Guidance for Industry
`Bioavailability and Bioequivalence
`Studies for Orally Administered
`Drug Products — General
`Considerations
`
`DRAFT GUIDANCE
`This guidance document is being distributed for comment purposes only.
`
`Comments and suggestions regarding this draft document should be submitted within 30 days of
`publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug
`Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be
`identified with the docket number listed in the notice of availability that publishes in the Federal
`Register.
`
`For questions regarding this draft document contact (CDER) Aida Sanchez 301-827-5847.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`July 2002
`BP
`
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`AMN1069
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`IPR2018-00943
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`

`

`Guidance for Industry
`Bioavailability and Bioequivalence
`Studies for Orally Administered
`Drug Products — General
`Considerations
`
`Additional copies are available from:
`Office of Training and Communication
`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)
`
`July 2002
`BP
`
`J:\!GUIDANC\4964dft.doc
`07/10/02
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`AMN1069
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`TABLE OF CONTENTS
`
`INTRODUCTION................................................................................................................. 1
`I.
`II. BACKGROUND ................................................................................................................... 2
`A. General .................................................................................................................................2
`B. Bioavailability.......................................................................................................................3
`C. Bioequivalence ......................................................................................................................4
`III. METHODS TO DOCUMENT BA AND BE...................................................................... 6
`A.
`Pharmacokinetic Studies.......................................................................................................6
`B.
`Pharmacodynamic Studies..................................................................................................10
`C. Comparative Clinical Studies..............................................................................................10
`D.
`In Vitro Studies...................................................................................................................10
`IV. COMPARISON OF BA MEASURES IN BE STUDIES................................................. 11
`V. DOCUMENTATION OF BA AND BE............................................................................. 12
`A.
`Solutions.............................................................................................................................12
`B.
`Suspensions.........................................................................................................................13
`C.
`Immediate-Release Products: Capsules and Tablets ...........................................................13
`D. Modified-Release Products..................................................................................................14
`E. Miscellaneous Dosage Forms...............................................................................................17
`VI. SPECIAL TOPICS.............................................................................................................. 18
`A.
`Food-Effect Studies.............................................................................................................18
`B. Moieties to Be Measured.....................................................................................................18
`C. Long Half-Life Drugs..........................................................................................................20
`D.
`First Point Cmax.................................................................................................................20
`E. Orally Administered Drugs Intended for Local Action.......................................................20
`F. Narrow Therapeutic Range Drugs ......................................................................................21
`ATTACHMENT A: General Pharmacokinetic Study Design and Data Handling ............. 22
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`Draft — Not for Implementation
`
`GUIDANCE FOR INDUSTRY1
`
`Bioavailability and Bioequivalence Studies for Orally Administered
`Drug Products — General Considerations
`
`This draft 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 is a revision
`of the October 2000 guidance. This revised guidance changes 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. The revisions should provide better guidance to sponsors
`conducting BA and BE studies for orally administered drug products. 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 non-orally 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). The guidance should 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
`
`1 This guidance has been prepared by the Biopharmaceutics Coordinating Committee in the Center for Drug
`Evaluation and Research (CDER) at the Food and Drug Administration (FDA).
`
`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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`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. For two orally administered drug products to be bioequivalent, the active drug
`ingredient or active moiety in the test product should exhibit the same rate and extent of
`absorption as the reference drug product.
`
`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)
` Analytical methods for an in vivo BA study (§ 320.29)
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` 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 may 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 obtained from 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. Additional
`comparative studies should 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)). The performance of the clinical trial dosage form
`may be optimized, in the context of demonstrating safety and efficacy, before marketing
`a drug product. The systemic exposure profiles of clinical trial material can be used as a
`benchmark for subsequent formulation changes and may be useful as a reference for
`future BE studies.
`
`Although BA studies have many pharmacokinetic objectives beyond formulation
`performance as described above, it should be noted 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, may 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. For this reason, similar approaches to measuring BA in an NDA should
`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 may 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. The determination to redocument BE during the IND period is generally
`left to the judgment of the sponsor, who may wish to use the principles of relevant
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`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 should be
`performed.
`
`A test product may 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 the performance of the test or reference product is more variable. In
`some cases, nondocumentation of BE may 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, a failure to document BE may suggest the product
`should be reformulated, the method of manufacture for the test product should be
`changed, and/or the BE study should 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)).
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`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 should
`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 Documentation (November 1995); 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 (September 1997). In the presence of
`certain major changes in components, composition, and/or method of manufacture
`after approval, in vivo BE should be redemonstrated. For approved NDAs, the
`drug product after the change should be compared to the drug product before the
`change. For approved ANDAs, the drug product after the change should 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 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
`
`4 If serial measurements of the drug or its metabolites in plasma, serum, or blood cannot be accomplished,
`measurement of urinary excretion may be used to document BE.
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`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.
`
`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 may 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 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 offer several scientific advantages compared to
`nonreplicate designs. The advantages of replicate study designs are that they (1)
`allow comparisons of within-subject variances for the test and reference products,
`(2) indicate whether a test product exhibits higher or lower within-subject
`variability in the bioavailability measures when compared to the reference
`product, (3) provide more information about the intrinsic factors underlying
`formulation performance, and (4) reduce the number of subjects needed in the BE
`study. The recommended method of analysis of nonreplicate or replicate studies
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`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 (January 2001).
`
`5.
`
`Study Population
`
`Unless otherwise indicated by a specific guidance, subjects recruited for in vivo
`BE studies should 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. If the drug product is intended for use in both sexes, the sponsor should
`attempt to include similar proportions of males and females in the study. If the
`drug product is to be used predominantly in the elderly, the sponsor should
`attempt to include as many subjects of 60 years of age or older as possible. The
`total number of subjects in the study should provide adequate power for BE
`demonstration, but it is not expected that there will be sufficient power to draw
`conclusions for each subgroup. Statistical analysis of subgroups is not
`recommended. Restrictions on admission into the study should 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, sponsors and/or applicants should 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 may 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). If a multiple-dose study design is important, appropriate dosage
`administration and sampling should be carried out to document attainment of
`steady state.
`
`7.
`
`Bioanalytical Methodology
`
`Bioanalytical methods for BA and BE studies should be accurate, precise,
`selective, sensitive, and reproducible. A separate FDA guidance entitled
`Bioanalytical Method Validation (May 2001) is available to assist sponsors in
`validating bioanalytical methods.
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`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. Reliance on systemic exposure measures should
`reflect comparable rate and extent of absorption, which in turn should 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 may 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
`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. The partial area should be truncated at the population
`median of Tmax values for the reference formulation. At least two quantifiable
`samples should be collected before the expected peak time to allow adequate
`estimation of the partial area.
`
`b.
`
`Peak Exposure
`
`Peak exposure should be assessed by measuring the peak drug concentration
`(Cmax) obtained directly from the data without interpolation.
`
`c.
`
`Total Exposure
`
`For single-dose studies, the measurement of total exposure should 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/z, Ct is the
`last measurable drug concentration and z is the terminal or elimination
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`rate constant calculated according to an appropriate method. The terminal
`half-life (t1/2) of the drug should also be reported.
`
`For steady-state studies, the measurement of total exposure should be the area
`under the plasma, serum, or blood concentration-time curve from time zero to
`time • over a dosing interval at steady state (AUC0-•), where • 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 may be useful
`to provide supportive evidence of BA or BE. However, the use of comparative clinical
`trials as an approach to demonstrate BE is generally considered insensitive and should be
`avoided where possible (21 CFR 320.24). The use of BE studies with clinical trial
`endpoints may 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, 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 document BE for nonbioproblem drugs approved before
`1962 remain acceptable (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.
`Di