Guidance for Industry
`Bioequivalence Studies with
`Pharmacokinetic Endpoints for Drugs
`Submitted Under an ANDA
`DRAFT GUIDANCE
`This guidance document is being distributed for comment purposes only.
`
`Comments and suggestions regarding this draft document should be submitted within 90 days of
`publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to the Division of Dockets Management (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 Diana Solana-Sodeinde at 240-402-3908.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`December 2013
`Biopharmaceutics
`
`ALKERMES EXHIBIT 2026
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 24
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`Guidance for Industry
`
`Bioequivalence Studies with
`Pharmacokinetic Endpoints for Drugs
`Submitted Under an ANDA
`
`
`
`Additional copies are available from:
`Office of Communication
`Division of Drug Information, WO51, Room 2201
`Center for Drug Evaluation and Research
` Food and Drug Administration
`10903 New Hampshire Ave.
`Silver Spring, MD 20993-0002
`Phone: 301-796-3400; Fax: 301-847-8715
`druginfo@fda.hhs.gov
` http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
`
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`
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`
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`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`December 2013
`Biopharmaceutics
`
`
`
`
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`Contains Nonbinding Recommendations
`Draft – Not for Implementation
`
`TABLE OF CONTENTS
`
`INTRODUCTION............................................................................................................. 1
`I.
`BACKGROUND ............................................................................................................... 2
`II.
`ESTABLISHING BIOEQUIVALENCE ........................................................................ 2
`III.
`A. Pharmacokinetic Studies...............................................................................................................3
`1. General Considerations ............................................................................................................3
`2. Pilot Study .................................................................................................................................3
`3. Pivotal Bioequivalence Studies .................................................................................................3
`4. Study Designs ............................................................................................................................3
`5. Study Population .......................................................................................................................4
`6. Single-Dose Studies...................................................................................................................5
`7. Steady-State Studies ..................................................................................................................5
`8. Bioanalytical Methodology .......................................................................................................5
`9. Pharmacokinetic Measures of Rate and Extent of Exposure ....................................................5
`10. Fed Bioequivalence Studies.......................................................................................................6
`11. Sprinkle Bioequivalence Studies................................................................................................7
`12. Bioequivalence Studies of Products Administered in Specific Beverages.................................7
`B. General Considerations on Other Bioequivalence Studies.........................................................7
`1. In Vitro Tests Predictive of Human In Vivo Bioavailability (In Vitro-In Vivo Correlation
`Studies) ......................................................................................................................................7
`2. Pharmacodynamic.....................................................................................................................7
`3. Comparative Clinical Studies....................................................................................................8
`4. In Vitro Studies..........................................................................................................................8
`ESTABLISHING BIOEQUIVALENCE FOR DIFFERENT DOSAGE FORMS ..... 8
`IV.
`A. Oral Solutions.................................................................................................................................8
`B.
`Immediate Release Products: Capsules and Tablets ..................................................................8
`1. Preapproval...............................................................................................................................8
`2. Postapproval ...........................................................................................................................10
`C. Suspensions...................................................................................................................................10
`D. Modified Release Products..........................................................................................................10
`1. Delayed Release Products.......................................................................................................10
`2. Extended Release Products .....................................................................................................10
`3. Bioequivalence Studies............................................................................................................11
`4. Demonstration of Bioequivalence: Additional Strengths .......................................................11
`5. Postapproval Changes ............................................................................................................11
`E. Chewable Tablets.........................................................................................................................12
`V.
`SPECIAL TOPICS ......................................................................................................... 12
`A. Moieties to Be Measured .............................................................................................................12
`1. Parent Drug Versus Metabolites.............................................................................................12
`2. Enantiomers Versus Racemates ..............................................................................................12
`
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`3. Drug Products with Complex Mixtures as the Active Ingredients ..........................................13
`B. Long Half-Life Drugs ..................................................................................................................13
`C. First Point Cmax.............................................................................................................................13
`D. Alcoholic Beverage Effects On Modified Release Drug Products ...........................................14
`E. Endogenous Compounds.............................................................................................................14
`F. Orally Administered Drugs Intended For Local Action ..........................................................15
`G.
`In Vitro Dissolution Testing........................................................................................................15
`1. Immediate Release Products ...................................................................................................15
`2. Modified Release Products......................................................................................................16
`ATTACHMENT: GENERAL DESIGN AND DATA HANDLING OF
`BIOEQUIVALENCE STUDIES WITH PHARMACOKINETIC ENDPOINTS ................ 17
`GLOSSARY................................................................................................................................. 20
`
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`Contains Nonbinding Recommendations
`Draft – Not for Implementation
`Guidance for Industry1
`
`Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs
`Submitted Under an ANDA
`
`
`
`
`
`This draft guidance, when finalized, will represent 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. You can use an alternative approach if the approach satisfies the requirements of
`the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
`staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
`the appropriate number listed on the title page of this guidance.
`
`
`
`I.
`
`INTRODUCTION
`
`This guidance provides recommendations to applicants planning to include bioequivalence (BE)
`information in abbreviated new drug applications (ANDAs) and ANDA supplements. The
`guidance describes how to meet the BE requirements set forth in the Federal Food, Drug, and
`Cosmetic Act (FD&C Act) and FDA regulations. The guidance is generally applicable to dosage
`forms intended for oral administration and to non-orally administered drug products in which
`reliance on systemic exposure measures is suitable for documenting BE (e.g., transdermal
`delivery systems and certain rectal and nasal drug products). We believe that the guidance will
`also be useful when planning BE studies intended to be conducted during the postapproval
`period for certain changes in an ANDA.
`
`This guidance revises and replaces parts of two FDA guidances for industry,2 relating to BE and
`fed BE studies to be submitted in ANDAs. This guidance does not address bioavailability (BA),
`BE, and food effect studies in investigational new drug applications (INDs) and new drug
`applications (NDAs). A separate guidance will soon be available that will address BA and BE
`studies for INDs, NDAs, and NDA supplements.3 FDA has determined that separating
`guidances according to application type will be beneficial to applicants.
`
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`1 This guidance was prepared by the Division of Bioequivalence in the Office of Generic Drugs, Office of
`Pharmaceutical Science, Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
`2 Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations and Food-
`Effect Bioavailability and Fed Bioequivalence Studies.
`3 Many guidances are referenced throughout this document, and they can be found on the Internet at
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update
`guidances periodically. To make sure you have the most recent version of a guidance, check this CDER guidance
`Web site.
`
`
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`In addition, FDA routinely publishes guidances on BE study design for specific products.4 FDA
`recommends that applicants consult this general guidance in conjunction with any relevant
`product-specific guidance when considering the appropriate BE study for a proposed product.
`
`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.
`
`To receive approval for an ANDA, an applicant generally must demonstrate, among other things,
`that its proposed drug product is bioequivalent to the reference listed drug (RLD, or reference
`product).5 The FD&C Act provides that a generic drug is bioequivalent to the listed drug if:
`
`BACKGROUND
`
`The rate and extent of absorption of the drug do not show a significant difference
`from the rate and extent of absorption of the listed drug when administered at the
`same molar dose of the therapeutic ingredient under similar experimental
`conditions in either a single dose or multiple doses....6
`
`For most products, the focus of BE studies is on the release of the drug substance from the drug
`product into the systemic circulation. During such BE studies, an applicant compares the
`systemic exposure profile of a test drug product to that of the RLD.
`
`
`III.
`
`Under FDA regulations, an applicant must use “the most accurate, sensitive, and reproducible
`approach available among those set forth” in 21 CFR 320.24(b) to demonstrate BE.7 As noted in
`21 CFR 320.24, in vivo and/or in vitro methods can be used to establish BE. In general
`descending order of preference, these include pharmacokinetic, pharmacodynamic, clinical, and
`in vitro studies.8
`
`
`ESTABLISHING BIOEQUIVALENCE
`
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`4 See guidance for industry on Bioequivalence Recommendations for Specific Products at
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm
`5 See section 505(j)(2)(A)(iv) of the FD&C Act; 21 CFR 314.94(a)(7).
`6 Section 505(j)(8)(B)(i) of the FD&C Act. See also section 505(j)(8)(B)(ii), (C) of the FD&C Act; 21 CFR
`320.1(e), and 320.23(b).
`7 See 21 CFR 320.24(a).
`8 See 21 CFR 320.24(b).
`
`
`
`2
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`Pharmacokinetic Studies
`
`A.
`
`1.
`
`General Considerations
`
`
`As provided above, the statutory definition of BE, expressed in terms of rate and extent of
`absorption of the active ingredient or moiety, emphasizes the use of pharmacokinetic endpoints
`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.9 BE frequently relies on
`pharmacokinetic endpoints such as C max (peak plasma concentration) and AUC (area under the
`plasma concentration time curve) that are reflective of rate and extent of absorption, respectively.
`
`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 demonstrate BE.
`
`2.
`
`If the applicant chooses, a pilot study in a small number of subjects can be carried out before
`proceeding with a full BE study. This pilot study can be used to validate analytical
`methodology, assess variability, optimize sample collection time intervals, and provide other
`information.
`
`3.
`
`General recommendations for a standard BE study based on pharmacokinetic measurements are
`provided in the Attachment.
`
`4.
`
`FDA recommends use of a two-period, two-sequence, two-treatment, single-dose, crossover
`study design, a single-dose parallel study design, or a replicate study design for BE studies. For
`most dosage forms that release drug intended to be systemically available, we recommend that
`applicants perform a two-period, two-sequence, two-treatment, single-dose, crossover study
`using healthy subjects. In this design, each study subject should receive each treatment (test, and
`RLD) in random order. The crossover design may not be practical for drugs with long
`pharmacokinetic half-lives (i.e., longer than 24 hours). In such cases, investigators can use a
`single-dose, parallel design where each treatment should be administered to a separate group of
`subjects with similar demographics. The general recommendations for study designs provided in
`the Attachment should be used in designing crossover studies as well.
`
`A replicate crossover study may be an appropriate alternative to the parallel or nonreplicate
`crossover study described above, and can be conducted as either a partial (three-way) or full
`(four-way) replication of treatment. In this design, one or both treatments should be
`administered to the same subject on two separate occasions. The replicate design has the
`advantage of using fewer subjects although each subject should receive more treatments than in
`
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`Pilot Study
`
`Pivotal Bioequivalence Studies
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`Study Designs
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`
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`9 See section 505(j)(8)(B) of the FD&C Act.
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`the two-treatment, crossover design. The replicate design is especially useful for highly variable
`drugs.
`
`We recommend that applicants use the average BE method of analysis with these study designs
`for establishing BE. In limited cases, applicants may use a scaled-average BE analysis approach
`for highly variable drugs.10 This analysis approach is typically used with a replicate study
`design. Recommendations for replicate study designs and the average BE approach method can
`be found in the guidance for industry on Statistical Approaches to Establishing
`11
`Bioequivalence.
`
`
`For applicants wishing to use variations of these study designs or analysis methods (e.g., a
`ommend that you submit a complete protocol for
`sequential design or scaled-average BE), we rec
`review and comment before starting the study.
`
`.
`
`Study Population
`
`In general, unless otherwise recommended in a specific guidance:
`
` 5
`
` Subjects recruited for in vivo BE studies should be 18 years of age or older.
`
` 
`
`
`
`In vivo BE study subjects should be repr
`taking into account age, sex, and race.
`
`esentative of the general population,
`
`If a drug product is intended for use in both sexes, the ap
`similar proportions of males and females in the study.
`
`plicant should include
`
`If the drug product is predominantly intended for use in the elderl
`should include as many subjects as possible at or above age 60.
`
`y, the applicant
`
` 
`
`
`
` 
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`
`
` 
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` The total number of subjects in a study should be sufficient to provide adequate
`statistical power for BE demonstration, but we do not expect that there
`will be
`sufficient power upon which to draw conclusions for each subgroup.
`
`
`
`
`In most cases, we do not recommend statistical analysis of subgroups.
`
`We also recommend that any restrictions on admission into a study be based primarily on safety
`considerations. Sometimes, safety considerations preclude the use of healthy volunteers. In such
`
`
`10 For highly variable drugs (intrasubject variability > 30%), applicants can conduct BE studies using a replicate
`design approach. Alternatively, a single-dose, randomized, three-period reference-scaled, average BE approach is
`also appropriate. The reference-scaled average BE approach adjusts the BE limits of highly variable drugs by
`scaling to the within-subject variability of the RLD in the study and imposes a limit of 0.8 to 1.25 on the geometric
`mean ratio. The within-subject variability of RLD should be determined using a three-way modified replicate-
`design study in which the RLD is given twice and the test product is given once. For general information on the
`reference-scaled approach, investigators should refer to the published book chapter, Davit B, Conner D. Reference-
`scaled average bioequivalence approach. In: Kanfer I, Shargel L, eds. Generic Drug Product Development –
`International Regulatory Requirements for Bioequivalence. New York, NY: Informa Healthcare, 2010:271-272.
`11 See footnote 3.
`
`
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`situations, applicants should attempt to enroll patients that the drug is intended to treat and who
`
`disease process and treatments are stable for the duration of the BE study. An IND for certain
`BE studies may be required, for example, for cytotoxic products.12
`
`se
`
`.
`
`Single-Dose Studies
`
` 6
`
`We usually recommend single-dose pharmacokinetic studies for both immediate and modified
`n
`release drug products to demonstrate BE because these studies are generally more sensitive tha
`nces in the release of the drug substance from the drug
`steady-state studies in assessing differe
`product into the systemic circulation.
`
`7.
`
`Steady-State Studies
`
`
`When safety considerations suggest using patients who are already receiving the medication,
`often the only way to establish BE without disrupting a patient's ongoing treatment is in a stead
`state study. We recommend that if a steady-state study is recommended, applicants carry out
`appropriate dosage administration and sampling to document the attainment of steady-state.
`
`.
`
`Bioanalytical Methodology
`
` 8
`
`y-
`
`e,
`
`We recommend applicants ensure that bioanalytical methods for BE studies are accurate, precis
`tical
`selective, sensitive, and reproducible. A separate draft guidance for industry on Bioanaly
`
`ethod Validation is available to assist applicants in validating bioanalytical methods.13 M
`
`
`Pharmacokinetic Measures of Rate and Extent of Exposure
`
`.
`9
`
`
`a.
`
`Rate of Absorption (Peak Exposure)
`
`
`For both single-dose and steady-state studies, we recommend that you assess the rate of
`absorption by measuring the peak drug concentration (Cmax) obtained directly from the data
`ncentrations (Tmax) can also provide
`without interpolation. The time-to-peak drug plasma co
`important infor ation regarding the rate of absorption.
`
`m
`
`b.
`
`Partial Exposure
`
`
`
`
`For orally administered immediate release drug products, BE can generally be demonstrated by
`measurements of peak and total exposure. We recommend the use of partial AUC as an early
`exposure measure under certain circumstances. The time to truncate the partial area should be
`related to a clinically relevant pharmacodynamic (PD) measure. We recommend that sufficien
`t
`quantifiable samples be collected to allow adequate estimation of the partial area. For further
`site to determine whether a
`information on specific products, applicants should consult our web
`product-specific guidance for the proposed product is available.14
`
`
`
`12 See 21 CFR 312.2(c) and 320.31.
`13 See footnote 3.
`14 See footnote 3.
`
`
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`For single-dose studies, we recommend that the indicators for extent of absorption be both of the
`following:
`
`
`Contains Nonbinding Recommendations
`Draft – Not for Implementation
`
`Extent of Absorption (Total Exposure)
`
` 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 a measurable concentration.
`
`
`c.
`
`
`
` Area under the plasma/serum/blood concentration-time curve from time
`zero to time infinity (AUC0-inf), where:
`AUC0-inf = AUC0-t + Ct/z
` Ct is the last measurable drug concentration
` z is the terminal or elimination rate constant calculated
`according to an appropriate method.
`
`
`For steady-state studies, we recommend that the indicator for extent of absorption be the area
`under the plasma, serum, or blood concentration-time curve over a dosing interval at steady-state
`(AUC0-tau), where tau is the length of the dosing interval.
`
`
`
`10.
`
`Fed Bioequivalence Studies
`
`
`Co-administration of food with oral drug products can influence BE. Therefore, fed BE studies
`can determine whether test and RLD products are bioequivalent when co-administered with
`meals. We usually recommend a single-dose, two-period, two-treatment, two-sequence,
`crossover study for fed BE studies. See Attachment for details on study design.
`
`When a fasting in vivo BE study is recommended for an orally administered, immediate release
`product, we recommend that applicants conduct a fed study, except when the dosage and
`administration section of the RLD labeling states that the product should be taken only on an
`empty stomach (e.g., the labeling states that the product should be administered 1 hour before or
`2 hours after a meal).
`
`For orally administered, immediate release products labeled to be taken only with food, fasting
`and fed studies are recommended, except when serious adverse events are anticipated with
`fasting administration. In these latter cases, we recommend that applicants conduct only a fed
`study; a fasting study is not recommended.
`
`For all orally administered, modified-release drug products, we recommend that applicants
`conduct a fed BE study in addition to a fasting BE study. These studies should usually be
`conducted on the highest strength of the drug product, unless safety considerations preclude the
`use of that dose in study subjects.
`
`
`
`
`6
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`Sprinkle Bioequivalence Studies
`
`12.
`
`11.
`
`If the label of a modified release RLD product states that the product can be administered
`sprinkled in soft foods, we recommend applicants conduct an additional BE study. For each
`treatment arm, the product should be sprinkled on one of the soft foods mentioned in the labeling
`of the RLD, normally applesauce. Aside from administration in the soft food, this additional
`study should follow the recommendations for the fasting BE study described in the Appendix.
`
`Bioequivalence Studies of Products Administered in Specific Beverages
`
`There are certain products with labeling that specifies that the product must be administered in a
`specific beverage. BE studies for these products should be administered mixed with one of the
`beverages mentioned in the labeling. If additional beverages are listed, applicants should
`provide evidence that using these additional beverages would not result in BE differences.
`
`If there are questions about the use of other vehicles, or the design or analysis of such BE
`studies, applicants should contact the appropriate staff in the Agency's Office of Generic Drugs
`(OGD).
`
`
`General Considerations on Other Bioequivalence Studies
`
`
`In certain circumstances other BE studies are recommended to support a demonstration of BE.
`Below are some general considerations regarding these other BE studies. Sponsors should
`consult FDA’s guidances for industry for additional information on these methods as well.15
`
`
`B.
`
`1.
`
`In Vitro Tests Predictive of Human In Vivo Bioavailability (In Vitro-In Vivo
`Correlation Studies)
`
`
`In vitro-in vivo correlation (IVIVC) is a scientific approach to describe the relationship between
`an in vitro attribute of a dosage form (e.g., the rate or extent of drug release) and a relevant in
`vivo response (e.g., plasma drug concentration or amount of drug absorbed). This model
`relationship facilitates the rational development and evaluation of extended-release dosage forms
`as a surrogate for bioavailability and/or BE testing, as well as a tool for formulation screening
`and setting of the dissolution/drug release acceptance criteria.
`
`Additional information specifically on the development and validation of an IVIVC can be found
`in the guidance for industry on Extended Release Oral Dosage Forms: Development, Evaluation,
`and Application of In Vitro/In Vivo Correlations.
`
`Pharmacodynamic
`
`2.
`
` suitably validated pharmacodynamic method can be used to demonstrate BE. However, we do
`not recommend pharmacodynamic studies for drug products that are intended to be absorbed into
`the systemic circulation and for which a pharmacokinetic approach can be used to establish BE.
`
`
`15 See footnote 3.
`
`
`
`
`
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`
`Contains Nonbinding Recommendations
`Draft – Not for Implementation
` Comparative Clinical Studies
`
`3.
`
`
`When it is not possible to use the previously described methods, well-controlled BE studies with
`clinical endpoints in patients can be used to establish BE.
`
`
`4.
`
`In Vitro Studies
`
`ESTABLISHING BIOEQUIVALENCE FOR DIFFERENT DOSAGE FORMS
`
`
`Under certain circumstances, BE can be evaluated using in vitro approaches (e.g.,
`dissolution/drug release testing) under 21 CFR 320.24(b). FDA does not recommend in vitro
`approaches for drug products that are intended to be systemically absorbed. Such approaches
`would be appropriate; however, in other circumstances (e.g., for drug products that bind bile
`acids in the gastrointestinal tract).
`
`
`IV.
`
`The following sections provide recommendations for establishing BE for specific dosage forms.
`As explained below, in certain cases BE testing may be waived.
`
`
`A.
`
`Oral Solutions
`
`
`For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, an in vivo BE testing
`requirement may be waived for certain products on the ground that in vivo BE is self-evident. In
`such instances, the applicant would be deemed to have complied with and fulfilled any
`requirement for in vivo BE data.16 For example, BE can be waived for an oral solution if the
`formulation has the same active ingredient in the same concentration and dosage form as the
`RLD, and does not contain any excipient that significantly affects drug absorption or
`availability.17
`
`B.
`
`
`Immediate Release Products: Capsules and Tablets
`
`1.
`
`Preapproval
`
`
`For immediate release capsule and tablet products, we recommend the following studies: (1) a
`single-dose, fasting study comparing the highest strength of the test and RLD products and (2) a
`single-dose, fed BE study comparing the highest strength of the test and RLD products (see
`section III.A.10).
`
`Conducting an in vivo study on a strength other than the highest may be appropriate for reasons
`of safety, with concurrence by the Division of Bioequivalence, OGD, if the following conditions
`are met:
`
`
`
` Linear elimination kinetics has been documented over the therapeutic dose
`range.
`
`16 See 21 CFR 320.22(b)(3).
`17 Ibid.
`
`
`
`
`
`8
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`Page 12 of 24
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`Contains Nonbinding Recommendations
`Draft – Not for Implementation
` The higher strengths of the test and RLD products are proportionally similar
`to their corresponding lower strength.
` Comparative dissolution testing on the higher strength of the test and RLD
`products has been submitted and found to be acceptable.
`
`
`An in vivo BE requirement for one or more strength(s) can be waived based on (i) acceptable BE
`study on the designated strength, (ii) acceptable in vitro dissolution testing of all the strengths,
`and (iii) proportional similarity of the formulations across all strengths.18
`
`This guidance defines proportionally similar in the following ways:
`
`
` All active and inactiv