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`DRAFT GUIDANCE
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`This guidance document is being distributed for comment purposes only.
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`Comments and suggestions regarding this draft document should be submitted within 90 days of
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`publication in the Federal Register of the notice announcing the availability of the draft guidance.
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`Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration,
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`5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the
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`docket number listed in the notice of availability that publishes in the Federal Register.
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`For questions regarding this draft document contact Wallace P. Adams (301) 594-5651 (CDER).
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`Guidance for Industry
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`Bioavailability and Bioequivalence
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`Studies for Nasal Aerosols and
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`Nasal Sprays for Local Action
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`5/3 7/99
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`US. Department of Health and Human Services
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`Food and Drug Administration
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`Center for Drug Evaluation and Research (CDER)
`June 1999
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`X:!CDERGUIDDU7()DFT. WP]?
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`Page 1 of 45
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` Insys Exhibit 2004
`CFAD v. Insys
`IPR2015-01799
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`Additional copies are available from:
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`Drug Information Branch (HFD-Z l 0)
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`Center for Drug Evaluation and Research (CDER)
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`5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
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`Internet at http://www.fda.gov/cder/guidance/index.htm
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`Guidance for Industry
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`Bioavailability and Bioequivalence
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`Studies for Nasal Aerosols and
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`Nasal Sprays for Local Action
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`May 27. 1999
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`US. Department of Health and Human Services
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`Food and Drug Administration
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`Center for Drug Evaluation and Research (CDER)
`June 1999
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`XleDERGUIDl2070DFT. WPD
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`Page 2 of 45
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`Table of Contents
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`INTRODUCTION .
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`BACKGROUND .
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`BIOAVAILABILITY AND BIOEQUIVALENCE DATA .
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`CMC TESTS AND IN VITRO BA TESTS (NONCOMPARATIVE) VERSUS
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`BE TESTS (COMPARATIVE)
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`FORMULATION AND CONTAINER AND CLOSURE SYSTEM .
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`FORMULATION .
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`CONTAINER AND CLOSURE SYSTEM .
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`May 27, 1999
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`BIOAVAILABILITY AND BIOEQUIVALENCE: CLINICAL STUDIES FOR LOCAL
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`DELIVERY .
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`GENERAL INFORMATION .
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`BE CLINICAL STUDY ENDPOINTS .
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`CLINICAL STUDY BATCHES .
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`CLINICAL BE STUDY DESIGNS AND SUBJECT INCLUSION CRITERIA l7
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`BIOAVAILABILITY AND BIOEQUIVALENCE: PK SYSTEMIC EXPOSURE
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`STUDIES .
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`BIOAVAILABILITY AND BIOEQUIVALENCE: PHARMACODYNAMIC OR
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`GENERAL INFORMATION .
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`BE STUDY ENDPOINTS FOR CORTICOSTEROIDS .
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`IX.
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`STATISTICAL ANALYSES .
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`IV. DOCUMENTATION OF BIOAVAILABILITY AND BIOEQUIVALENCE .
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`INDs/NDAs .
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`BIOAVAILABILITY AND BIOEQUIVALENCE: IN VITRO STUDIES .
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`BATCHES AND DRUG PRODUCT SAMPLE COLLECTION .
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`TESTS AND METRICS .
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`IN VITRO BA DATA .
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`INTERVAL APPROACH .
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`IN VITRO BE DATA: SUPPORTIVE NONPROFILE AND PROFILE
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`SMALLER CONTAINER SIZES .
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`XI.
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`REFERENCES .
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`Draft - Notfor Implementation
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`GUIDANCE FOR INDUSTRYl
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`Bioavailability and Bioequivalence Studies for
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`Nasal Aerosols and Nasal Sprays for Local Action
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`INTRODUCTION
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`Product quality approaches should be similar for all nasal aerosols and nasal sprays where the
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`active ingredient/active moiety is intended for local action, regardless of drug or drug class. This
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`guidance should be used with other, more general CMC and BA and BE guidances available from
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`This guidance is intended to provide recommendations to applicants who are planning product
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`.quality studies to measure bioavailability (BA) and/or establish (BE) in support of new drug
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`applications (NDAs) or abbreviated new drug applications (ANDAs) for locally acting drugs in
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`nasal aerosols (metered-dose inhalers (MDIs)) and nasal sprays (metered-dose spray pumps).
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`Product quality includes chemistry, manufacturing, and controls (CMC), microbiology, certain
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`BA information, and BE information (i.e., information that pertains to the identity, strength,
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`quality, purity, and potency of a drug product). Product quality BA and BE are reflective of
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`potency, in that release of the drug substance from the drug product should be assessed and
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`controlled to achieve a reproducibly potent product. BA studies can address many questions, but
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`this guidance discusses studies that focus on product performance (i.e., release of drug substance
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`from drug product). A BE study is normally used to compare a test product (T) to a precursor
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`product (R) —— the to-be-marketed product is compared to a pivotal clinical trial material; a
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`generic product is compared to a reference listed drug .
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`May 27, 1999
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`' This guidance has been prepared by the Oral Inhalation and Nasal Drug Products Technical Committee, Locally
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`Acting Drug Products Steering Committee, Biopharrnaceutics Coordinating Committee, with contributions from the
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`Inhalation Drug Products Working Group, the Chemistry, Manufacturing, and Controls Coordinating Committee, in the
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`Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration, This guidance represents the
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`Agency‘s current thinking on product quality information related to inhalation aerosols and metered dose spray pumps
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`for nasal delivery.
`It does not create or confer any rights for or on any person and does not operate to bind FDA or the
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`public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute,
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`regulations, or both.
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`Draft - Notfor Implementation
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`This guidance covers BA and BE studies of prescription corticosteroids, antihistamines,
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`anticholinergic drug products, and the over-the-counter (OTC) mast—cell stabilizer cromolyn
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`sodium. The guidance does not cover studies of nasal sprays included in an applicable OTC
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`monograph or studies of (1) metered-dose products intended to deliver drug systemically via the
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`nasal route2 or (2) drugs in nasal nonmetered dose atomizer (squeeze) bottles that require
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`premarket approval.
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`Note: Detailed chemistry, manufacturing, and controls information relevant to nasal aerosols and
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`nasals sprays are presented in two draft guidances, Metered Dose Inhaler (MDI) and Dry Powder
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`Inhaler(DPI) Drug Products — Chemistry, Manufacturing, and Controls Documentation
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`'(October 1998) and Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Product
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`(available June 1999). These draft guidances, when finalized, will provide complementary
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`information on the BA/BE testing methods recommended in this guidance.
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`II.
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`A.
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`BACKGROUND
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`BIOAVAILABILITY AND BIOEQUIVALENCE DATA
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`May 27, 1999
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`Bioavailability is defined at 21 CFR 320.1 as “the gate and extent to which the active ingredient
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`or active moiety is absorbed from a drug product and becomes available at the site of action. For
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`drug products that are not intended to be absorbed into the bloodstream, bioavailability may be
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`assessed by measurements intended to reflect the rate and extent to which the active ingredient or
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`active moiety becomes available at the site of action.” Bioequivalence is defined as “the absence
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`of a significant difference in the rate and extent to which the active ingredient or active moiety in
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`pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug
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`action when administered at the same molar dose under similar conditions in an appropriately
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`designed study.” BA and BE are closely related, and the same approach to measure BA in an
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`NDA should generally be followed in establishing BE for an NDA or ANDA. Although BA may
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`be comparative, establishing BE specifically involves a comparison of the BA of one product with
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`the BA of another product. BE is usually established using (1) criteria based on means and/or
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`variances for EA measures, (2) BE intervals (goalposts), which are standards to allow a
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`determination of equivalence when confidence intervals are computed using the specified criteria,
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`and (3) confidence intervals for the criteria.
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`2 21 CFR 341. Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the—Counter
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`Human Use.
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`Draft - Notfor Implementation
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`BA and BE data should be provided in accordance with the regulations.3 BA and BE may be
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`established by in vivo (pharmacokinetic (PK), pharrnacodynamic (PD), or clinical) and in vitro
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`studies, or, with suitable justification, by; in vitro studies alone.4 BA and BE assessments for
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`locally acting nasal aerosols and sprays are complicated because delivery to the sites of action
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`does not occur primarily after systemic absorption. Droplets and/or drug particles are deposited
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`topically, then absorbed and becomes available at local sites of action. Systemic exposure
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`following nasal administration can occur either from drug absorbed into the systemic circulation
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`from the nasal mucosa, or after ingestion and absorption from the gastrointestinal tract. A drug
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`administered nasally and intended for local action is therefore likely to produce systemic activity,
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`although plasma levels of the drug do not reflect the amount of the drug reaching nasal sites of
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`action. For these reasons, BA and BE studies should consider both local delivery and systemic
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`exposure or systemic absorption.
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`May 27, I999
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`For local delivery, BA is determined by several factors, including release of drug substance
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`from the drug product and availability to local sites of action. Release of drug from the
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`drug product is characterized by distribution patterns and droplet or drug particle size
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`within the nose that are dependent upon drug substance, formulation, and device
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`characteristics. Availability to local sites ofaction is a function of the above release
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`factors, as well as drug dissolution in the case of suspension products, absorption across
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`mucosal barriers to nasal receptors, and rate of removal from the nose. From a product
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`quality perspective, the critical issues are release of drug substance from drug product and
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`delivery to the mucosa. Other factors are of lesser importance. A critical question in
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`assessing product quality BA and BE is the extent to which one can rely on in vitro
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`methods alone, or upon in vitro methods plus clinical endpoints, to measure (benchmark)
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`BA and/or establish BE. In vitro methods are less variable, easier to control, and more
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`likely to detect differences between products if they exist, but the clinical relevance of
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`these tests, or the magnitude of the differences in the tests, is not always clearly
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`established. Clinical endpoints may be highly variable and relatively insensitive in
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`detecting differences between products, but can unequivocally establish effectiveness.
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`1.
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`Local Delivery BA/BE Concepts
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`In this guidance, the recommended approach for solution formulations of locally acting
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`nasal drug products is to rely on in vitro methods to assess BA and BE. This approach is
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`based on the assumption that in vitro studies would be more sensitive indicators of drug
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`delivery to nasal sites of action than would be clinical studies. Drug particle size
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`3 21 CFR 320.21, Requirements for submission ofin vivo bioavailability and bioequivalence data.
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`4 2| CFR 320.24, Types of evidence to establish bioavailability or bioequivalence.
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`X: iCDERGUIDl207ODFT. WPD
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`Draft - Notfor Implementation
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`distribution (PSD) in suspension formulations has the potential to influence the rate and
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`extent of availability to nasal Sites of action and to the systemic circulation. For
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`suspension formulation products: however, due to the inability to adequately characterize
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`drug PSD (see section V.B.2), in vivo_studies should be conducted as part of the studies
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`establishing product quality BA and BE. In vitro studies should be coupled with a clinical
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`study for BA, or a BE study with a clinical endpoint for BE, to determine the delivery of
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`drug substance to local nasal sites of action. An in vivo systemic exposure or systemic
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`absorption study should also be conducted for suspensions (see section II.A.2). For
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`solution formulations, see section IV.B.I.
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`2.
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`Systemic Exposure and Systemic Absorption BA/BE Concepts
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`Locally acting drugs are intended to produce their effects upon delivery to nasal sites of
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`action without relying upon systemic absorption. Although systemic absorption may
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`contribute to clinical efficacy for certain corticosteroids and antihistamines, the
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`consequences of systemic absorption (e.g., HPA suppression by corticosteroids) are
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`generally undesirable. In the absence of validated in vitro methodology for
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`characterization of drug PSD for suspension products, and when measurable plasma levels
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`can be obtained, this guidance recommends PK studies to measure systemic exposure BA
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`or establish systemic exposure BE (section VII). For suspension products that do not
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`produce sufficient concentrations to assess systemic exposure, clinical studies or BE
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`studies with a clinical endpoint should be used to measure systemic absorption BA and
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`establish systemic absorption BE, respectively (section VIII). For a schematic
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`representation of recommended studies, see the Decision Tree for In Vivo Product Quality
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`BA and BE Studies for Nasal Aerosols and Nasal Sprays (p. 35).
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`May 27, 1999
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`BA recommendations in this guidance are limited to product quality BA. For investigational new
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`drugs (INDS) and NDAS, not only should product quality BA be provided, but BA/PK studies
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`should also be included in the Human Pharrnacokinetics section (Item 6) of the NDA for nasal
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`aerosols and nasal sprays for local action, whether formulated as solutions or suspensions, and
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`whether or not validated methods of determining drug PSD are available. These PK data provide
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`biopharrnaceutic and clinical pharmacology information beyond product quality BA
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`characterization.
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`CMC TESTS AND IN VITRO BA TESTS (NONCOMPARATIVE) VERSUS BE
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`TESTS (COMPARATIVE)
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`Generally CMC tests help characterize the identity, strength, quality, purity, and potency of the
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`drug product and assist in setting specifications (tests, methods, acceptance criteria) to allow
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`batch release. These tests have a different purpose than do BA/BE tests, which focus on release
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`X: lCDERGUlDl207ODFT. WPD
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`Draft - Notfor Implementation
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`III.
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`A.
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`FORMULATION AND CONTAINER AND CLOSURE SYSTEM
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`FORMULATION
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`of drug substance from drug product. Some of the in vitro BA/BE tests described in this
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`guidance for nasal aerosols and sprays may be the same as CMC tests for characterization and/or
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`batch release. A specification (test, method, acceptance criterion) for a CMC test for batch
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`release is usually based on general or specific manufacturing experience. For example, a CMC
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`test such as close content uniformity has acceptance criteria based on repeated manufacturing of
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`batches. Bioequivalence limits for BE studies are not usually based on manufacturing experience,
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`but are part of equivalence comparisons between test and reference products. Equivalence
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`comparisons normally include (1) a criterion to allow the comparison, (2) a confidence interval for
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`the criterion, and (3) a BE limit for the criterion. BE limits may be based on a priori judgments
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`and may be scaled to variability of the reference product (see Section IX). When conducted
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`'premarket for an NDA, some of the in vitro BA tests described in this guidance can be
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`noncomparative and serve primarily to document (benchmark) the product quality BA of a
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`pioneer product.
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`May 27. 1999
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`Particle size, morphic form, and state of solvation of the active ingredient have the potential to
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`affect the BA of the drug product as a result of different solubilities and/or rates of dissolution.
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`For an ANDA of a suspension formulation, the PSD of the active drug in the dosage form should
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`be the same as that of the reference listed drug, as discussed in Section V.B. Comparative
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`information on the morphic form of the drug particles, and size and number of drug aggregates in
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`the dosage form, should be provided. In addition, documentation of the same anhydrous or
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`solvate form should be provided. For suspension formulations marketed in more than one
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`strength, the drug substance in each strength product should be micronized under identical
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`parameters, and the PSD of the resultant bulk drug should be identical in each strength product.
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`B.
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`CONTAINER AND CLOSURE SYSTEM
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`Nasal aerosols consist of the formulation, container, valve, actuator, dust cap, associated
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`accessories (e.g., spacers), and protective packaging, which together constitute the drug product.
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`Similarly, nasal sprays consist of the formulation, container, pump, actuator, protection cap, and
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`protective packaging, which together constitute the drug product.
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`For nasal aerosols and nasal sprays approved under an ANDA, BE should be documented on the
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`basis of validated in vivo and vitro tests, or, in some cases, validated in vitro tests alone may be
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`appropriate. Assurance of equivalence on the basis of in vitro tests is greatest when the test
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`product uses the same brand and model of devices (particularly the metering valve or pump and
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`the actuator) as used in the reference product. If this is not feasible, valve, pump, and actuator
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`Page 9 of 45
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`Draft - Notfor Implementation
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`designs should be as close as possible in all critical dimensions to those of the reference product.
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`Metering chamber volumes should be the same. For nasal aerosols, overall actuator design
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`(Byron 1990), including actuator orifice\diameter, should be the same. For a nasal spray, spray
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`characteristics may be affected by features of the pump design, including the precompression
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`mechanism, actuator design, including specific geometry of the orifice (Kublic and Vidgren 1998),
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`and design of the swirl chamber. The external dimensions of the test actuator should ensure
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`comparable depth of nasal insertion to the reference actuator. A test product should attain prime
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`within the labeled number of actuations for the reference product. Consideration should be given
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`to the dead volume of the device, including the internal diameter and length of the diptube,
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`because this volume can influence the number of actuations required to prime a spray pump.
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`May 27, 1999
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`For lNDs/NDAs, in vitro BA studies for solutions and suspensions, and in vivo studies for
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`suspensions, should be provided. These data are useful as a benchmark to characterize the in
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`vitro performance, and for suspensions, the in vivo performance of the product based on the
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`clinical efficacy and either systemic exposure for a PK study, or systemic absorption for a clinical
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`safety study. Where the formulation and/0r method of manufacture of the pivotal clinical trial
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`product changes in terms of physicochemical characteristics of the drug substance, the excipients,
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`or the device characteristics, BE data using in vitro tests (for solutions and suspensions) and in
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`vivo tests (for suspensions) may be useful in certain circumstances during the preapproval period
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`to ensure that the to—be-marketed product (T) is comparable to very similar clinical trial batches
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`and/or to batches used for stability testing (R) (section VA. 1). Sponsors should discuss the
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`usefulness of these BE approaches with appropriate CDER review staff.
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`IV. DOCUMENTATION OF BIOAVAILABILITY AND BIOEQUIVALENCE
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`A.
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`INDs/NDAs
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`B.
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`ANDAs
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`Solution Formulations
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`In Vivo studies, such as seasonal allergic rhinitis (SAR) studies to establish equivalent
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`delivery to nasal sites, or HPA suppression studies for corticosteroids to establish
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`equivalent systemic absorption, are not considered necessary for nasally administered
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`solution drug products intended for local action. Thus, reliance on in vitro tests alone to
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`document BE is suitable for nasal solution formulation products intended for local action.
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`This approach is based on an understanding that for solution products, equivalent in vitro
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`performance, inactive ingredients that are qualitatively (Q) the same and quantitatively
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`(Q2) essentially the same as the inactive ingredients in the reference listed drug, and
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`adherence to container and closure recommendations of section III will ensure comparable
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`X.‘ \CDERGUIDl2070DFT. WPD
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`Page 10 of 45
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`Draft - Notfor Implementation
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`delivery to the nasal mucosa and to the gastrointestinal tract. Quantitatively essentially
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`the same has been determined by CDER to mean that the concentration or amount of the
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`inactive ingredient(s) in the test product should not differ by more than i5 percent of the
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`concentration or amount in the reference listed drug. Suggested methodology and
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`validation approaches for the recommended tests are provided in section V. Suggested
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`methods to allow comparisons using a criterion, BE limits, and a confidence interval
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`approach are discussed in section IX. When in vitro data fail to meet acceptance criteria,
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`the applicant is encouraged to modify the test product to attain equivalent in vitro
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`performance. Because of insensitivity to potential differences between T and R, in vivo
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`studies will not be sufficient in the face of in vitro studies that fail to document BE.
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`To document BE for suspension nasal formulation products intended for local action, both
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`in vitro and in vivo data should be used. Inactive ingredients also should be qualitatively
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`(Q) the same and quantitatively (Q2) essentially the same as the inactive ingredients in the
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`reference listed drug, and the container and closure recommendations of section III should
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`be followed.
`In vivo studies should include both a pharrnacokinetic study (systemic
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`exposure) and a BE study with a clinical endpoint (local delivery). This approach is only
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`applicable for those suspension formulationproducts that produce sufficiently high drug
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`concentrations in blood or plasma afier nasal administration to obtain meaningful AUC
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`and Cmax data. Methodology and validation approaches for the recommended tests are
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`provided for the in vitro studies in section V, and for the in vivo studies in sections VI and
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`VII. As with solutions, in vivo studies will not be sufficient in the face of in vitro studies
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`that fail to establish BE ( i.e., in vitro BE studies that fail to meet the statistical test
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`discu