Guidance for Industry
`Bioavailability and Bioequivalence
`Studies for Orally Administered Drug
`Products — General Considerations
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`March 2003
`BP
`
`Revision 1
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`AMN1045
`IPR of Patent No. 7,919,499
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`

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`Guidance for Industry
`Bioavailability and Bioequivalence
`Studies for Orally Administered Drug
`Products — General Considerations
`
`Additional copies are available from:
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
` http://www.fda.gov/cder/guidance/index.htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`March 2003
`BP
`
`Revision 1
`
`AMN1045
`IPR of Patent No. 7,919,499
`
`

`

`TABLE OF CONTENTS
`
`BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FOR ORALLY
`ADMINISTERED DRUG PRODUCTS — GENERAL CONSIDERATIONS...................... 1
`I.
`INTRODUCTION................................................................................................................. 1
`II. BACKGROUND ................................................................................................................... 2
`A. General............................................................................................................................................2
`B. Bioavailability.................................................................................................................................3
`C. Bioequivalence................................................................................................................................4
`III. METHODS TO DOCUMENT BA AND BE...................................................................... 6
`A. Pharmacokinetic Studies...............................................................................................................6
`Pharmacodynamic Studies............................................................................................................9
`B.
`C. Comparative Clinical Studies .......................................................................................................9
`In Vitro Studies ............................................................................................................................10
`D.
`IV. COMPARISON OF BA MEASURES IN BE STUDIES................................................. 11
`V. DOCUMENTATION OF BA AND BE............................................................................. 11
`A.
`Solutions........................................................................................................................................12
`Suspensions...................................................................................................................................12
`B.
`C.
`Immediate-Release Products: Capsules and Tablets................................................................12
`D. Modified-Release Products .........................................................................................................14
`E. Miscellaneous Dosage Forms ......................................................................................................17
`VI. SPECIAL TOPICS ............................................................................................................. 17
`A. Food-Effect Studies......................................................................................................................17
`B. Moieties to Be Measured .............................................................................................................17
`C. Long Half-Life Drugs ..................................................................................................................19
`D. First Point Cmax..........................................................................................................................19
`E. Orally Administered Drugs Intended for Local Action............................................................20
`F. Narrow Therapeutic Range Drugs .............................................................................................20
`ATTACHMENT: GENERAL PHARMACOKINETIC STUDY DESIGN ......................... 21
`AND DATA HANDLING........................................................................................................... 21
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`Guidance for Industry1
`
`BA and BE Studies for Orally Administered Drug Products —
`General Considerations
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this
`topic. It does not create or confer any rights for or on any person and does not operate to bind
`FDA or the public. An alternative approach may be used if such approach satisfies the
`requirements of the applicable statutes and regulations.
`
`I.
`
`INTRODUCTION
`
`This guidance is intended to provide recommendations to sponsors and/or applicants planning to
`include bioavailability (BA) and bioequivalence (BE) information for orally administered drug
`products in investigational new drug applications (INDs), new drug applications (NDAs),
`abbreviated new drug applications (ANDAs), and their supplements. This guidance contains
`advice on how to meet the BA and BE requirements set forth in part 320 (21 CFR part 320) as
`they apply to dosage forms intended for oral administration.2 The guidance is also generally
`applicable to nonorally administered drug products where reliance on systemic exposure
`measures is suitable to document BA and BE (e.g., transdermal delivery systems and certain
`rectal and nasal drug products). We believe that the guidance will be useful for applicants
`planning to conduct BA and BE studies during the IND period for an NDA, BE studies intended
`for submission in an ANDA, and BE studies conducted in the postapproval period for certain
`changes in both NDAs and ANDAs.3
`
`This guidance revises the October 2000 guidance. We have revised our recommendations
`regarding (1) study design and dissolution methods development, (2) comparisons of BA
`measures, (3) the definition of proportionality, and (4) waivers for bioequivalence studies. The
`guidance also makes other revisions for clarification. We believe that these revisions provide
`clear guidance to sponsors conducting BA and BE studies for orally administered drug products.
`
`
`2 These dosage forms include tablets, capsules, solutions, suspensions, conventional/immediate release, and
`modified (extended, delayed) release drug products.
`
`3 Other Agency guidances are available that consider specific scale-up and postapproval changes (SUPAC) for
`different types of drug products to help satisfy regulatory requirements in part 320 and § 314.70 (21 CFR 314.70).
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`FDA's guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`II.
`
`BACKGROUND
`
`A.
`
`General
`
`Studies to measure BA and/or establish BE of a product are important elements in support of
`INDs, NDAs, ANDAs, and their supplements. As part of INDs and NDAs for orally
`administered drug products, BA studies focus on determining the process by which a drug is
`released from the oral dosage form and moves to the site of action. BA data provide an estimate
`of the fraction of the drug absorbed, as well as its subsequent distribution and elimination. BA
`can be generally documented by a systemic exposure profile obtained by measuring drug and/or
`metabolite concentration in the systemic circulation over time. The systemic exposure profile
`determined during clinical trials in the IND period can serve as a benchmark for subsequent BE
`studies.
`
`Studies to establish BE between two products are important for certain changes before approval
`for a pioneer product in NDA and ANDA submissions and in the presence of certain
`postapproval changes in NDAs and ANDAs. In BE studies, an applicant compares the systemic
`exposure profile of a test drug product to that of a reference drug product (RLD). For two orally
`administered drug products to be bioequivalent, the active drug ingredient or active moiety in the
`test product must exhibit the same rate and extent of absorption as the reference drug product
`(see 21 CFR 320.1(e) and 320.23(b)).
`
`Both BA and BE studies are required by regulations, depending on the type of application being
`submitted. Under § 314.94, BE information is required to ensure therapeutic equivalence
`between a pharmaceutically equivalent test drug product and a reference listed drug. Regulatory
`requirements for documentation of BA and BE are provided in part 320, which contains two
`subparts. Subpart A covers general provisions, while subpart B contains 18 sections delineating
`the following general BA/BE requirements:
`
`• Requirements for submission of BA and BE data (§ 320.21)
`• Criteria for waiver of an in vivo BA or BE study (§ 320.22)
`• Basis for demonstrating in vivo BA or BE (§ 320.23)
`• Types of evidence to establish BA or BE (§ 320.24)
`• Guidelines for conduct of in vivo BA studies (§ 320.25)
`• Guidelines on design of single-dose BA studies (§ 320.26)
`• Guidelines on design of multiple-dose in vivo BA studies (§ 320.27)
`• Correlations of BA with an acute pharmacological effect or clinical evidence
`(§ 320.28)
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`• Analytical methods for an in vivo BA study (§ 320.29)
`• Inquiries regarding BA and BE requirements and review of protocols by FDA
`(§ 320.30)
`• Applicability of requirements regarding an IND application (§ 320.31)
`• Procedures for establishing and amending a BE requirement (§ 320.32)
`• Criteria and evidence to assess actual or potential BE problems (§ 320.33)
`• Requirements for batch testing and certification by FDA (§ 320.34)
`• Requirements for in vitro batch testing of each batch (§ 320.35)
`• Requirements for maintenance of records of BE testing (§ 320.36)
`• Retention of BA samples (§ 320.38)
`• Retention of BE samples (§ 320.63)
`
`B.
`
`Bioavailability
`
`Bioavailability is defined in § 320.1 as:
`
`the rate and extent to which the active ingredient or active moiety is absorbed from a
`drug product and becomes available at the site of action. For drug products that are
`not intended to be absorbed into the bloodstream, bioavailability may be assessed by
`measurements intended to reflect the rate and extent to which the active ingredient or
`active moiety becomes available at the site of action.
`
`This definition focuses on the processes by which the active ingredients or moieties are released
`from an oral dosage form and move to the site of action.
`
`From a pharmacokinetic perspective, BA data for a given formulation provide an estimate of the
`relative fraction of the orally administered dose that is absorbed into the systemic circulation
`when compared to the BA data for a solution, suspension, or intravenous dosage form (21 CFR
`320.25(d)(2) and (3)). In addition, BA studies provide other useful pharmacokinetic information
`related to distribution, elimination, the effects of nutrients on absorption of the drug, dose
`proportionality, linearity in pharmacokinetics of the active moieties and, where appropriate,
`inactive moieties. BA data can also provide information indirectly about the properties of a drug
`substance before entry into the systemic circulation, such as permeability and the influence of
`presystemic enzymes and/or transporters (e.g., p-glycoprotein).
`
`BA for orally administered drug products can be documented by developing a systemic exposure
`profile. A profile can be obtained by measuring the concentration of active ingredients and/or
`active moieties and, when appropriate, its active metabolites over time in samples collected from
`the systemic circulation. Systemic exposure patterns reflect both release of the drug substance
`from the drug product and a series of possible presystemic/systemic actions on the drug
`substance after its release from the drug product. We recommend that additional comparative
`studies be performed to understand the relative contribution of these processes to the systemic
`exposure pattern.
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`One regulatory objective is to assess, through appropriately designed BA studies, the
`performance of the formulations used in the clinical trials that provide evidence of safety and
`efficacy (21 CFR 320.25(d)(1)). Before marketing a drug product, the performance of the clinical
`trial dosage form can be optimized, in the context of demonstrating safety and efficacy. The
`systemic exposure profiles of clinical trial material can be used as a benchmark for subsequent
`formulation changes and can be useful as a reference for future BE studies.
`
`Although BA studies have many pharmacokinetic objectives beyond formulation performance as
`described above, we note that subsequent sections of this guidance focus on using relative BA
`(referred to as product quality BA) and, in particular, BE studies as a means to document product
`quality. In vivo performance, in terms of BA/BE, can be considered to be one aspect of product
`quality that provides a link to the performance of the drug product used in clinical trials and to
`the database containing evidence of safety and efficacy.
`
`C.
`
`Bioequivalence
`
`Bioequivalence is defined in § 320.1 as:
`
`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.
`
`As noted in the statutory definitions, both BE and product quality BA focus on the release of a
`drug substance from a drug product and subsequent absorption into the systemic circulation. As
`a result, we recommend that similar approaches to measuring BA in an NDA generally be
`followed in demonstrating BE for an NDA or an ANDA. Establishing product quality BA is a
`benchmarking effort with comparisons to an oral solution, oral suspension, or an intravenous
`formulation. In contrast, demonstrating BE is usually a more formal comparative test that uses
`specified criteria for comparisons and predetermined BE limits for such criteria.
`
`1.
`
`IND/NDAs
`
`BE documentation can be useful during the IND or NDA period to establish links
`between (1) early and late clinical trial formulations; (2) formulations used in clinical
`trial and stability studies, if different; (3) clinical trial formulations and to-be-marketed
`drug product; and (4) other comparisons, as appropriate. In each comparison, the new
`formulation or new method of manufacture is the test product and the prior formulation
`or method of manufacture is the reference product. We recommend that the
`determination to redocument BE during the IND period be generally left to the judgment
`of the sponsor, who can wish to use the principles of relevant guidances (in this guidance,
`see sections II.C.3, Postapproval Changes, and III.D, in Vitro Studies) to determine when
`changes in components, composition, and/or method of manufacture suggest further in
`vitro and/or in vivo studies be performed.
`
`A test product can fail to meet BE limits because the test product has higher or lower
`measures of rate and extent of absorption compared to the reference product or because
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`the performance of the test or reference product is more variable. In some cases,
`nondocumentation of BE can arise because of inadequate numbers of subjects in the
`study relative to the magnitude of intrasubject variability, and not because of either high
`or low relative BA of the test product. Adequate design and execution of a BE study will
`facilitate understanding of the causes of nondocumentation of BE.
`
`Where the test product generates plasma levels that are substantially above those of the
`reference product, the regulatory concern is not therapeutic failure, but the adequacy of
`the safety database from the test product. Where the test product has levels that are
`substantially below those of the reference product, the regulatory concern becomes
`therapeutic efficacy. When the variability of the test product rises, the regulatory concern
`relates to both safety and efficacy, because it may suggest that the test product does not
`perform as well as the reference product, and the test product may be too variable to be
`clinically useful.
`
`Proper mapping of individual dose-response or concentration-response curves is useful in
`situations where the drug product has plasma levels that are either higher or lower than
`the reference product and are outside usual BE limits. In the absence of individual data,
`population dose-response or concentration-response data acquired over a range of doses,
`including doses above the recommended therapeutic doses, may be sufficient to
`demonstrate that the increase in plasma levels would not be accompanied by additional
`risk. Similarly, population dose- or concentration-response relationships observed over a
`lower range of doses, including doses below the recommended therapeutic doses, may be
`able to demonstrate that reduced levels of the test product compared to the reference
`product are associated with adequate efficacy. In either event, the burden is on the
`sponsor to demonstrate the adequacy of the clinical trial dose-response or concentration-
`response data to provide evidence of therapeutic equivalence. In the absence of this
`evidence, failure to document BE may suggest the product should be reformulated, the
`method of manufacture for the test product be changed, and/or the BE study be repeated.
`
`2.
`
`ANDAs
`
`BE studies are a critical component of ANDA submissions. The purpose of these studies
`is to demonstrate BE between a pharmaceutically equivalent generic drug product and the
`corresponding reference listed drug (21 CFR 314.94 (a)(7)). Together with the
`determination of pharmaceutical equivalence, establishing BE allows a regulatory
`conclusion of therapeutic equivalence.
`
`3.
`
`Postapproval Changes
`
`Information on the types of in vitro dissolution and in vivo BE studies that we
`recommend be conducted for immediate-release and modified-release drug products
`approved as either NDAs or ANDAs in the presence of specified postapproval changes is
`provided in the FDA guidances for industry entitled SUPAC-IR: Immediate Release
`Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry,
`Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence
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`Documentation; and SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-
`Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro
`Dissolution Testing, and In Vivo Bioequivalence Documentation. In the presence of
`certain major changes in components, composition, and/or method of manufacture after
`approval, we recommend that in vivo BE be redemonstrated. For approved NDAs, we
`also recommend that the drug product after the change be compared to the drug product
`before the change. For approved ANDAs, we also recommend that the drug product after
`the change be compared to the reference listed drug. Under section 506A(c)(2)(B) of the
`Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 356a(c)(2)(B)), postapproval
`changes requiring completion of studies in accordance with part 320 must be submitted in
`a supplement and approved by FDA before distributing a drug product made with the
`change.
`
`III. METHODS TO DOCUMENT BA AND BE
`
`As noted in § 320.24, several in vivo and in vitro methods can be used to measure product
`quality BA and to establish BE. In descending order of preference, these include
`pharmacokinetic, pharmacodynamic, clinical, and in vitro studies. These general approaches are
`discussed in the following sections of this guidance. Product quality BA and BE frequently rely
`on pharmacokinetic measures such as AUC and Cmax that are reflective of systemic exposure.
`
`A.
`
`1.
`
`Pharmacokinetic Studies
`
`General Considerations
`
`The statutory definitions of BA and BE, expressed in terms of rate and extent of
`absorption of the active ingredient or moiety to the site of action, emphasize the use of
`pharmacokinetic measures in an accessible biological matrix such as blood, plasma,
`and/or serum to indicate release of the drug substance from the drug product into the
`systemic circulation.4 This approach rests on an understanding that measuring the active
`moiety or ingredient at the site of action is generally not possible and, furthermore, that
`some relationship exists between the efficacy/safety and concentration of active moiety
`and/or its important metabolite or metabolites in the systemic circulation. To measure
`product quality BA and establish BE, reliance on pharmacokinetic measurements may be
`viewed as a bioassay that assesses release of the drug substance from the drug product
`into the systemic circulation. A typical study is conducted as a crossover study. In this
`type of study, clearance, volume of distribution, and absorption, as determined by
`physiological variables (e.g. gastric emptying, motility, pH), are assumed to have less
`interoccasion variability compared to the variability arising from formulation
`performance. Therefore, differences between two products because of formulation
`factors can be determined.
`
`4 If serial measurements of the drug or its metabolites in plasma, serum, or blood cannot be accomplished,
`measurement of urinary excretion can be used to document BE.
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`2.
`
`Pilot Study
`
`If the sponsor chooses, a pilot study in a small number of subjects can be carried out
`before proceeding with a full BE study. The study can be used to validate analytical
`methodology, assess variability, optimize sample collection time intervals, and provide
`other information. For example, for conventional immediate-release products, careful
`timing of initial samples may avoid a subsequent finding in a full-scale study that the first
`sample collection occurs after the plasma concentration peak. For modified-release
`products, a pilot study can help determine the sampling schedule to assess lag time and
`dose dumping. A pilot study that documents BE can be appropriate, provided its design
`and execution are suitable and a sufficient number of subjects (e.g., 12) have completed
`the study.
`
`3.
`
`Pivotal Bioequivalence Studies
`
`General recommendations for a standard BE study based on pharmacokinetic
`measurements are provided in Attachment A.
`
`4.
`
` Study Designs
`
`Nonreplicate crossover study designs are recommended for BE studies of immediate-
`release and modified-release dosage forms. However, sponsors and/or applicants have
`the option of using replicate designs for BE studies for these drug products. Replicate
`study designs may offer several scientific advantages compared to nonreplicate designs.
`The advantages of replicate study designs may be that they (1) allow comparisons of
`within-subject variances for the test and reference products, (2) provide more information
`about the intrinsic factors underlying formulation performance, and (3) reduce the
`number of subjects participating in the BE study. The recommended method of analysis
`of nonreplicate or replicate studies to establish BE is average bioequivalence, as
`discussed in section IV. General recommendations for nonreplicate study designs are
`provided in Attachment A. Recommendations for replicate study designs can be found in
`the guidance for industry Statistical Approaches to Establishing Bioequivalence.
`
`5.
`
`Study Population
`
`We recommend that, unless otherwise indicated by a specific guidance, subjects recruited
`for in vivo BE studies be 18 years of age or older and capable of giving informed
`consent. This guidance recommends that in vivo BE studies be conducted in individuals
`representative of the general population, taking into account age, sex, and race. We
`recommend that if the drug product is intended for use in both sexes, the sponsor attempt
`to include similar proportions of males and females in the study. If the drug product is to
`be used predominantly in the elderly, we also recommend that the sponsor attempt to
`include as many subjects of 60 years of age or older as possible. We recommend that the
`total number of subjects in the study provide adequate power for BE demonstration, but it
`is not expected that there will be sufficient power to draw conclusions for each subgroup.
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`Statistical analysis of subgroups is not recommended. We recommend that restrictions
`on admission into the study generally be based solely on safety considerations. In some
`instances, it may be useful to admit patients into BE studies for whom a drug product is
`intended. In this situation, we recommend that sponsors and/or applicants attempt to
`enter patients whose disease process is stable for the duration of the BE study. In
`accordance with § 320.31, for some products that will be submitted in ANDAs, an IND
`may be required for BE studies to ensure patient safety.
`
`6.
`
`Single-Dose/Multiple-Dose Studies
`
`Instances where multiple-dose studies can be useful are defined under
`§ 320.27(a)(3). However, this guidance generally recommends single-dose
`pharmacokinetic studies for both immediate- and modified-release drug products to
`demonstrate BE because they are generally more sensitive in assessing release of the
`drug substance from the drug product into the systemic circulation (see section V). We
`recommend that if a multiple-dose study design is important, appropriate dosage
`administration and sampling be carried out to document attainment of steady state.
`
`7.
`
`Bioanalytical Methodology
`
`We recommend sponsors ensure that bioanalytical methods for BA and BE studies are
`accurate, precise, selective, sensitive, and reproducible. A separate FDA guidance
`entitled Bioanalytical Method Validation is available to assist sponsors in validating
`bioanalytical methods.
`
`8.
`
`Pharmacokinetic Measures of Systemic Exposure
`
`Both direct (e.g., rate constant, rate profile) and indirect (e.g., Cmax, Tmax, mean
`absorption time, mean residence time, Cmax normalized to AUC) pharmacokinetic
`measures are limited in their ability to assess rate of absorption. This guidance, therefore,
`recommends a change in focus from these direct or indirect measures of absorption rate
`to measures of systemic exposure. Cmax and AUC can continue to be used as measures
`for product quality BA and BE, but more in terms of their capacity to assess exposure
`than their capacity to reflect rate and extent of absorption. We recommend that reliance
`on systemic exposure measures reflect comparable rate and extent of absorption, which in
`turn would achieve the underlying statutory and regulatory objective of ensuring
`comparable therapeutic effects. Exposure measures are defined relative to early, peak,
`and total portions of the plasma, serum, or blood concentration-time profile, as follows:
`
`a. Early Exposure
`
`For orally administered immediate-release drug products, BE can generally be
`demonstrated by measurements of peak and total exposure. An early exposure
`measure may be informative on the basis of appropriate clinical efficacy/safety
`trials and/or pharmacokinetic/pharmacodynamic studies that call for better control
`of drug absorption into the systemic circulation (e.g., to ensure rapid onset of an
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`analgesic effect or to avoid an excessive hypotensive action of an
`antihypertensive). In this setting, the guidance recommends use of partial AUC as
`an early exposure measure. We recommend that the partial area be truncated at
`the population median of Tmax values for the reference formulation. We also
`recommend that at least two quantifiable samples be collected before the expected
`peak time to allow adequate estimation of the partial area.
`
`b.
`
`Peak Exposure
`
`We recommend that peak exposure be assessed by measuring the peak drug
`concentration (Cmax) obtained directly from the data without interpolation.
`
`c.
`
`Total Exposure
`
`For single-dose studies, we recommend that the measurement of total exposure
`be:
`
`•
`
`•
`
`Area under the plasma/serum/blood concentration-time curve from time
`zero to time t (AUC0-t), where t is the last time point with measurable
`concentration for individual formulation.
`
`Area under the plasma/serum/blood concentration-time curve from time
`zero to time infinity (AUC0-∞), where AUC0-∞ = AUC0-t + Ct/λz, Ct is the
`last measurable drug concentration and λz is the terminal or elimination
`rate constant calculated according to an appropriate method. We
`recommend that the terminal half-life (t1/2) of the drug also be reported.
`
`For steady-state studies, we recommend that the measurement of total exposure be
`the area under the plasma, serum, or blood concentration-time curve from time
`zero to time tau over a dosing interval at steady state (AUC0-tau), where tau is the
`length of the dosing interval.
`
`B.
`
`Pharmacodynamic Studies
`
`Pharmacodynamic studies are not recommended for orally administered drug products when the
`drug is absorbed into the systemic circulation and a pharmacokinetic approach can be used to
`assess systemic exposure and establish BE. However, in those instances where a
`pharmacokinetic approach is not possible, suitably validated pharmacodynamic methods can be
`used to demonstrate BE.
`
`C.
`
`Comparative Clinical Studies
`
`Where there are no other means, well-controlled clinical trials in humans can be useful to
`provide supportive evidence of BA or BE. However, we recommend that the use of comparative
`clinical trials as an approach to demonstrate BE generally be considered insensitive and be
`avoided where possible (21 CFR 320.24). The use of BE studies with clinical trial endpoints can
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`be appropriate to demonstrate BE for orally administered drug products when measurement of
`the active ingredients or active moieties in an accessible biological fluid (pharmacokinetic
`approach) or pharmacodynamic approach is infeasible.
`
`D.
`
`In Vitro Studies
`
`Under certain circumstances, product quality BA and BE can be documented using in vitro
`approaches (21 CFR 320.24(b)(5) and 21 CFR 320.22(d)(3)). For highly soluble, highly
`permeable, rapidly dissolving, and orally administered drug products, documentation of BE
`using an in vitro approach (dissolution studies) is appropriate based on the biopharmaceutics
`classification system.5 This approach may also be suitable under some circumstances in
`assessing BE during the IND period, for NDA and ANDA submissions, and in the presence of
`certain postapproval changes to approved NDAs and ANDAs. In addition, in vitro approaches to
`documenting BE for nonbioproblem drugs approved before 1962 remain appropriate (21 CFR
`320.33).
`
`Dissolution testing is also used to assess batch-to-batch quality, where the dissolution tests, with
`defined procedures and acceptance criteria, are used to allow batch release. We recommend that
`dissolution testing is also used to (1) provide process control and quality assurance, and (2)
`assess whether further BE studies relative to minor postapproval changes be conducted, where
`dissolution can function as a signal of bioinequivalence. In vitro dissolution characterization is
`encouraged for all product formulations investigated (including prototype formulations),
`particularly if in vivo absorption characteristics are being defined for the different product
`formulations. Such efforts may enable the establishment of an in vitro-in vivo correlation.
`When an in vitro-in vivo correlation or association is available (21 CFR 320.24(b)(1)(ii)), the in
`vitro test can serve not only as a quality control spe