because absorption is mainly controlled by when, where, and how a drug is released from a formulation, an alternative approach for the assessment of bioequivalence may be directed to the comparison of in vivo drug delivery profiles (iDDPs) before the drug is absorbed (8). In doing so, equivalence in the rate and extent of drug absorption may be established by showing the similarity of iDDPs between products in comparison.
Schematically, from the entry of a formulation into the body to the point at which the drug reaches systemic circulation or the site of action, an iDDP may consist of some or all of the following steps: deposition, transit, retention, release, and transport. In this setting, the relative contribution of each step to an iDDP may depend on the dosage form, drug product, route of administration, or clinical indication under consideration. For example, various dosage forms are made with distinct objectives that can be manifested in their iDDPs. Where the drug is deposited will be an important point for nasal sprays and aerosols, as well as locally acting GI products and dermatological medications. In contrast, maneuvering drug transit through the GI tract is the primary goal in the design of orally administered extended-release products. Although control of retention time in the stomach is essential for floating systems, the location of drug release in the intestine is the focus for delayed-release dosage forms (e.g., enteric-coated tablets). On the other hand, consideration of transport process is crucial for achieving bioequivalence of liposomal products and other similar lipid-based formulations, given the unique characteristics of these dosage forms.
Equivalence by design
From product design and manufacturing perspectives, bioequivalence can be advanced by matching the iDDP of the reference product during test-product development, which is particularly important for complex pharmaceutical dosage forms and delivery systems. Technically, this objective can be achieved using an approach analogous to the quality-by-design (QbD) paradigm that the ICH and FDA are currently promoting for pharmaceutical development (9). As illustrated in the FDA Q8(R1) guidance, the application of a QbD approach must begin with predefined objectives; namely, a quality target product profile as related to quality, safety, and efficacy (9). After the quality target product profile is defined, one will identify critical quality attributes of the product and use these attributes as the benchmark to design formulation and manufacturing process. In parallel with the QbD concept, an equivalence-by-design (EbD) approach can start with determining the target (or reference) product profile based on the critical steps of its iDDP as related to bioequivalence. Once the target (reference) iDDP is defined, one may identify biomarkers or in vitro markers to characterize critical steps of the target (reference) iDDP. The test formulation and manufacturing process can then be designed with the use of these markers to match the target iDDP.
Characterization of the iDDPs
A question that may arise about the proposed EbD approach is whether there are in vitro markers or biomarkers available for characterization of iDDPs. Literature information indicates that the in vivo drug delivery pathways may not be well documented for most pharmaceutical products, presumably because of the paucity of methodology for study in this area. Nonetheless, some of the research tools may have been applied for these purposes during drug discovery and development.
One example is the application of in vitro dissolution or release testing for predicting drug release in vivo.In vitro dissolution and release testing has been routinely used to guide drug development as well as predict bioequivalence between products before and after changes in formulation or manufacturing. The key issue is whether these methods adequately emulate critical in vivo release or dissolution processes. As dictated in US regulations, in vitro dissolution or release testing can be used as an indicator for bioequivalence if it is correlated with and predictive of human in vivo bioavailability data (2, 10). Indeed, a major problem with many of the current in vitro dissolution and/or release methods lies in the lack of correlation between in vitro and in vivo data.
Other methods may be used to explore the course of drug delivery in the body. For instance, radio-labeled studies and imaging techniques such as gamma scintigraphy have been applied to examine drug deposition, transit, retention, or release from several types of dosage forms in drug discovery and development (11–15). Current methods may be modified or improved for iDDP characterization. In addition, the markers of iDDPs may be identified through the integration of knowledge and methodologies from various disciplines such as biophysics, biochemistry, biopharmaceutics, and other relevant fields. It is hoped that the continuous innovation in pharmaceutical industry may facilitate the development of more biomarkers or in vitro markers to characterize the iDDPs.
Potential factors affecting iDDPs
Several pharmaceutical factors are known to influence the course of drug delivery and release in vivo, which may include formulation, excipient, dosage form, product design, and manufacturing process. In addition, biopharmaceutical considerations ought to be given with respect to the potential effects of certain excipients on drug bioavailability and possible drug/formulation interactions with intrinsic or extrinsic factors. Although most excipients on the market are devoid of pharmacologic action, some common excipients (e.g., sorbitol and polysorbate 80) have been shown to exert unintended influence on iDDPs and in turn, bioavailability and bioequivalence (16). Similarly, the impact of various intrinsic and extrinsic factors on iDDPs and drug absorption may have been underestimated.
The ICH E5 document has provided several good examples of intrinsic and extrinsic factors that may influence pharmacokinetic and pharmacodynamic responses of many drugs (17). As illustrated, important intrinsic factors may include genetic, physiological, and pathological conditions of the patient. On the other hand, relevant extrinsic factors may be related to the environment (e.g., climate, sunlight, and pollution), food intake (e.g., beverage and diet), lifestyle (e.g., smoking and exercise), and concomitant medications.
The potential interplay between pharmaceutical characteristics such as formulation and intrinsic factors such as gender has also been studied and reported in the literature (18). In this case, bioequivalence studies were conducted on two extended-release products containing the same drug substance. Higher plasma concentrations were obtained in females (compared with males) from Product A, yet no gender difference was found for Product B. Investigation with in vitro dissolution testing at various pH values also showed dissimilar dissolution profiles between the two formulations. In the case of Product A, a lower fraction of the drug dissolved at pH 4.5 and a higher fraction dissolved at pH 6.8, possibly reflecting more drugs in the ileum and perhaps in the colon. For Product B, however, most of the drug dissolved at pH 4.5, suggesting a rapid release at the duodenum and jejunum. Literature information revealed that women tend to have longer gastric emptying time and longer intestinal transit time. With all the data collected, therefore, the pharmacokinetic differences observed in this study have been attributed to the potential interaction between formulation and gender, as evidenced by the different drug release profiles from the two formulations and differing GI transit time in men and women.
Apart from intrinsic factors, the impact of extrinsic factors on iDDPs may be exemplified by the market withdrawal of Palladone (hydromorphone HCl extended-release, Purdue Pharma, Cranbury, NJ) capsules in 2005. As a derivative of morphine, hydromorphone is known to be a potent centrally acting analgesic drug. Palladone was withdrawn because this extended-release product consisted of a matrix system that was found to be prone to dose dumping when taken with alcohol. A similar problem occurred with fentanyl transdermal delivery systems. It was suspected that an increased rate and extent of drug permeation through the skin might have occurred after some of the fentanyl patches were exposed to heat.
Overall, the potential interplay between pharmaceutical attributes and intrinsic/extrinsic factors may be investigated during the course of drug development. These interactions may be proactively explored through in vitro,in silico, or in vivo methods that allow for the study of iDDPs before drug absorption.
Theoretical considerations prescribe that bioequivalence may be assessed by focusing comparisons on the in vivo drug delivery profiles (iDDPs) between formulations. The rationale for this approach rests on the premises that absorption process is the key determinant for bioequivalence, given constant clearance within each individual across formulations. Because drug absorption is chiefly controlled by when, where, and how the drug is released from the formulation, it follows that bioequivalence assessment may be made by means of the comparison of iDDPs between products. Similarly, to achieve bioequivalence of advanced pharmaceutical dosage forms or delivery systems, one can first determine the critical characteristics of the reference iDDP and then use this information as the target profile for design and manufacturing of the test product. It is surmised that in vitro markers or biomarkers are available or can be developed to characterize the pivotal stage(s) of an IDDP. In analogy to the QbD paradigm for pharmaceutical development, this equivalence-by-design (EbD) approach can be applied to devise the test product by mapping the target iDDP through the use of in vitro markers or biomarkers. Ultimately, successful design of an equivalent product can be accomplished with a better understanding of all the relevant factors that may have potential impact on the iDDPs of the products in comparison.
Mei-Ling Chen, PhD, is associate director at the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Building 51, Rm. 4108, Silver Spring, MD 20993-0002, tel. 301.796.1658, fax 301.796.9997, firstname.lastname@example.org
1. FDA, Electronic Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs, Rockville, MD), www.fda.gov/cder/ob/default.htm, accessed Sept. 21, 2009.
2. "Bioavailability and Bioequivalence Requirements," in Code of Federal Regulations, Title 21, Food and Drugs (General Services Administration, Washington DC, 2009), Part 320.
3. FDA, Critical Path Opportunities for Generic Drugs, May 1, 2007, www.fda.gov/oc/initiatives/criticalpath/reports/generic.html, accessed Sept. 21, 2009.
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6. FDA, Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (Rockville, MD, Aug. 2000).
7. FDA, Interim Guidance: Cholestyramine Powder: In Vitro Bioequivalence (Rockville, MD, July 1993).
8. M.-L. Chen and V.H.L. Lee, "Equivalence-by-Design: Targeting In Vivo Drug Delivery Profile," Pharm. Res. 25, 2723–2730 (2008).
9. FDA, Guidance for Industry: Q8(R1) Pharmaceutical Development (Rockville, MD, June 2009).
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16. M.-L. Chen et al., "A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol," Pharm. Res. 24, 73–80 (2007).
17. FDA, "Guidance for Industry: Ethnic Factors in the Acceptability of Foreign Clinical Data," Fed. Regist. 63 (111), 31790–31796 (June 10, 1998).
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