Guidance for Industry
`Bioavailability and Bioequivalence
`Studies Submitted in NDAs or INDs —
`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`DRAFT GUIDANCE
`This guidance document is being distributed for comment purposes only.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 60 days of
`publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit electronic comments to http://www.regulations.gov. Submit written
`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 the CDER Office of Clinical Pharmacology
`at 301-796-5008 or OCP@fda.hhs.gov.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`March 2014
`Biopharmaceutics
`
`(cid:36)(cid:81)(cid:71)(cid:85)(cid:91)(cid:3)(cid:21)(cid:19)(cid:19)(cid:24)
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`
`

`

`Guidance for Industry
`Bioavailability and Bioequivalence
`Studies Submitted in NDAs or INDs—
`General Considerations
`
`Additional copies are available from:
`
`Office of Communications
`Division of Drug Information, WO51, Room 2201
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10903 New Hampshire Avenue, Silver Spring, MD 20993
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
`Phone: 301-796-3400; Fax: 301-847-8714
`druginfo@fda.hhs.gov
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`March 2014
`Biopharmaceutics
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION................................................................................................................. 1
`
`II. BACKGROUND ................................................................................................................... 2
`A. GENERAL ............................................................................................................................. 3
`B. BIOAVAILABILITY ................................................................................................................ 3
`C. BIOEQUIVALENCE ................................................................................................................ 4
`III. METHODS TO DOCUMENT BA AND BE...................................................................... 6
`A. PHARMACOKINETIC STUDIES ............................................................................................... 6
`B. OTHER APPROACHES TO SUPPORT BA/BE......................................................................... 10
`IV. DOCUMENTING BA AND BE FOR VARIOUS DOSAGE FORMS .......................... 12
`A. SOLUTIONS AND OTHER SOLUBILIZED DOSAGE FORMS..................................................... 12
`IMMEDIATE-RELEASE PRODUCTS....................................................................................... 12
`B.
`C. MODIFIED-RELEASE PRODUCTS......................................................................................... 13
`D. BATCH SIZE ....................................................................................................................... 16
`V. ADDITIONAL INFORMATION ON IN VITRO APPROACHES ............................... 16
`A.
` IN VITRO STUDIES CONDUCTED IN SUPPORT OF A WAIVER OF AN IN VIVO BA OR BE DATA
`REQUIREMENT ................................................................................................................... 16
`B.
` IN VITRO STUDIES CONDUCTED IN SUPPORT OF DEMONSTRATING BA OR BE .................. 17
`VI. SPECIAL TOPICS ............................................................................................................. 20
`A. ALCOHOLIC BEVERAGE EFFECTS ON MR DRUG PRODUCTS .............................................. 20
`B. ENANTIOMERS VERSUS RACEMATES .................................................................................. 20
`C. DRUG PRODUCTS WITH COMPLEX MIXTURES AS THE ACTIVE INGREDIENTS .................... 20
`D. LONG-HALF-LIFE DRUGS .................................................................................................. 21
`E. ORALLY ADMINISTERED DRUGS INTENDED FOR LOCAL ACTION....................................... 21
`F. COMBINATION/COADMINISTERED DRUG PRODUCTS ......................................................... 21
`G. ENDOGENOUS SUBSTANCES ............................................................................................... 22
`H. DRUG PRODUCTS WITH HIGH INTRASUBJECT VARIABILITY .............................................. 23
`APPENDIX A: GENERAL STUDY DESIGN AND DATA HANDLING ........................... 24
`
`

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`Draft – Not for Implementation
`
`Contains Nonbinding Recommendations
`Guidance for Industry1
`Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs —
`General Considerations
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`This guidance provides recommendations to sponsors and/or applicants planning to include
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`bioavailability (BA) and bioequivalence (BE) information for drug products in investigational
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`new drug applications (INDs), new drug applications (NDAs), and NDA supplements (referred
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`to as the NDA BA and BE Draft Guidance).2 This guidance contains advice on how to meet the
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`22 BA and BE requirements set forth in 21 CFR part 320 as they apply to dosage forms intended for
`oral administration.3 The guidance may also be applicable to non-orally administered drug
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`products when reliance on systemic exposure measures is suitable to document BA and BE (e.g.,
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`transdermal delivery systems and certain rectal and nasal drug products). The guidance should
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`be helpful for applicants conducting BA and BE studies during the IND period for an NDA and
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`also for applicants conducting BE studies during the postapproval period for certain changes to
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`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
`
`1 This guidance was developed by the Office of Clinical Pharmacology, Office of Translational Sciences, and the
`Office of New Drugs Quality Assessment, Office of Pharmaceutical Science, in the Center for Drug Evaluation and
`Research (CDER) at the U.S. Food and Drug Administration (FDA).
`2 BA and BE information for drug products in abbreviated new drug applications (ANDAs) and ANDA supplements
`are not the subject of this guidance. FDA has issued a separate draft guidance on this topic entitled Bioequivalence
`Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (December 2013) (ANDA BE Draft
`Guidance). The ANDA BE Draft Guidance, when finalized, will represent FDA’s current thinking on this topic.
`Many guidances are referenced throughout this document. The guidance referred to in this footnote, as well as
`others referenced throughout the remainder of the document, can be found on the FDA Drugs guidance Web page 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 the FDA Drugs
`guidance Web page.
`
`3 These dosage forms include tablets, capsules, solutions, suspensions, conventional/immediate-release drug
`products, and modified (extended, delayed)-release drug products.
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`Draft — Not for Implementation
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`drug products that are the subject of an NDA.4 This guidance document is not intended to
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`provide recommendations on studies conducted in support of demonstrating comparability or
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`biosimilarity for biological products licensed under section 351 of the Public Health Service
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`31 Act.5
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`33 When finalized, this guidance will revise and replace the parts of FDA’s March 2003 guidance
`for industry on Bioavailability and Bioequivalence Studies for Orally Administered Drug
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`Products – General Considerations (the March 2003 BA and BE Guidance) relating to BA and
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`36 BE studies for INDs, NDAs, and NDA supplements.6 Since the March 2003 BA and BE
`37 Guidance was issued, FDA has determined that providing information on BA and BE studies in
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`separate guidances according to application type will be beneficial to sponsors and applicants.
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`Thus, FDA is issuing this NDA BA and BE Draft Guidance and, as previously noted, has issued
`the ANDA BE Draft Guidance for ANDA and ANDA supplements.7
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`42 We recognize that this guidance cannot address every issue pertaining to the assessment of BA
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`or BE studies for INDs and NDAs, so we suggest sponsors and applicants contact the appropriate
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`review division for guidance on specific questions not addressed by this guidance.
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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 guidance documents means that something is
`suggested or recommended, but not required.
`
`II. BACKGROUND
`
`4 Bioequivalence is a statutory term reflected in the Federal Food, Drug, and Cosmetic Act (FD&C Act) in section
`505(j) (21 U.S.C. 355(j)), which requires ANDA applicants to demonstrate, among other things, that the proposed
`generic product is bioequivalent to its reference listed drug. Section 505(j)(2)(A)(iv) of the FD&C Act; see also
`section 505(j)(8) of the FD&C Act. There is no similar statutory requirement for an NDA applicant either under
`section 505(b)(1) or (b)(2) of the FD&C Act to demonstrate bioequivalence of its proposed product to another
`product. As a scientific matter, however, the same or a similar showing of the bioavailability of two products in the
`NDA context may be needed for the purposes of evaluating the safety or effectiveness of a product. For ease of the
`reader, we refer to such evaluations of the relative bioavailability for two or more products as an evaluation of
`bioequivalence in this guidance.
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`5 For information on these types of studies, see FDA’s Drugs guidance Web page. See footnote #2 for information
`on accessing this Web page.
`
`6 Revisions to the March 2003 BA and BE Guidance include (1) expansion of the section on modified-release
`products, (2) addition of a section on concomitant administration of drug products and combination drug products,
`(3) addition of a section on alcoholic beverage effects on modified-release dosage forms, (4) addition of an
`endogenous substance section, (5) addition of a section on drug products with high intrasubject variability, and (6)
`removal of references to BE studies conducted for ANDAs. The guidance also makes other revisions for
`clarification.
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`7 See footnote #2.
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`Contains Nonbinding Recommendations
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`54 BA assessment of formulations is a component of new drug development. The approaches of
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`evaluating BA and BE discussed in this guidance are designed to aid FDA evaluation of the
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`safety and effectiveness of a product that is the subject of an IND, NDA, or NDA supplement.
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`In this endeavor, we use the totality of information available in the submission, which includes,
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`among other things, information gathered using the principles of BE, exposure-response
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`evaluations, and clinical trial results. The evaluation of BE in the generic drug context, by
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`contrast, is used to support a determination that a generic product may be substituted for its
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`reference listed drug, and involves consideration of different types of data permitted in an
`62 ANDA. Accordingly, the approaches discussed in this guidance may differ from similar
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`discussions of BE in the ANDA BE Draft Guidance. For example, this NDA BA and BE Draft
`64 Guidance recommends assessment of the effect of food on BA using the approaches set forth in
`FDA’s 2002 guidance for industry on Food-Effect Bioavailability and Fed Bioequivalence
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`Studies (the 2002 Food-Effect Guidance). Fasting BE studies generally are sufficient, given the
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`totality of information we consider in evaluating INDs, NDAs, or NDA supplements. In
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`contrast, we recommend in the ANDA BE Draft Guidance fed and fasting BE studies that will
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`provide specific information to support a demonstration of BE under section 505(j) of the FD&C
`70 Act, and in turn, to support substitutability. Even though the ANDA BE Draft Guidance revises
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`and replaces the parts of the 2002 Food-Effect Guidance pertaining to ANDAs and ANDA
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`supplements, this NDA BA and BE Draft Guidance does not replace the 2002 Food-Effect
`73 Guidance relating to studies for INDs, NDAs, and NDA supplements.8
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`Bioequivalence means the absence of a significant difference in the rate and extent to which the
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`active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives
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`become available at the site of drug action when administered at the same molar dose under
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`similar conditions in an appropriately designed study (21 CFR 320.1(e)). Studies to establish
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`87 BE between two products are important for certain formulation or manufacturing changes
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`occurring during the drug development and postapproval stages. In BE studies, the exposure
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`profile of a test drug product is compared to that of a reference drug product.
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`93 BA for a given formulation provides an estimate of the relative fraction of the orally
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`administered dose that is absorbed into the systemic circulation. BA for orally administered drug
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`products can be documented by comparing a systemic exposure profile to that of a suitable
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`reference product. A profile can be generated by measuring the concentration of active
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`A.
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`General
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`Studies to measure BA and/or establish BE of a product are important elements in support of
`INDs, NDAs, and NDA supplements. Bioavailability means 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 (21 CFR 320.1(a)). BA data provide an estimate of the fraction of the drug
`absorbed, as well as provide information related to the pharmacokinetics of the drug.
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`B.
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`Bioavailability
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`8 Accordingly, we are in the process of revising the 2002 Food-Effect Guidance.
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`3
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`Draft — Not for Implementation
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`Contains Nonbinding Recommendations
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`ingredients and/or active moieties over time and, when appropriate, active metabolites over time
`in samples collected from the systemic circulation. Systemic exposure profiles 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.
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`C.
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`Bioequivalence
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`FDA’s regulations at 21 CFR 320.25 set forth guidelines for in vivo BA studies. As provided in
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`this regulation, the reference product for BA studies should be a solution, suspension, or
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`intravenous (IV) dosage form (21 CFR 320.25(d)(2) and (3)). The purpose of conducting a BA
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`study with an oral solution as a reference is to assess the impact of formulation on BA.
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`106 Conducting a BA study with an IV reference enables assessment of the impact of route of
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`administration on BA and defines the absolute BA of the drug released from the drug product.
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`112 As noted previously, both BA and BE focus on the release of a drug substance from a drug
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`product and subsequent absorption into systemic circulation. As a result, we recommend that
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`approaches to determining BE generally follow approaches similar to those used for BA.
`115 Demonstrating BE involves a more formal comparative test that uses specific references with
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`specified criteria for comparisons and predetermined BE limits for such criteria.
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`1.
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`Preapproval Changes
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`BE documentation can be useful during the IND period to compare (1) early and late
`clinical trial formulations; (2) formulations used in clinical trials and stability studies, if
`different; (3) clinical trial formulations and to-be-marketed drug products, if different;
`and (4) product strength equivalence, as appropriate. In each comparison, the new
`formulation, formulation produced by the new method of manufacture, or new strength is
`the candidate, or test product and the prior formulation, prior method of manufacture, or
`prior strength is the reference product. The decision to document BE during drug
`development is generally left to the judgment of the sponsor, using the principles of
`relevant guidances (in this guidance, see sections II.C.2, Postapproval Changes, and
`III.D, In Vitro Studies) to determine when changes in components, composition, and/or
`method of manufacture suggest that further in vitro and/or in vivo studies be performed.
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`2.
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`Postapproval Changes
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`In the presence of certain major changes in components, composition, manufacturing site,
`and/or method of manufacture after approval, FDA recommends that in vivo BE be
`demonstrated for the drug product after the change in comparison to the drug product
`before the change. Under section 506A(c)(2) of the Federal Food, Drug, and Cosmetic
`Act (FD&C Act) (21 U.S.C. 356a(c)(2)), certain postapproval changes that require
`completion of studies must be submitted in a supplement and approved by FDA before
`distributing a drug product made with the change.
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`Draft — Not for Implementation
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`Contains Nonbinding Recommendations
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`Information on the types of recommended in vitro dissolution and in vivo BE studies for
`immediate-release and modified-release drug products approved as NDAs for specified
`postapproval changes is provided in the following FDA guidances:
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`(cid:120)
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`(cid:120)
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`SUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale-Up and
`Postapproval Changes: Chemistry, Manufacturing, and Control; In Vitro
`Dissolution Testing, and In Vivo Bioequivalence Documentation
`SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and
`Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro
`Dissolution Testing, and In Vivo Bioequivalence Documentation
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`3.
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`BE Considerations
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`BE studies are usually conducted using a crossover design. For such studies, intrasubject
`variability should be considered when determining the study sample size. In cases when
`a parallel design is necessary to evaluate BE, consideration should be given to total
`variability, including intersubject variability instead of just intrasubject variability.
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`A test product might fail to demonstrate bioequivalence because it has measures of rate
`and/or extent of absorption compared to the reference product outside acceptable higher
`or lower limits. For example, when the test product results in a systemic exposure that is
`significantly higher than that of the reference product, the concern is the typically limited
`experience from a safety standpoint for higher systemic concentrations. When the test
`product has a systemic exposure that is significantly lower than that of the reference
`product, the concern is potentially a lack of therapeutic efficacy of the test product.
`When the variability of the test product is greater than the reference product, the concern
`relates to both safety and efficacy, because it may suggest that the performance of the test
`product is not comparable to the reference product, and the test product may be too
`variable to be clinically useful.
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`When BE is not demonstrated, the sponsor should demonstrate that the differences in rate
`and extent of absorption do not significantly affect the safety and efficacy based on
`available dose-response or concentration-response data. In the absence of this evidence,
`failure to demonstrate BE may suggest that the test product should be reformulated, or
`the method of manufacture for the test product should be changed, or additional safety or
`efficacy data may be needed for the test product. In some cases, conclusions of BE based
`on the peak drug concentration (Cmax) and area under the plasma concentration time curve
`(AUC) between the test product and the reference product may be insufficient to
`demonstrate that there is no difference in safety or efficacy if the systemic concentration-
`time profiles of the test product and the reference product are different (e.g., time to reach
`peak drug concentration (Tmax) is different). For example, differences in the shape of the
`systemic concentration profile between the test and reference products could imply that
`the test product may not produce the same clinical response as the reference product. In
`such cases, additional data analysis (e.g., partial AUCs), exposure-response evaluation, or
`clinical studies may be recommended to evaluate the BE of the two products.
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`5
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`Draft — Not for Implementation
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`Contains Nonbinding Recommendations
`
`III.
`
` METHODS TO DOCUMENT BA AND BE
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`190 Under FDA’s regulations, applicants must use the most accurate, sensitive, and reproducible
`191 method available to demonstrate BA or BE of a product (21 CFR 320.24(a)). As noted in 21
`192 CFR 320.24, several in vivo and in vitro methods can be used to measure BA and to establish
`193 BE. These include, in general order of preference, pharmacokinetic (PK) studies, in vitro tests
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`predictive of human in vivo BA (in vitro-in vivo correlation), pharmacodynamic (PD) studies,
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`studies with clinical benefit endpoints, and other in vitro studies. In addition, where in vivo data
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`are appropriate to demonstrate BA, our regulations provide guidelines on specific types of in
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`vivo BA studies (see 21 CFR 320.25 through 320.29). This guidance predominantly focuses on
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`the use of PK studies to document BA or BE.
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`A.
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`1.
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`Pharmacokinetic Studies
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`General Considerations
`
`FDA’s regulations generally define BA and BE in terms of rate and extent of absorption
`of the active ingredient or moiety to the site of action.9 For in vivo studies, the
`regulations also provide for use of PK 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.10 BA and BE frequently rely on PK measures such
`as AUC to assess extent of systemic exposure and Cmax and Tmax to assess rate of systemic
`absorption. PK-based comparisons to describe relative BA or make BE determinations
`are predicated on an understanding that measuring the active moiety or ingredient at the
`site of action is generally not possible and on an assumption that some relationship exists
`between the efficacy/safety and concentration of the active moiety and/or its important
`metabolite(s) in the systemic circulation. A typical study is conducted as a crossover
`study. The crossover design reduces variability caused by patient-specific factors, thereby
`increasing the ability to discern differences because of formulation.
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`2.
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`Pilot Study
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`If the sponsor chooses, a pilot study in a small number of subjects can be carried out
`before proceeding with a full-scale BA or BE study. The pilot study can be used to
`validate analytical methodology, assess PK variability, determine sample size to achieve
`adequate power, optimize sample collection time intervals, and determine the length of
`the washout period needed between treatments. 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 Cmax. For
`modified-release products, a pilot study can help determine the sampling schedule needed
`
`9 21 CFR 320.1(a) and (e).
`10 See, e.g., 21 CFR 320.24(b)(1)(i). If serial measurements of the drug or its metabolites in plasma, serum, or blood
`cannot be accomplished, then measurement of urinary excretion can be used.
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`Contains Nonbinding Recommendations
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`to assess lag time and dose dumping. The results of a pilot study can be used as the sole
`basis to document BA or BE provided the study’s design and execution are suitable and a
`sufficient number of subjects have completed the study.
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`3.
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`Full-Scale Study
`
`General recommendations for a standard BA or BE study based on PK measurements are
`provided in Appendix A. Nonreplicate crossover study designs are recommended for BA
`and 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.
`Replicate crossover designs are used to allow estimation of (1) within-subject variance
`for the reference product, or for both the test and reference products, and (2) the subject
`by formulation interaction variance component. This design accounts for the inter-
`occasion variability that may confound the interpretation of a BE study as compared to a
`non-replicate crossover approach. The recommended method of analysis for nonreplicate
`or replicate studies to evaluate BE is average BE, as discussed in section IV.
`Recommendations for conducting and evaluating replicate study designs can be found in
`the FDA guidance for industry Statistical Approaches to Establishing Bioequivalence.
`
`4.
`
`Study Population
`
`Subjects recruited for BA or BE studies should be 18 years of age or older and capable of
`giving informed consent. In general, BA and BE studies should be conducted in healthy
`volunteers if the product can be safely administered to this population. A study in healthy
`volunteers is likely to produce less PK variability compared with that in patients with
`potentially confounding factors such as underlying and/or concomitant disease and
`concomitant medications. Male and female subjects should be enrolled in BA and BE
`studies unless there is a specific reason to exclude one sex. Such exclusions could be
`related to the drug product being indicated in only one sex or a greater potential for
`adverse reactions in one sex compared to the other. For example, oral contraceptives are
`evaluated in female subjects because the indication is specific to females. If a drug has
`the potential to be a teratogen, the drug product should be evaluated in male subjects.
`Female subjects enrolled in the study should not be pregnant at the beginning of the study
`and should not become pregnant during the study. In some instances (e.g., when safety
`considerations preclude use of healthy subjects), it may be necessary to evaluate BA and
`BE in patients for whom the drug product is intended. In this situation, sponsors and/or
`applicants should attempt to enroll patients whose disease process is expected to be stable
`for the duration of the study.
`
`5.
`
`Single-Dose and Multiple-Dose (Steady State) Testing
`
`This guidance generally recommends single-dose PK studies to assess BA and BE
`because they are generally more sensitive than steady-state studies in assessing rate and
`extent of release of the drug substance from the drug product into the systemic
`circulation.
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`Contains Nonbinding Recommendations
`
`FDA’s regulations at 21 CFR 320.27 provide guidelines on the design of a multiple-dose
`in vivo BA study. This regulation also identifies instances in which multiple-dose BA
`studies may be required:
`
`i. There is a difference in the rate of absorption but not in the extent of absorption.
`ii. There is excessive variability in bioavailability from subject to subject.
`iii. The concentration of the active drug ingredient or therapeutic moiety, or its
`metabolite(s), in the blood resulting from a single dose is too low for accurate
`determination by the analytical method.
`iv. The drug product is an extended-release dosage form.11
`
`We recommend that if a multiple-dose study design is performed, appropriate dosage
`administration and sampling be carried out to document attainment of steady state.
`
`6.
`
`Bioanalytical Methodology
`
`We recommend that sponsors ensure that bioanalytical methods for BA and BE studies
`be accurate, precise, specific, sensitive, and reproducible. A separate FDA guidance,
`Bioanalytical Method Validation, is available to assist sponsors in validating
`bioanalytical methods.12
`
`7.
`
`Administration Under Fasted/Fed Conditions
`
`The BA or BE study should be conducted under fasting conditions (after an overnight fast
`of at least 10 hours) except when tolerability issues are anticipated with fasting. In these
`cases, we recommend that applicants conduct only a fed study. A separate FDA
`guidance, Food-Effect Bioavailability and Fed Bioequivalence Studies is available to
`assist sponsors.
`
`8.
`
`Moieties to Be Measured
`
`The active ingredient that is released from the dosage form or its active moiety and, when
`appropriate, its active metabolites13 should be measured in biological fluids collected in
`BA studies.
`
`Measurement of the active ingredient or the active moiety, rather than metabolites, is
`generally recommended for BE studies because the concentration-time profile of the
`active ingredient or the active moiety is more sensitive to changes in formulation
`performance than that of the metabolite, which is more reflective of metabolite formation,
`distribution, and elimination. The following are instances when an active metabolite(s)
`should be measured.
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`11 21 CFR 320.27(a)(3).
`12 See also 21 CFR 320.29.
`13 See 21 CFR 320.24(b)(1)(i).
`
`8
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`Draft — Not for Implementation
`
`Contains Nonbinding Recommendations
`
`(cid:120) Measurement of a metabolite(s) is necessary when the active ingredient or the active
`moiety concentrations are too low to allow reliable analytical measurement in blood,
`plasma, or serum. In this case, the metabolite should be measured in lieu of the active
`ingredient or active moiety. We recommend that the confidence interval approach be
`applied to the metabolite data obtained from these studies.
`
`(cid:120) Measurement of a metabolite(s) is necessary in addition to the active ingredient or
`active moiety if the metabolite is formed by presystemic metabolism and contributes
`meaningfully to efficacy and/or safety. The confidence interv